Pembrolizumab Plus Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A Cost-Effectiveness Analysis.
In 2021, KEYNOTE-590 (NCT03189719) showed that pembrolizumab plus 5-fluorouracil and cisplatin (PPF) has more benefits than 5-fluorouracil and cisplatin (PF) as a first-line regimen to treat individuals with advanced esophageal cancer. However, given that it is expensive, controversies over the value of using this compared to competitive strategies remain. Hence, we conducted a cost-effectiveness evaluation of pembrolizumab plus chemotherapy. A Markov model was applied in evaluating the efficacy and cost of PPF and PF over a 7-year horizon and measured the health outcomes in life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The economic data included were relevant to patients in the USA and China. We also performed one-way and probabilistic sensitivity analyses to determine the uncertainties relevant to the model. Willingness to pay thresholds (WTP) of $150,000/QALY (USA) and $35,673/QALY (China) were used to calculate a probability for the cost-effectiveness of PPF. PPF yielded 0.386-0.607 QALYs (0.781-1.195 LYs) compared with PF. In our analysis, compared with receiving PF, patients with advanced esophageal cancer receiving PPF had an ICER of $577,461/QALY in the USA and $258,261/QALY in China, those for esophageal squamous cell carcinoma were $550,211/QALY in the USA and $244,580/QALY in China, and a programmed cell death ligand 1 combined positive score (PD-L1 CPS) ≥ 10 was associated with a cost of $479,119/QALY in the USA and $201,355/QALY in China. Sensitivity analysis found the price of pembrolizumab to be the biggest influence. From the economic perspectives of the USA and China, a first-line regimen of PPF for esophageal cancer therapy may not be as cost-effective as PF. However, patients with esophageal cancer and PD-L1 CPS ≥ 10 may gain the most LYs from initial PPF treatment.


Effects of amino acid alterations in penicillin-binding proteins (PBPs) 1a, 2b, and 2x on PBP affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor in 18 clinical isolates of penicillin-susceptible, -intermediate, and -resistant pneumococci.
Amino acid alterations in or flanking conserved motifs making up the active binding sites of penicillin-binding proteins (PBPs) 1a, 2b, and 2x of pneumococci were correlated with changes in affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor for these PBPs. Four penicillin-susceptible (PSSP), eight penicillin-intermediate (PISP), and six penicillin-resistant (PRSP) pneumococci were studied by DNA sequencing of the penicillin-binding sites of the pbp1a, -2x, and -2b genes of strains and by determining 50% inhibitory concentrations of the seven agents for PBP1a, -2x, and -2b. Two PSSP strains had alterations in PBP2x (L(546)-->V) (one strain) or PBP2b (T(445)-->A) (one strain). All eight PISP strains had at least two alterations--T(338)-->P or A or H(394)-->Y in PBP2X and T(445)-->A in BPB2b. All PRSP strains had the same changes seen in PISP strains, as well as T(371)-->A or S substitutions in PBP1a. The two most resistant PRSP strains had a second change in PBP2x (M(339)-->F) in a conserved motif. The affinities of penicillin and ampicillin for all three PBPs were decreased for PRSP and most PISP strains. The affinity of amoxicillin for PBP1a and -2x was decreased only for PRSP. Cefaclor and cefprozil showed decreased affinity of PRSP but not PISP for all three PBPs. Cefuroxime showed decreased affinity of PISP and PRSP for PBP1a and -2x but no change for PBP2b. Cefditoren showed no difference in PBP affinity based on penicillin or cefditoren MICs, indicating a different PBP target for this agent. Overall, the MICs for and PBP affinities of the strains correlated with the changes found in the PBP active binding sites.


Fluorescence properties of dibenzofluorescein in aqueous solution.
The deprotonation of dibenzofluorescein (DBFL), a long wavelength fluorescence probe, results in the simultaneous occurrence of neutral form, monoanion and dianion under physiological conditions. The fluorescence properties of the former two cannot be measured directly because they are always coexistent with some other species. By measuring the fluorescence under various pHs we computed the fluorescence parameters for each species involved in the prototropic equilibria of DBFL, including each species' emission spectrum, excitation spectrum, emission and excitation maximum, fluorescence quantum yield and lifetime. It was found that the monoanion is the most fluorescent chromospheres (Phif=0.66, compared to Phif=0.25 for dianion, 0.18 for cation and 0.0 for the neutral form). Together with the computed pKas, we are able to suggest that the monoanion plays a major role under physiological conditions when DBFL is used as a fluorescence probe, contrary to the assumption in literature.


Liquid-based cytology and HPV DNA test in anal specimens from women with cervical cancer.
Cervical and anus cancers have similarities: association with HPV infection, epithelial transformation zone, and precursor lesions. However, it is still unclear whether women with cervical cancer should be screened to identify high-grade squamous intraepithelial lesions and anal cancer. We aimed to identify high-risk HPV and cytological atypia in anal samples from women diagnosed with invasive squamous cell carcinoma of the cervix. We conducted a cross-sectional study between July 2016 and August 2017 in reference services in oncology in the State of Ceará, Brazil. We studied 59 patients diagnosed with frankly invasive squamous cell carcinoma of the cervix (at least stages IB) and 60 women in a control group. We performed liquid-based cytology (Surepath™) and HPV test (Cobas® 4800 System Test) of anal samples. To determine statistical significance with a confidence interval of 95%, we used Fisher's exact test and Student's t-test using the GraphPad Prism 7.0 software. The mean age in the control group was 56.7 ± 8.5 years, while in the group of women with cervical squamous cancer, it was 54.3 ± 14.8. The liquid-based cytology results of the satisfactory cases were: negative for intraepithelial lesion or malignancy (NLM): 51 cases (85%) in the control group and 38 (64.4%) in the study group (p = .0116). The HPV test was negative more frequently in the control group (n = 56, 93.3%) than in the study group (n = 17, 31.5%) (p < .0001). HPV 16 was the most frequent type (67.6%). There is a higher frequency of high-risk HPV and atypical cytology in women with cervical cancer than without lesions. Thus, this group should be considered as a target population for screening.


Strand-specific transcriptomes of Enterohemorrhagic Escherichia coli in response to interactions with ground beef microbiota: interactions between microorganisms in raw meat.
Enterohemorrhagic Escherichia coli (EHEC) are zoonotic agents associated with outbreaks worldwide. Growth of EHEC strains in ground beef could be inhibited by background microbiota that is present initially at levels greater than that of the pathogen E. coli. However, how the microbiota outcompetes the pathogenic bacteria is unknown. Our objective was to identify metabolic pathways of EHEC that were altered by natural microbiota in order to improve our understanding of the mechanisms controlling the growth and survival of EHECs in ground beef. Based on 16S metagenomics analysis, we identified the microbial community structure in our beef samples which was an essential preliminary for subtractively analyzing the gene expression of the EHEC strains. Then, we applied strand-specific RNA-seq to investigate the effects of this microbiota on the global gene expression of EHEC O2621765 and O157EDL933 strains by comparison with their behavior in beef meat without microbiota. In strain O2621765, the expression of genes connected with nitrate metabolism and nitrite detoxification, DNA repair, iron and nickel acquisition and carbohydrate metabolism, and numerous genes involved in amino acid metabolism were down-regulated. Further, the observed repression of ftsL and murF, involved respectively in building the cytokinetic ring apparatus and in synthesizing the cytoplasmic precursor of cell wall peptidoglycan, might help to explain the microbiota's inhibitory effect on EHECs. For strain O157EDL933, the induced expression of the genes implicated in detoxification and the general stress response and the repressed expression of the peR gene, a gene negatively associated with the virulence phenotype, might be linked to the survival and virulence of O157:H7 in ground beef with microbiota. In the present study, we show how RNA-Seq coupled with a 16S metagenomics analysis can be used to identify the effects of a complex microbial community on relevant functions of an individual microbe within it. These findings add to our understanding of the behavior of EHECs in ground beef. By measuring transcriptional responses of EHEC, we could identify putative targets which may be useful to develop new strategies to limit their shedding in ground meat thus reducing the risk of human illnesses.


Salvage and storage of infectious disease protein targets in the SSGCID high-throughput crystallization pathway using microfluidics.
The MPCS Plug Maker is a microcapillary-based protein-crystallization system for generating diffraction-ready crystals from nanovolumes of protein. Crystallization screening using the Plug Maker was used as a salvage pathway for proteins that failed to crystallize during the initial observation period using the traditional sitting-drop vapor-diffusion method. Furthermore, the CrystalCards used to store the crystallization experiments set up by the Plug Maker are shown be a viable container for long-term storage of protein crystals without a discernable loss of diffraction quality with time. Use of the Plug Maker with SSGCID proteins is demonstrated to be an effective crystal-salvage and storage method.


A new species of the genus Malaia Heller, 1892 (Scarabaeidae: Rutelinae: Anomalini) from Sulawesi Island, Indonesia.
New species of the genus Malaia Heller, 1892 (subgenus Malaia) found in Sulawesi Selatan, Indonesia, named M. (M.) medea Kaneko Wada, new species, is described. This species is similar to M. (M.) simulatrix Heller, 1892 but is readily distinguished by several characters.


The intracellular handling of insulin-related peptides in isolated pancreatic islets. Evidence for differential rates of degradation of insulin and C-peptide.
Islets of Langerhans isolated from adult rats were maintained in tissue culture for 3 days in the continued presence of [3H]leucine. Labelled proinsulin, C-peptide and insulin were measured by quantitative h.p.l.c., a method which also allowed for resolution of C-peptide I and II, and of insulin I and II (the products of the two rat insulin genes). The results showed that: (1) at early times, proinsulin was the major radiolabelled product; with progressive time in culture, intra-islet levels of [3H]proinsulin decreased, despite continuous labelling with [3H]leucine, indicating that the combined rates of proinsulin conversion into insulin and of proinsulin release, exceeded the rate of synthesis; (2) insulin I levels were always greater than those of insulin II, both in the islets and for products released to the medium; (3) the molar ratio of [3H]insulin I and II to their respective 3H-labelled C-peptides increased with time for products retained within islets, reaching a value close to 3:1 by 3 days; by contrast, for products released to the medium during the culture period, the ratio was always close to unity; (4) when islets were incubated with [3H]leucine for 2 days, and then left for a further 1 day without label (chase period), the intra-islet [3H]insulin/[3H]C-peptide ratios rose to values as high as 9:1. Again, for material released to the medium, the values were close to 1:1; (5) it is concluded that C-peptide is degraded more rapidly than insulin within islet cells, thereby accounting for the elevated insulin/C-peptide ratios. The difference between the ratios observed in the islets and those for material released to the medium is taken to indicate that degradation occurs in a discrete cellular compartment and not in the secretory granule itself.


Exploring the prevalence and antibiotic resistance profile of Klebsiella pneumoniae and Klebsiella oxytoca isolated from clinically ill companion animals from North of Portugal.
Klebsiella spp. is an important pathogen in humans and animals and due to the indiscriminate use of antibiotics, its prevalence and antibiotic resistance has increased in companion animals. The main goal of this study was to investigate the prevalence and antibiotic resistance of Klebsiella spp. isolated from clinically ill cats and dogs admitted in veterinary clinics in the North of Portugal. A total of 255 clinical specimens were collected and, after isolation, the identification of Klebsiella strains was performed using the BBL Crystal™ identification system and confirmed by PCR-based sequencing with specific primers. Antibiotic resistance profile was determined through the disc diffusion method. Beta-lactam resistance genes were screened through a multiplex PCR assay. Fifty Klebsiella strains were isolated and, 39 were identified as Klebsiella pneumoniae and 11 as Klebsiella oxytoca. Thirty-one were recovered from dogs and 19 from cats. The Klebsiella isolates were recovered mainly from skin wounds, respiratory tract, and from urine. Fifty percent of K. oxytoca and K. pneumoniae isolates revealed to be Multidrug Resistant (MDR) strains, with most of them positive for the presence of blaTEM-like and blaSHV genes. This data shows that MDR Klebsiella are highly disseminated in companion animals and that extended-spectrum beta-lactamases can be easily found among these isolates. This highlights the potential role of dogs and cats as a reservoir of resistant Klebsiella spp. that have the potential to be transmitted to humans.


Virtual reality exercise programs ameliorate frailty and fall risks in older adults: A meta-analysis.
Virtual reality (VR) technology constitutes a promising rehabilitation strategy, but its effect on frailty in older adults remains inconclusive. This study examined the effects of interactive VR training programs on lower-limb muscle strength, walking speed, balance, and fall risks in older adults with frailty. Various electronic databases comprising PubMed, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, Embase, the Chinese Electronic Periodical Service, the Chinese National Knowledge Infrastructure, and gray literature were searched from their inception through December 31, 2022 for relevant studies. Randomized controlled trials that examined the effects of interactive VR training programs on lower-limb muscle strength, balance, walking speed, and fall risks as measured by validated scales or methods. in older adults aged 65 years and older with frailty were included. A random-effects model was employed to examine the overall effect size, and the trim-and-fill method was adopted to examine publication bias. For those studies that defined frailty using fall risks, substantial evidence demonstrated that interactive VR training interventions increased lower-limb muscle strength (Hedges' g = 0.35, p = 0.015), walking speed (Hedges' g = 0.29, p = 0.003), balance (Hedges' g = 0.62, p = 0.011), and fall risks (Hedges' g = -0.61, p < 0.001). Studies that defined frailty in accordance with the Fried frailty phenotype criteria indicated that interactive VR training interventions only increased walking speed (Hedges' g = 0.28, p = 0.023) and balance (Hedges' g = 0.27, p = 0.049). Interactive VR training programs may benefit older adults with frailty with respect to walking speed and balance. More studies with good study quality are required to validate the effects of interactive VR exercise training on these frailty-related parameters in older adults.


Prescription system to calculate precise doses of Chinese herbal medicine to avoid toxic effects.
Traditional Chinese Medicine (TCM) is a therapeutic system which has been practiced for thousands of years. Although for much of its history the decoction of medicinal herbs was the most common method of consuming the herbal treatments, TCM prescriptions are now primarily prepared using concentrated Chinese herbal extracts (CCHE) in powder or granular form. However, determining the precise dose of each single Chinese herbal constituent within a prescription creates a challenge in clinical practice due to the potential risk of toxicity. To alleviate this, we invented the Chinese Intelligence Prescription System (CIPS) to calculate the exact dose of each single herb within an individual prescription. In this study, we applied CIPS in a real-world setting to analyze clinical prescriptions collected and prepared at the TCM Pharmacy of China Medical University Hospital (CMUH). Our investigation revealed that 3% of all prescriptions filled in a 1-month period contained inexact dosages, suggesting that more than 170,000 prescriptions filled in Taiwan in a given month may contain potentially toxic components. We further analyzed the data to determine the excess dosages and outline the possible associated side effects. In conclusion, CIPS offers TCM practitioners the ability to prepare exact Chinese herbal medicine (CHM) prescriptions in order to avoid toxic effects, thereby ensuring patient safety.


EXECUTER2 modulates the EXECUTER1 signalosome through its singlet oxygen-dependent oxidation.
Oxidative post-translational modifications of specific chloroplast proteins contribute to the initiation of retrograde signaling. The Arabidopsis thaliana EXECUTER1 (EX1) protein, a chloroplast-localized singlet oxygen (1O2) sensor, undergoes tryptophan (Trp) 643 oxidation by 1O2, a chloroplast-derived and light-dependent reactive oxygen species. The indole side chain of Trp is vulnerable to 1O2, leading to the generation of oxidized Trp variants and priming EX1 for degradation by a membrane-bound FtsH protease. The perception of 1O2 via Trp643 oxidation and subsequent EX1 proteolysis facilitate chloroplast-to-nucleus retrograde signaling. In this study, we discovered that the EX1-like protein EX2 also undergoes 1O2-dependent Trp530 oxidation and FtsH-dependent turnover, which attenuates 1O2 signaling by decelerating EX1-Trp643 oxidation and subsequent EX1 degradation. Consistent with this finding, the loss of EX2 function reinforces EX1-dependent retrograde signaling by accelerating EX1-Trp643 oxidation and subsequent EX1 proteolysis, whereas overexpression of EX2 produces molecular phenotypes opposite to those observed in the loss-of- function mutants of EX2. Intriguingly, phylogenetic analysis suggests that EX2 may have emerged evolutionarily to attenuate the sensitivity of EX1 toward 1O2. Collectively, these results suggest that EX2 functions as a negative regulator of the EX1 signalosome through its own 1O2-dependent oxidation, providing a new mechanistic insight into the regulation of EX1-mediated 1O2 signaling.


Macular pigment is associated with glare-affected visual function and central visual field loss in glaucoma.
To evaluate the relationship between macular pigment optical density (MPOD) and glare disability in open-angle glaucoma. A cross-sectional analysis of baseline data (88 subjects; median age, 67 (range 36-84) years) collected during the Macular Pigment and Glaucoma Trial (ISRCTN registry number: 56985060). MPOD at 0.25°, 0.5° and 1° of retinal eccentricity was measured using customised heterochromatic flicker photometry. Mesopic contrast sensitivity with glare (mCSg), photostress recovery time (PRT) and self-reported glare symptoms were evaluated. Fourier-domain optical coherence tomography was used to analyse ganglion cell complex (GCC) and identify foveal involvement. Low spatial frequency (f) mCSg was significantly correlated with MPOD at 0.25°(3 cycles per degree (cpd): r=0.25, p=0.04) and 0.5° (3 cpd: r=0.23, p=0.04) of retinal eccentricity. Those with foveal GCC loss exhibited lower MPOD, had worse low spatial fmCSg (1.5 cpd and 3 cpd, p=0.02 each) and prolonged PRT (p=0.02) in comparison with those without foveal involvement. The depth of central 10° field loss was related to MPOD at all eccentricities (p<0.01 for all). Those who reported glare symptoms had a significantly lower MPOD at all retinal eccentricities (0.25° and 1°: p=0.05 each; 0.5°: p=0.04), including those with foveal involvement (0.25°: p=0.05; 0.5°: p<0.01; 1°: p=0.01). Macular pigment level may be an important consideration among those experiencing disability glare in glaucoma, including those with foveal involvement. ISRCTN56985060, Post-results.


A hitherto undescribed cause of prosthetic mitral valve obstruction.
A case is described in which severe prosthetic mitral valve obstruction was produced by entanglement of sutures across the central axis of the prosthesis on its ventricular side. The entangled sutures prevented the tilting disc occluder from falling into the left ventricular cavity during ventricular diastole.


Allosteric inhibition of human exonuclease1 (hExo1) through a novel extended β-sheet conformation.
Human Exonuclease1 (hExo1) participates in the resection of DNA double-strand breaks by generating long 3'-single-stranded DNA overhangs, critical for homology-based DNA repair and activation of the ATR-dependent checkpoint. The C-terminal region is essential for modulating the activity of hExo1, containing numerous sites of post-translational modification and binding sites for partner proteins. Analytical Ultracentrifugation (AUC), Dynamic Light Scattering (DLS), Circular Dichroism (CD) spectroscopy and enzymatic assays. AUC and DLS indicates the C-terminal region has a highly extended structure while CD suggest a tendency to adopt a novel left-handed β-sheet structure, together implying the C-terminus may exhibit a transient fluctuating structure that could play a role in binding partner proteins known to regulate the activity of hExo1. Interaction with 14-3-3 protein has a cooperative inhibitory effect upon DNA resection activity, which indicates an allosteric transition occurs upon binding partner proteins. This study has uncovered that hExo1 consist of a folded N-terminal nuclease domain and a highly extended C-terminal region which is known to interact with partner proteins that regulates the activity of hExo1. A positively cooperative mechanism of binding allows for stringent control of hExo1 activity. Such a transition would coordinate the control of hExo1 by hExo1 regulators and hence allow careful coordination of the process of DNA end resection. The assays presented herein could be readily adapted to rapidly identify and characterise the effects of modulators of the interaction between the 14-3-3 proteins and hExo1. It is conceivable that small molecule modulators of 14-3-3 s-hExo1 interaction may serve as effective chemosensitizers for cancer therapy.


Epidemiology of multiple sclerosis in U.S. veterans: 2. Latitude, climate and the risk of multiple sclerosis.
An analysis of ten climatic factors and elevation for the counties of birth of 4371 U.S. white male veterans with multiple sclerosis and matched controls has been made in relation to birthplace latitude. The climatic factors include an air pollution index, concentrations of minerals in ground water, measures of annual solar radiation, both in energy per unit area and in hours of sunshine, mean annual periods of high and low temperatures, and measures of annual rainfall and average humidity. These variables all significantly influence the risk of multiple sclerosis when analyzed alone, but when they are adjusted for latitude, their effect is found to be due to their correlation with this variable.


Application of zeolite based nanocomposites for wastewater remediation: Evaluating newer and environmentally benign approaches.
The presence of heavy metal ions and emerging pollutants in water poses a great risk to various biological ecosystems as a result of their high toxicity. Consequently, devising efficient and environmentally friendly methods to decontaminate these waters is of high interest to many researchers around the world. Among the varied water treatment and desalination means, adsorption and photocatalysis have been widely employed. However, the discussion and analysis of the use of zeolite-based composites as adsorbents are somehow minimal. The porous aluminosilicates (zeolites) are excellent candidates in wastewater treatment owing to various mechanisms of pollutants removal that they possess. The purpose of this review is thus to provide a synopsis of the current developments in the fabrication and application of nanocomposites based on zeolite as adsorbents and photocatalysts for the extraction of heavy metals, dyes and emerging pollutants from wastewaters. The review goes on to look into the effect of weight ratio on photocatalyst, photodegradation pathways, and various factors that influence photocatalysis and adsorption.


Systemic sclerosis and risk of cardiovascular disease: A PRISMA-compliant systemic review and meta-analysis of cohort studies.
Systemic sclerosis (SSc) is an autoimmune disorder leading to extensive fibrosis and microvascular injury. Macrovascular disease is well documented in other autoimmune rheumatic diseases such as systemic lupus erythematosus and rheumatoid arthritis. However, the link is unclear between SSc and macrovascular disease, particularly atherosclerotic cardiovascular disease (CVD). This meta-analysis aimed to investigate the association between SSc and CVD. A thorough literature search was conducted in the Cochrane, Embase, Medline, and PubMed to identify all cohort studies comparing the risk of CVD with and without SSc. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of cardiovascular end points were calculated. The risk of bias of included studies was assessed by the Newcastle-Ottawa scale. Seven cohort studies with a total of 14,813 study participants were included. In a comparison of SSc patients versus non-SSc controls, the pooled HR for cardiovascular disease was 2.36 (95% CI 1.97-2.81); for peripheral vascular disease was 5.27 (95%CI 4.27-6.51); for myocardial infarction was 2.36 (95% CI 1.71-3.25); and for stroke was 1.52 (95% CI 1.18-1.96). This meta-analysis revealed that SSc was associated with an increased risk of CVD. Clinicians who manage patients with SSc should be aware of the increased cardiovascular burden and undertake preventive measures.


[Study of caries polarization in 2-5 year-old children of Shenyang, China].
To investigate dental caries polarization in 2-5 year-old children. 3 799 random samples of 2-5 year-old children from attending kindergarten in Shenyang were selected. Means of dmft index and SiC index for each age group were calculated by WHO Collaborating Center. The subjects of each age group were further divided into subgroups of different level of dmft: the dmft of subgroup I was 0, the dmft of subgroup II was 1, the dmft of subgroup III was 2, the dmft of sub-group IV was equal to or more than 3. The obtained data were analyzed statistically with SPSS 10.0. 4.5% of 2-year-old children were carriers of 60.0% of the total dmft in that age group, 13.2% of 3-year-old children were carriers of 69.4% of the total dmft in that age group, 34.4% of 4-year-old children were carriers of 86.6% of the total dmft in that age group, and 47.8% of 5-year-old children were carriers of 89.8% of the total dmft of that age group. This study supports the assertion that a small percentage of persons with high dental caries rate and a large percentage of caries-free persons of early childhood caries.


Dopamine-receptor blocking agent-associated akathisia: a summary of current understanding and proposal for a rational approach to treatment.
Dopamine-receptor blocking agent-associated akathisia (DRBA-A) is an adverse effect that can significantly limit the use of these important medications for the treatment of a variety of psychiatric diseases, yet there is no unifying theory regarding its pathophysiology. This knowledge gap limits clinicians' ability to effectively manage DRBA-A and mitigate negative outcomes in an already vulnerable patient population. Based on a review of the current literature on the subject, it is hypothesized that dopaminergic and noradrenergic signaling is perturbed in DRBA-A. Accordingly, it is proposed that the optimal agent to manage this extrapyramidal symptom should increase dopamine signaling in the affected areas of the brain and counteract compensatory noradrenergic signaling via antagonism of adrenergic or serotonergic receptors.


Management Strategies in the Intensive Care Unit to Improve Psychosocial Outcomes.
Critical care nurses work in challenging environments that are often sterile, impersonal, noisy, and frightening to patients and their families. Nurses act as liaisons between medical professionals and patients and their families in multiple specialty intensive care units. Critical care nursing practice, guided by the American Nurses Association Code of Ethics, respects patients' religious, spiritual, and cultural beliefs, contributing to holistic care delivery. Therapeutic psychosocial outcomes of holistic care delivery and patient advocacy are explored. Personalized psychosocial care through treating patients holistically will support and maintain positive psychosocial outcomes in intensive care units across the country.


[Intervention of the police in France, in the family setting, in cases of child abuse].
Intervention of Police Forces in France in the Family Setting When Child Abuse and Neglect are Noticed. French police forces, in charge of safety of persons and effects, are accustomed to intervening in family circles when child abuse occurs, and, also, each time a child's security and health are seriously threatened. They can intervene on their own, or respond to orders from an attorney or judge for children (Procureur de la République, Juge d'Instruction, Juge des Enfants). Their investigation is more easily accomplished when child abuse and neglect have just been discovered and traces of violence are still noticeable (Flagrant délit). They establish judicial procedures concerning offences committed against children, especially child abuse and neglect. But they also conduct inquiries of a social nature in order to inform a magistrate of a dangerous situation or behavior of young people under 18. This enables the judge for children to prescribe educative assistance measures. Doctors and social workers are still reluctant to notify policemen and judges, although they do not have to respect professional secrecy in any cases of injuries against children. In order to improve prevention and protection of victims of child abuse and neglect, it is truly necessary to coordinate activities of all those who intervene in pathologic family behavior: doctors, social workers, judges and policemen.


Relationship between RANO-PRO Working Group standardised priority constructs and disease progression among malignant glioma patients: A retrospective cohort study.
Recognising the importance of clinical outcomes assessments (COAs), the Response Assessment in Neuro-Oncology-Patient Reported Outcome (RANO-PRO) Working Group recommended inclusion of core symptoms and functions in clinical care or research for malignant glioma patients. This study evaluated the association of the recommended symptoms (pain, perceived cognition, seizures, aphasia, symptomatic adverse events) and functions (weakness, walking, work, usual activities) with disease progression in these patients. In this retrospective cohort study, patients with malignant glioma were included from the US National Cancer Institute Neuro-Oncology Branch Natural History Study (NOB-NHS) which follows primary central nervous system tumour patients aged 18 years and older throughout their disease trajectory. The M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT), EQ-5D-3L, Karnofsky Performance Status (KPS), and Neurologic Function scores (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons at first assessment and over time to a second assessment. Radiographic disease progression was determined on the interpretation of the imaging study by a radiologist and neuro-oncologist using standard criteria as part of clinical trial participation or routine standard of care. The priority constructs were evaluated to provide initial evidence of their relevance, relationship to disease status over time, and sensitivity to change in a diverse group of patients with malignant glioma. Seven hundred and sixty-five patients had enrolled into the NOB-NHS between September 1, 2016 and January 31, 2020. Three hundred and thirty-six patients had a diagnosis of a malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, and gliosarcoma) and were included in the current study. The sample was 64% male (n = 215), 36% female (n = 121), median age of 52 years (IQR = 18.75), 82% White (n = 276), and 65% had tumour recurrence (n = 219). One hundred and fifty-four (46%) had radiographic disease progression. Difficulty remembering, fatigue, and weakness were worse in the group whose imaging was interpreted as radiographic disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (1.1 < difference < 1.8). Patients with disease progression were four times more likely to have a poor KPS (≤80) and worse NFS. Among patients with disease progression at a second assessment (n = 112), all symptoms, except seizures, worsened between first assessment and disease progression and up to 22% of patients (n = 25) reported worsening mobility, self-care, and usual activity; 46% (n = 51) and 35% (n = 30) had worsened KPS and NFS, respectively. On average, 4 symptoms or functions (SD = 3) were reported as moderate-to-severe and 30% (n = 33) and 23% (n = 26) had a change to moderate-to-severe fatigue and walking, respectively, at time of disease progression. Over 7% of patients with worsening (n = 7 of 100) reported every symptom and function as having changed the most severely including seizures with fatigue and activity reported as the top symptom and function, respectively. The identified core symptoms and functions worsened at the time of progression, supporting the relevance and sensitivity of the priority constructs identified by the RANO-PRO Working Group for clinical care and clinical trials for malignant glioma patients. The Natural History Study is supported by Intramural Project 1ZIABC011786-03.


Study of the bioavailability of different formulations of 8-methoxypsoralen in the dog.
The absolute bioavailability of 8-methoxypsoralen in gelatin capsules and as a solution was studied in dogs. A dose of 2 mg kg-1 was given. Both for the solution and the gelatin capsules, a large variation in bioavailability was found between the different dogs. For the gelatin capsules in 1 dog out of 4 an absolute bioavailability of more than 100 per cent was found; for the solution a bioavailability of more than 100 per cent was found in all 4 dogs. Resorption was more rapid and bioavailability higher for the solution than for the gelatin capsules. Relative bioavailability of an emulsion and of a solution of 8-methoxypsoralen was studied in 2 dogs. A faster resorption and a higher bioavailability were found for the solution.


Sex and frequency of pain episodes are associated with acute pain trajectories in adolescents with sickle cell disease.
Acute pain episodes are a major cause of health care utilization (HCU) in sickle cell disease (SCD), and adolescence is associated with increased pain frequency. We sought to determine whether there were differences in acute pain trajectories by sex and frequency of pain episodes among adolescents with SCD who presented to the emergency department (ED). Retrospective review of electronic health records from a large, multicampus, pediatric SCD program. Of the 113 adolescents included, the mean age was 16.6 (SD 0.9), 41.6% (n = 47) were female, 77.9% (n = 88) had HbSS or a similarly severe genotype, and 43.4% (n = 49) had ≥3 episodes of HCU for pain, which we defined as having history of high HCU for pain. Those with a history of high HCU for pain had higher mean pain intensity scores at presentation, were more likely to receive either intravenous or intranasal opioids, and were more likely to be hospitalized. In a model considering the 3-way interaction between sex, history of high HCU for pain, and follow-up time from the initial pain intensity score, adjusted for opioid per kilogram body weight, and prescription of hydroxyurea, adolescent female patients with high HCU for pain had the slowest decline in pain intensity during treatment for acute pain in the ED. Sex and history of high HCU for pain are associated with acute pain trajectories in adolescents with SCD presenting to the ED. These novel findings should be confirmed in future prospective studies.


Physical function predicts improvement in quality of life in elderly Icelanders after 12 weeks of resistance exercise.
Little is known about the effects of resistance training on health related quality of life (HRQL) in the elderly. The main purpose of the study was to investigate the effects of resistance training on strength, body composition, functional capacity and HRQL in independent living elderly people. We hypothesised that resistance training would improve lean mass, muscle strength, physical function and HRQL. Subjects (N = 237, 73.7±5.7 yrs, 58.2% female) participated in a 12-week resistance exercise program (3 times/week; 3 sets, 6-8 repetitions at 75-80% of the 1-repetition maximum) designed to increase strength and muscle mass of major muscle groups. Body composition, quadriceps- and grip strength, timed up and go test (TUG), six minute walk for distance (6MW) and HRQL were measured at baseline and endpoint. Two hundred-and-four participants completed the study. Although the increase in lean mass was small (+0.8 kg, P<0.01), quadriceps strength (+53.5 N), grip strength (+3.0 lb), TUG (-0.6 sec), 6MW (+33.6 m) and HRQL (+1.2 t-score) improved significantly (all P<0.01). Changes in 6MW predicted improvement in HRQL after 12 weeks. Our study shows that a 12-week resistance exercise program significantly improves lean mass, muscle strength, physical function and HRQL in elderly individuals, and that improvements in physical function predict improvements in HRQL. Our study indicates that resistance training should be promoted for the elderly as it has the potential to improve physical performance, thereby prolonging healthy, independent aging.


There are two major types of hepatitis C virus in Japan.
The polymerase chain reaction (PCR) was used to detect hepatitis C virus (HCV) in plasma from chronic non-A, non-B hepatitis patients. By choice of adequate primers, 19 of 24 samples (79%) were found positive. Sequence analysis of amplified 400 bp cDNA fragments encoding a portion of NS5 gene suggested that HCV can be classified into two types (named K1 and K2) in Japan. Slot blot hybridization of the fragments indicated that 13 were HCV-K1 and 6 were HCV-K2, which show 80% and 67% nucleotide sequence homology, respectively, with that of the prototype.


Frequent isolation of Propionibacterium acnes from the shoulder dermis despite skin preparation and prophylactic antibiotics.
In vitro, Propionibacterium acnes (P acnes) is highly susceptible to commonly used antibiotics and antiseptics, yet in vivo, it still causes postsurgical infections of the shoulder. We hypothesized that the local environment within the pilosebaceous glands protects P acnes and that incision of the skin transects these glands, exposing viable P acnes to the wound. Fifty consecutive patients undergoing open shoulder surgery were prospectively studied. Prophylactic antibiotics were administered to all patients. Microbiologic swabs of the skin surface were taken before and after skin preparation with 70% alcoholic chlorhexidine. The skin was incised, and a further swab and dermal biopsy specimen were taken. P acnes was cultured in 21 of 50 prepreparation skin surface swabs (42%), 7 of 50 postpreparation skin surface swabs (14%), 26 of 50 dermal swabs (52%), and 20 of 50 dermal biopsy specimens (40%). There was a significantly higher incidence of P acnes growth from the skin surface (P = .009) and dermis (P = .01) of patients aged ≤50 years old and in the dermal biopsy specimens of patients undergoing revision surgery (P = .01) and a trend toward increased incidence of P acnes in men. P acnes growth from a prepreparation skin surface swab had a sensitivity of 69%, specificity of 88%, positive predictive value of 86%, and negative predictive value of 72% at predicting subsequent P acnes growth from the dermal swab or biopsy specimen. Viable P acnes persists within the skin dermis, despite standard antimicrobial precautions. These findings suggest that incising the skin is likely to lead to deep seeding of the surgical wound, which has implications for the pathogenesis and prevention of postsurgical shoulder infections.


Dynamic human retinal pigment epithelium (RPE) and choroid architecture based on single-cell transcriptomic landscape analysis.
The retinal pigment epithelium (RPE) and choroid are located behind the human retina and have multiple functions in the human visual system. Knowledge of the RPE and choroid cells and their gene expression profiles are fundamental for understanding retinal disease mechanisms and therapeutic strategies. Here, we sequenced the RNA of about 0.3 million single cells from human RPE and choroids across two regions and seven ages, revealing regional and age differences within the human RPE and choroid. Cell-cell interactions highlight the broad connectivity networks between the RPE and different choroid cell types. Moreover, the transcription factors and their target genes change during aging. The coding of somatic variations increases during aging in the human RPE and choroid at the single-cell level. Moreover, we identified ELN as a candidate for improving RPE degeneration and choroidal structure during aging. The mapping of the molecular architecture of the human RPE and choroid improves our understanding of the human vision support system and offers potential insights into the intervention targets for retinal diseases.


Optimal sampling strategy for estimation of spatial genetic structure in tree populations.
Fine-scale spatial genetic structure (SGS) in natural tree populations is largely a result of restricted pollen and seed dispersal. Understanding the link between limitations to dispersal in gene vectors and SGS is of key interest to biologists and the availability of highly variable molecular markers has facilitated fine-scale analysis of populations. However, estimation of SGS may depend strongly on the type of genetic marker and sampling strategy (of both loci and individuals). To explore sampling limits, we created a model population with simulated distributions of dominant and codominant alleles, resulting from natural regeneration with restricted gene flow. SGS estimates from subsamples (simulating collection and analysis with amplified fragment length polymorphism (AFLP) and microsatellite markers) were correlated with the 'real' estimate (from the full model population). For both marker types, sampling ranges were evident, with lower limits below which estimation was poorly correlated and upper limits above which sampling became inefficient. Lower limits (correlation of 0.9) were 100 individuals, 10 loci for microsatellites and 150 individuals, 100 loci for AFLPs. Upper limits were 200 individuals, five loci for microsatellites and 200 individuals, 100 loci for AFLPs. The limits indicated by simulation were compared with data sets from real species. Instances where sampling effort had been either insufficient or inefficient were identified. The model results should form practical boundaries for studies aiming to detect SGS. However, greater sample sizes will be required in cases where SGS is weaker than for our simulated population, for example, in species with effective pollen/seed dispersal mechanisms.


Accuracy, stability, and continuity of AVHRR, SeaWiFS, MODIS, and VIIRS deep blue long-term land aerosol retrieval in Asia.
The deep blue (DB) aerosol algorithm applied to four satellite instruments, AVHRR, SeaWiFS, MODIS, and VIIRS, produced a long-term aerosol data set since 1989. This study first evaluated and compared the accuracy, stability, and continuity of four DB aerosol optical depth (AOD) products in Asia using AErosol RObotic NETwork measurements. Then, the regional AOD spatial distributions, coverages, and series trends are analyzed. The results show that VIIRS DB has the highest accuracy and stability, with an expected error (EE, ±(0.05 + 20%)) of 76.59% and stability of approximately 0.027 per decade. The performance of MODIS DB is slightly worse than that of VIIRS. However, their AOD pattern, coverage, and trend are comparable. The performance of AVHRR (EE = 58.10%) and the stability of SeaWiFS (0.093 per decade) are less good. Therefore, SeaWiFS DB data should be used with caution for trend analysis. The AOD accuracy and coverage together determine the AOD pattern and the continuity of multi-sensor data. In addition to consistent algorithm accuracy, it is necessary to consider the influences in sensor sampling and inappropriate-pixel screening schemes in the joint multi-sensor analysis. Encouragingly, although multiple DB products have different AOD averages of regional series, their changing trends are consistent. Error analysis shows that the AOD bias characteristic is different in different surface conditions. This indicates that the surface reflectance estimated by the DB algorithm using different techniques is divergent, which may be the direction for the improvement of the algorithm.


The effect of intravesical hyaluronic acid therapy on urodynamic and clinical outcomes among women with interstitial cystitis/bladder pain syndrome.
Treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) is often delayed because of a lack of objective data during diagnosis. This study was conducted to determine the clinical validity of using urodynamic studies to investigate the effect of intravesical hyaluronic acid (HA) treatment among women with IC/BPS. Thirty patients with IC/BPS undergoing 6-month intravesical instillation of HA were recruited. Pretreatment evaluation involved a urinalysis and urinary culture, urinary cytology, a 3-day voiding diary, and cystoscopy with hydrodistention of the bladder. Urodynamic study was performed before and after HA treatment. Symptomatic changes were assessed using a questionnaire covering lower urinary tract symptoms, the O'Leary-Sant symptom index and problem indexes (ICSI and ICPI), and the visual analog scale for pain and urgency. Patient demographics, urinary symptoms, ICSI/ICPI scores, pain and urgency scores, and urodynamic results before and after HA treatment were compared. Urinary frequency, nocturia, urgency, pelvic pain, bladder capacity, ICSI, and ICPI were significantly improved after HA treatment. Comparing urodynamic parameters, the volumes at first desire to void (FDV) and maximum cystometric capacity were significantly increased after HA treatment. Before HA treatment, a negative correlation existed between the ICSI and ICPI and urodynamic parameters, including maximum flow rate and bladder capacity, but there were no significant correlations after treatment. Before HA treatment, a negative correlation was discovered between nocturia and FDV. However, after HA treatment, there were no significant correlations between urinary symptoms and urodynamic parameters. Our results indicate that the improvement of urinary symptoms of IC/BPS after HA treatment is associated with increased FDV and maximum cystometric capacity. The value of FDV and the frequency of nocturia after treatment may become useful objective indicators for prognosis of IC/BPS.


Density-Matrix Embedding Theory Study of the One-Dimensional Hubbard-Holstein Model.
We present a density-matrix embedding theory (DMET) study of the one-dimensional Hubbard-Holstein model, which is paradigmatic for the interplay of electron-electron and electron-phonon interactions. Analyzing the single-particle excitation gap, we find a direct Peierls insulator to Mott insulator phase transition in the adiabatic regime of slow phonons in contrast to a rather large intervening metallic phase in the anti-adiabatic regime of fast phonons. We benchmark the DMET results for both on-site energies and excitation gaps against density-matrix renormalization group (DMRG) results and find good agreement of the resulting phase boundaries. We also compare the full quantum treatment of phonons against the standard Born-Oppenheimer (BO) approximation. The BO approximation gives qualitatively similar results to DMET in the adiabatic regime but fails entirely in the anti-adiabatic regime, where BO predicts a sharp direct transition from Mott to Peierls insulator, whereas DMET correctly shows a large intervening metallic phase. This highlights the importance of quantum fluctuations in the phononic degrees of freedom for metallicity in the one-dimensional Hubbard-Holstein model.


Effects of caffeine on ultraviolet-induced base-pair substitution and frameshift mutagenesis in Salmonella.
Using an excision-deficient, di-auxotrophic, strain of Salmonella typhimurium we have shown that caffeine significantly inhibits the formation of ultraviolet-induced base-pair substitution mutations, but has only a marginal effect on the formation of frameshift mutations in the same population of cells.


Gnatho-thoracopagus conjoined twins with near di-symmetry: a case report of an unusual form of conjoined twinning.
The term gnatho-thoracopagus was used previously to describe a remote case of conjoined twins with union involving the mandible. Few reported cases of this type of union exist in the literature. A case of ventrally conjoined twins, with union involving the mandible and near di-symmetry, is presented here and compared with similar previously reported cases. The presented case represents an example of prosopo-thoracopagus, an intermediate between cephalopagus and thoracopagus conjoined twins, although this case does have unique variations.


Working together to improve record keeping.
Implementing changes in a hospital setting requires a structured approach to change management. This article describes the process of a project undertaken to improve record keeping in a children's hospital.


Using remote learning to teach clinicians manual wheelchair skills: a cohort study with pre- vs post-training comparisons.
To test the hypothesis that remote learning to teach clinicians manual wheelchair skills is efficacious. A convenience sample of therapists (physical and occupational) and students were enrolled in pairs in a cohort study with pre- versus post-training comparisons. The intervention was a hybrid of self-study and hands-on practice paired with remote feedback for ten intermediate and advanced manual wheelchair skills. Participants practiced with self-selected frequency and duration, uploading a session log and video(s) to an online platform. A remote trainer provided asynchronous feedback prior to the next practice session. Capacity and confidence in completing the ten skills were evaluated using the Wheelchair Skills Test Questionnaire (WST-Q). Knowledge of wheelchair skills training and motor learning was assessed using a 62-item Knowledge Test. Secondary outcome measures included skill achievement, as confirmed by submitted video recordings, and participant feedback about the training. Across 41participants, scores were higher at follow-up compared to baseline for WST-Q capacity (73.9 ± 19.1 vs 16.8 ± 15.6, p < 0.001), WST-Q confidence (80.1 ± 12.2 vs 47.6 ± 18.2, p = 0.003) and knowledge (70.8 ± 7.5 vs 67.0 ± 5.4, p = 0.004). Remote learning can increase wheelchair skills capacity and confidence as well as knowledge about such training and assessment. This model should be further investigated as a delivery method for training rehabilitation professionals. NCT01807728.Implications for rehabilitationWheelchair skills training is one of the 8 steps of wheelchair provision as outlined by the World Health Organization.Wheelchair skills are not a core part of most clinical curriculums and many clinicians cite a lack of resources and uncertainty on how to implement wheelchair skills training into practice as major barriers to providing such training.Remote learning offers the benefits of structured wheelchair skills training with expert feedback on an individual's own schedule that is not afforded by one-day "bootcamp"-type courses or on-the-job training, which are how many clinicians currently learn wheelchair skills.In a sample of physical and occupational therapists and students, remote learning was effective at increasing capacity and confidence to perform manual wheelchair skills as well as knowledge of wheelchair training.


Joint purification of mangano and cuprozinc superoxide dismutases from a single source--a simplified method.
Preliminary studies which raised questions as to the efficacy of ammonium sulfate precipitation in separating mangano from cuprozinc superoxide dismutase and the adequacy of cyanide sensitivity in monitoring such separation led to the use of electrophoresis with activity and protein staining to monitor purification. This, together with exploitation of the differing isoelectric points of the two enzymes permitting separate elution from the same DE-52 column, led to a simplified method for purification of these enzymes using the same starting material and purification steps initially. The specific activity was 2900 and 3200 units/mg protein and yields were 18 and 20% for mangano and cuprozine superoxide dismutase, respectively.


Trichoderma atroviride F6 improves phytoextraction efficiency of mustard (Brassica juncea (L.) Coss. var. foliosa Bailey) in Cd, Ni contaminated soils.
Trichoderma atroviride F6, isolated from decaying feather and resistant to 100 mg l(-1) Cd2+ and 250 mg l(-1) Ni2+, was applied for rhizoremediation of Cd, Ni and Cd-Ni combination contaminated soils through association with Brassica juncea (L.) Coss. var. foliosa. The strain significantly alleviated the cellular toxicity of cadmium and nickel to plants. Inoculation of B. juncea (L.) Coss. var. foliosa with T. atroviride F6 resulted a 110%, 40% and 170% increase in fresh weight in Cd, Ni and Cd-Ni contaminated soils, respectively (P<0.05). The translocation factors and metal bioconcentration factors calculated for the inoculated plant were increased compared to the noninoculated plants. The results indicated that the efficiency of phytoextraction for B. juncea (L.) Coss. var. foliosa enhanced after inoculating with T. atroviride F6. The fungal treated plants grown in Cd-Ni combination contaminated soils showed higher phytoextraction efficiency than those in Cd or Ni contaminated soils. Thus, it is suggested that the fungus T. atroviride F6 endowed with organic-degrading capabilities could be exploited for fungi-assisted phytoremediation of mixed organic-metal contaminated soils.


The oli1 gene and flanking sequences in mitochondrial DNA of Saccharomyces cerevisiae: the complete nucleotide sequence of a 1.35 kilobase petite mitochondrial DNA genome covering the oli1 gene.
As part of our genetic and molecular analysis of mutants of Saccharomyces cerevisiae affected in the oli1 gene (coding for mitochondrial ATPase subunit 9) we have determined the complete nucleotide sequence of the mtDNA genome of a petite (23-3) carrying this gene. Petite 23-3 (1,355 base pairs) retains a continuous segment of the relevant wild-type (J69-1B) mtDNA genome extending 983 nucleotides upstream, and 126 nucleotides downstream, of the 231 nucleotide oli1 coding region. There is a 15-nucleotide excision sequence in petite 23-3 mtDNA which occurs as a direct repeat in the wild-type mtDNA sequence flanking the unique petite mtDNA segment (interestingly, this excision sequence in petite 23-3 carries a single base substitution relative to the parental wild-type sequence). The putative replication origin of petite 23-3 is considered to be in its single G,C rich cluster, which differs in just one nucleotide from the standard oriS sequence. The DNA sequences in the intergenic regions flanking the oli1 gene of strain J69-1B (and its derivatives) have been systematically compared to those of the corresponding regions of mtDNA in strains derived from the D273-10B parent (sequences from the laboratory of A. Tzagoloff). The nature and distribution of the sequence divergences (base substitutions, base deletions or insertions, and more extensive rearrangements) are considered in the context of functions associated with mitochondrial gene expression which are ascribed to specialized sequences in the intergenic regions of the yeast mitochondrial genome.


[Scleritis posterior in child--case report].
We present the case of 13-years old girl with recurrent unilateral painful proptosis and associated with other ocular features: loss of vision, disc edema, macular edema, folds at the posterior pole. Ultrasound examination with CT scan were necessary to make the differential diagnosis of orbital tumors. The patognomonic sign "T" on B scan was extremely essential in the clinical diagnosis of posterior scleritis.


The effect of electrode positioning on the ocular vestibular evoked myogenic potential to air-conducted sound.
To assess the effect of electrode position on the amplitude and latency of ocular vestibular evoked myogenic potentials (oVEMPs) produced by air-conducted (AC) sound with a view to optimisation of the recording paradigm. Eight otologically normal subjects (16 ears) were stimulated by 500 Hz AC tone bursts at 95 dBnHL; oVEMP traces were recorded below the eye contralateral to the acoustic stimulation. Five independent oVEMP measurements were recorded with the active electrode in equally spaced positions in the infra-orbital plane relative to a reference electrode positioned 2 cm below the lower lid in the orbital midline. These measurements included the accepted standard-montage in which the electrodes were positioned vertically above and below each other in the orbital midline. A further recording was made using a belly-tendon montage with reference to the inferior oblique muscle. Of the six recording paradigms tested the largest amplitude oVEMP response was found using the belly-tendon montage with an n10 average of 5.67 ± 3.42 μV (sd). This was significantly larger than the amplitude recorded using the standard-montage (p < 0.01). With the reference electrode in the orbital midline, the position of the active electrode in the infra-orbital plane was found to significantly alter the response magnitude. As the active electrode was moved laterally the response reduced in amplitude, however when moved medially the response polarity reversed indicating the existence of a null-point at which no response was present. The location of oVEMP recording electrodes significantly alters the response amplitude. Whilst the standard-montage provides a reasonable method for recording oVEMPs, the belly-tendon montage results in a significantly larger amplitude response. Furthermore medial and lateral variations in the position of the active electrode using the standard-montage significantly affect the magnitude and polarity of the response. The standard-montage used for recording oVEMPs is sensitive to the placement of the active electrode. Small variations in position result in significant changes in the n(10) amplitude and this may account for the variability reported in the literature. Using the belly-tendon montage, larger amplitude responses can be elicited which may improve the robustness with which oVEMPs can be collected. However this enhancement in response amplitude must be balanced against the increased possibility of signal contamination from neighbouring extraocular muscles.


The role of simultaneous abdominal surgery and wound classification in ventriculoperitoneal shunt complication.
To evaluate whether simultaneous abdominal surgery or wound contamination at the time of ventriculoperitoneal (VP) shunt placement are associated with increased shunt complications. Pediatric patients who underwent VP shunt placement were identified using the National Surgical Quality Improvement Program Pediatric database. VP shunt complication rates were compared between patients who underwent simultaneous abdominal surgeries at the time of VP shunt placement vs those who did not and between those with clean/clean-contaminated and contaminated/dirty wound classifications. Adjusted analysis was performed using 1:5 case-control matching. Among 2715 patients who underwent VP shunt placement, 21 had simultaneous abdominal procedures and were matched with 105 control patients. No significant difference was found in overall (34.3 vs 14.3%, p = 0.07), infectious (8.6 vs 4.8%, p = 1.000), or non-infectious (25.7 vs 9.5%, p = 0.156) shunt complications in the simultaneous vs non-simultaneous group, respectively. In a separate analysis of wound classification, 12 patients with contaminated/dirty wounds were matched with 60 patients with clean/clean-contaminated wounds. The rates of shunt infections for clean/clean-contaminated and contaminated/dirty cases were 10.0 and 16.7%, respectively (p = 0.613). In our matched case-control study, neither simultaneous abdominal surgery nor wound contamination at the time of VP shunt placement demonstrated significant increased risk of 30-day post-operative complication.


Multilocus gene-specific characterization of 'Candidatus Phytoplasma australasia' associated with shoot proliferation disease of small cardamom in India.
Symptoms of excessive shoot proliferation were observed in the Njallani cultivar of small cardamom accompanied by stunting of stalks with fewer degenerated capsules at Nedumkandam Panchayat of Idukki district of Kerala in 2017. Five symptomatic Elettaria cardamomum shoot proliferation (ECSP) plant samples were collected and processed for DNA extraction and PCR assays utilizing universal phytoplasma 16S ribosomal-specific primers pair, P1/P7 followed by R16F2n/R16R2. Sequence comparison analysis of the R16F2n/R16R2 region of 16SrRNA gene showed 100% sequence identity with the 'Candidatus Phytoplasma australasia'- related strain. Phylogeny and virtual RFLP analyses of 16S rRNA gene sequences confirmed the association of 'Ca. P. australasia' strain subgroup D with ECSP disease. The association of 16SrII group was further established and validated by amplifying phytoplasma-specific multilocus candidate genes by utilizing specific primers of secA, secY, SAP11, and tuf genes. The multilocus gene sequence comparison analysis again confirmed the association of 'Ca. P. australasia' with the ECSP phytoplasma isolate. This is the first report of phytoplasma association with small cardamom.


Hemifacial spasm due to intracranial tumor. An international survey of botulinum toxin investigators.
Hemifacial spasm (HFS) due to intracranial mass lesions is rare. Most cases are thought to be due to compression of the facial nerve by small vessels near the root of the facial nerve. A survey was undertaken of all botulinum toxin investigators to determine the incidence of imaged mass lesions causing HFS. Responders contributed information on 1676 patients with HFS. Of this group, nine tumors were reported for an incidence of 0.54% of patients. However, of this group only 52.5% underwent computed tomography (CT) or magnetic resonance (MR) scanning so the incidence of tumor causing HFS could be as high as 1.0%. No one tumor type was predominant, and most patients were women older than 50 years of age. The incidence compares with another large series of HFS patients in which one tumor was found in 367 patients. The authors also report as an illustrative case a 26-year-old man with HFS due to a presumed lipoma of the cerebellopontine angle. This diagnosis can be made with increased certainty with MR scanning. If the incidence of unsuspected diagnostically significant mass lesions is 1 in 200 patients with HFS referred for botulinum toxin injection, the cost of detecting one such lesion would be $100,000 at an average imaging cost of $500 per MR imaging or CT examination. Although mass lesions are uncommon, any patient with HFS whose general clinical course could justify intervention should be considered for imaging studies to rule out treatable conditions other than vascular compression.


Standardization of protocol design for user training in EEG-based brain-computer interface.
Brain-computer interfaces (BCIs) are systems that enable a person to interact with a machine using only neural activity. Such interaction can be non-intuitive for the user hence user training methods are developed to increase one's understanding, confidence and motivation, which would in parallel increase system performance. To clearly address the current issues in the BCI user training protocol design, here it is divided intointroductoryperiod and BCIinteractionperiod. First, theintroductoryperiod (before BCI interaction) must be considered as equally important as the BCI interaction for user training. To support this claim, an extensive literature review demonstrates that BCI performance can depend on the methodologies presented in such introductory period. To standardize its design, the user training models from human-computer interaction field are adjusted to the BCI context. Second, during the user-BCI interaction, the interface can take a large spectrum of forms (2D, 3D, size, colour etc) and modalities (visual, auditory or haptic etc) without following any design standard or guidelines. Namely, studies that explore perceptual affordance on neural activity, show that motor neurons can be triggered from a simple observation of certain objects, and depending on objects' properties (size, location etc) neural reactions can vary greatly. Surprisingly, the effects of perceptual affordance were not investigated in the BCI context. Both inconsistent introductions to BCI as well as variable interface designs make it difficult to reproduce experiments, predict their outcomes and compare results between them. To address these issues, a protocol design standardization for BCI user training is proposed.


Prevalence of Parkinson's disease and other types of parkinsonism in the Aeolian Archipelago, Sicily.
To estimate prevalence of Parkinson's disease (PD) and other types of parkinsonism in the Aeolian Archipelago, Sicily. We studied the frequency of PD and other types of parkinsonism in the Aeolian Archipelago (population 13,431). All potential cases were identified from available medical information sources. To ensure the completeness of the case-findings, a screening questionnaire was also mailed to residents aged 40 years and over. Subjects were considered prevalent if they fulfilled the SNES diagnostic criteria for PD, on prevalence day (January 1, 2001). We identified 17 patients with parkinsonism from medical sources, and 4 from mail-survey. Prevalence for all types of parkinsonism was 156.3/100,000 (95% CI 99.4-234.8). Fourteen subjects fulfilled diagnostic criteria for PD giving a crude prevalence of 104.2/100,000 (95% CI 59.4-170.7) and 422.5/100,000 in the population aged 60 years and over. Prevalence of all types of parkinsonism and PD found in the Aeolian Archipelago is lower than that previously reported in Sicily.


Optimizing IVF with sexed sperm in cattle.
Sperm-sorting by flow cytometry separates X-sperm from Y-sperm with an accuracy as high as 90% or more. This technology offers farmers and the livestock industry the potential to nearly double productivity, by producing the desired sex to optimize breeding programs. Sorting speed and fertility variation of sorted sperm, however, remain limiting factors for widespread application, particularly in traditional AI programs. Alternatively, in vitro fertilization is a feasible and efficient means to increase the fertilization efficiency of sex-sorted sperm in cattle. Procedures to increase fertilization rate and improve embryo quality include optimizing heparin concentrations for semen of each bull, reducing fertilization drop size to increase sperm concentration, use of fructose instead of glucose in culture media, and use of vitrification protocols with extremely rapid cooling and warming rates.


The accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic) in the differentiation between transfusion-related acute lung injury and transfusion-related circulatory overload in the critically ill.
The diagnostic workup of transfusion-related acute lung injury (TRALI) requires an exclusion of transfusion-associated circulatory overload (TACO). Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic (NT-pro-BNP) accurately diagnosed TACO in preliminary studies that did not include patients with TRALI. In this prospective cohort study, two critical care experts blinded to serum levels of BNP and NT-pro-BNP determined the diagnosis of TRALI, TACO, and possible TRALI based on the consensus conference definitions. The accuracy of BNP and NT-pro-BNP was assessed based on the area under the receiver operating curve (AUC). Of 115 patients who developed acute pulmonary edema after transfusion, 34 were identified with TRALI, 31 with possible TRALI, and 50 with TACO. Median BNP was 375 pg per mL (interquartile range [IQR], 123 to 781 pg/mL) in TRALI, 446 pg per mL (IQR, 128 to 743 pg/mL) in possible TRALI, and 559 pg per mL (IQR, 288 to 1348 pg/mL) in TACO patients (p = 0.038). The NT-pro-BNP levels among patients with TRALI, possible TRALI, and TACO differed significantly with a median value of 1559 pg per mL (IQR, 629 to 5114 pg/mL), 2349 pg/mL (IQR, 919 to 4610 pg/mL), and 5197 pg/mL (IQR, 1695 to 15,714 pg/mL; p = 0.004), respectively. The accuracy of BNP and NT-pro-BNP to diagnose TACO was moderate with an AUC of 0.63 (95% confidence interval [CI], 0.51-0.74) and 0.70 (95% CI, 0.59 to 0.80). Natriuretic peptides are of limited diagnostic value in a differential diagnosis of pulmonary edema after transfusion in the critically ill patients.


Identifying the components of asthma health status in children with mild to moderate asthma.
Weak and inconsistent correlations between measurements of asthma health status suggest that the disease is composed of nonoverlapping components. Factor analysis was used to explore the relationships between measures of asthma morbidity and to identify heterogeneous components of asthma health status in children 5 to 12 years old. Results were compared across time (baseline and 48-month visit) and treatment arms. Analyses were conducted in 7 different study windows in a database from a large clinical trial of children with mild to moderate asthma (n = 1041). Measurements of lung function, symptoms, and health care utilization from daily diary cards, serum IgE levels, total eosinophil count, skin test positivity, and airway hyperresponsiveness were included. Data on fractional exhaled nitric oxide and sputum eosinophil cationic protein were included in a subgroup of patients. In each of the study windows, factor analysis identified 5 factors that explained between 50% and 60% of the common variance. Factors identified included (1) inflammatory markers, (2) symptoms/medication use, (3) asthma exacerbations, and measures of lung function, which subdivided into (4) FEV(1) and forced vital capacity, and (5) bronchodilator response and the FEV(1)/forced vital capacity ratio. Exploratory analyses suggest that fractional exhaled nitric oxide account for the atopy/inflammatory marker factor, and sputum measurements account for a sixth, separate factor. The consistent identification of a 5-factor structure across time and treatment arms suggests that each of these factors provides independent information in the assessment of asthma.


Numerical simulation of reactive extraction of benzoic acid from wastewater via membrane contactors.
Membrane-based non-dispersive solvent extraction is used in many chemical processes due to its significant benefits such as straightforward scale-up and low energy consumption. A mechanistic model was developed to predict recovery of benzoic acid (BA) from wastewater using membrane contactors. Model equations were derived for benzoic acid transport in the membrane module, and solved using FEM. The model findings were compared with experimental results, and an average deviation of 4% was observed between experimental and simulation results. Simulations showed that change in organic phase flowrate and initial concentration of BA does not have considerable effect on the removal efficiency of benzoic acid. In addition, increasing feed flowrate leads to the enhancement of convective mass transfer flux in the tube side of membrane contactor which decreases removal efficiency of benzoic acid.


TRH attenuates scopolamine-induced memory impairment in humans.
The brain tripeptide thyrotropin-releasing hormone (TRH) has been demonstrated to facilitate cholinergic neurotransmission. To test its interaction with the cholinergic system in humans, high-dose TRH (0.5 mg/kg) or placebo was administered intravenously (IV) to normal controls pretreated with scopolamine (0.5-0.75 mg IV), a centrally active muscarinic antagonist, which has been used to model aspects of the memory impairment of normal aging and of dementia. Compared to placebo, TRH markedly attenuated scopolamine-induced impairment of some measures of memory, most notably on a selective reminding task. This cognitive study is the first in humans to suggest a neuromodulatory effect of a peptide on the cholinergic system, and suggests a facilitatory role for TRH in human memory processes.


Mucosal delivery of therapeutic and prophylactic molecules using lactic acid bacteria.
Studies of lactic acid bacteria (LAB) as delivery vehicles have focused mainly on the development of mucosal vaccines, with much effort being devoted to the generation of genetic tools for antigen expression in different bacterial locations. Subsequently, interleukins have been co-expressed with antigens in LAB to enhance the immune response that is raised against the antigen. LAB have also been used as a delivery system for a range of molecules that have different applications, including anti-infectives, therapies for allergic diseases and therapies for gastrointestinal diseases. Now that the first human trial with a Lactococcus strain that expresses recombinant interleukin-10 has been completed, we discuss what we have learnt, what we do not yet understand and what the future holds for therapy and prophylaxis with LAB.


On the characterization of the heterogeneous mechanical response of human brain tissue.
The mechanical characterization of brain tissue is a complex task that scientists have tried to accomplish for over 50 years. The results in the literature often differ by orders of magnitude because of the lack of a standard testing protocol. Different testing conditions (including humidity, temperature, strain rate), the methodology adopted, and the variety of the species analysed are all potential sources of discrepancies in the measurements. In this work, we present a rigorous experimental investigation on the mechanical properties of human brain, covering both grey and white matter. The influence of testing conditions is also shown and thoroughly discussed. The material characterization performed is finally adopted to provide inputs to a mathematical formulation suitable for numerical simulations of brain deformation during surgical procedures.


Histomorphometric assessment of bone necrosis produced by two cryosurgery protocols using liquid nitrogen: an experimental study on rat femurs.
The aim of this study was to evaluate the effects of liquid nitrogen cryosurgery on the femoral diaphysis of rats. The femoral diaphyses of 42 Wistar rats were exposed to three local and sequential applications of liquid nitrogen for 1 or 2 min, intercalated with periods of 5 min of passive thawing. The animals were sacrificed after 1, 2, 4 and 12 weeks and the specimens obtained were processed and analyzed histomorphometrically. The depth and extent of peak bone necrosis were 124.509 µm and 2087.094 µm for the 1-min protocol, respectively, and 436.424 µm and 12046.426 µm for the 2-min protocol. Peak necrosis was observed in the second experimental week with both cryotherapy protocols. The present results indicate that the 2-min protocol produced more marked bone necrosis than the 1-min protocol. Although our results cannot be entirely extrapolated to clinical practice, they contribute to the understanding of the behavior of bone tissue submitted to different cycles of liquid nitrogen freezing and may serve as a basis for new studies.


Identification of nuclear substrates of the cyclic AMP-dependent protein kinase in Dictyostelium discoideum.
A search for nuclear substrates of the cAMP-dependent protein kinase (cAMP-d PK) of Dictyostelium discoideum led to the identification of several such proteins. Identification was based initially on increased phosphorylation of the proteins in nuclear extracts catalyzed by added cAMP-d PK. One protein of Mr 38,000 was phosphorylated also in intact nuclei and in vivo; the amount of phosphoprotein or the level of phosphorylation increased during development. Both the Mr 38,000 protein and another substrate of Mr 195,000 were found in the nuclei of prespore and prestalk cells. Phosphorylation of other potential substrates of the cAMP-d PK was either prespore or prestalk cell-specific.


Anxiety sensitivity cognitive concerns predict suicidality among smokers.
Anxiety along with anxiety-related risk factors is receiving increased attention in regard to its role in elevated suicidality. One such risk factor, anxiety sensitivity (AS), refers to a fear of anxiety-related symptoms. Emerging research indicates that components of AS, particularly the AS subfactor focused on cognitive arousal concerns, are significantly associated with elevated suicidality in samples of diverse clinical outpatients, clinical outpatients with PTSD symptoms, and Air Force cadets undergoing a stressful life experience. Cigarette smokers represent another relevant population for this line of research due to recent reports indicating that cigarette smoking and nicotine dependence may be related to elevated suicidality. Study 1 examined the role of AS and the AS subfactors in a large sample (n=343) of community adult smokers. Study 2 examined the role of AS and AS subfactors in a sample of "pack-a-day" adult smokers (n=78) who were seeking outpatient treatment for substance abuse issues. Study 1 results were consistent with our a priori hypothesis that AS cognitive concerns would be significantly associated with suicidality. Additionally, after covarying for relevant substance use variables, Study 2 results were also consistent with our hypothesis that AS cognitive concerns were significantly associated with suicidality. Limitations included the use of suicide related outcomes, not death by suicide, and cross-sectional design. These findings suggest that suicide potential in cigarette smokers may be related to AS cognitive concerns and add to the emerging literature suggesting AS cognitive concerns are a risk factor for suicidality.


A teflon culture dish for high-magnification microscopy and measurements in single cells.
A simple tissue culture dish is described which permits the use of oil immersion optics (X 100) while maintaining access to cells in culture. In combination with a micro-CO2-incubator (Ince et al. 1983) long-term as well as short-term experiments can be performed under microscopical control. The teflon dish is re-usable, resistant to sterilization procedures, and easy to assemble. Standard glass coverslips with adherent cells are secured to the dish by an aluminium ring with a bayonet fitting. Both phase-contrast and interference-contrast microscopy with high magnification can be used. The dish is of particular use in electrophysiological investigations where the patch-clamp technique is used and frequent exchange of cultures is required. With this unit, single ion channel activity in cultured human monocytes was measured. The dish has also been used in studies in which membrane potential measurements were performed with glass microelectrodes in small cells under culture conditions. The applications described include video time-lapse sequences of phagocytosis with micro-organisms presented to mouse peritoneal macrophages with broken-tipped pipettes. This easy to use, multi-purpose dish offers the cell physiologist a valuable aid for the manipulation and observation of single cells in culture.


Ultrasound prognostic factors after laser surgery for twin-twin transfusion syndrome to predict survival at 6 months.
To evaluate the significance of ultrasound findings, detected one or two weeks after laser surgery for twin-twin transfusion syndrome, in predicting the mortality at 6 months of age. Ultrasound evaluation including fetal biometry, amniotic fluid volume estimation and Doppler examination was performed between 7 and 14 days after surgery for 181 cases. The presence of one or more effusions and single fetal death were also determined. Associations between ultrasound findings and mortality at 6 months of age were evaluated using multiple logistic regression analysis. Of the total 181 pairs, 145 (80.1%) donor and 160 (88.1%) recipient twins survived in utero for more than 7 days after surgery, and hence were included in the analysis. The survival rate at 6 months was 66.9% for the donor and 80.7% for the recipient twins. Risk factors for death in the donor were the presence of severe intrauterine growth restriction and effusions. In recipients, elevation in the middle cerebral artery peak systolic velocity coincided with fetal death, but this occurred in only three cases. Ultrasound risk factors one week after surgery included severe intrauterine growth restrictions and effusions in the donor twins.


The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity.
The mer receptor tyrosine kinase mediates phagocytosis of apoptotic cells and modulates cytokine production; it is also required for prevention of systemic autoimmune disease. Using a mer-specific antibody, we have confirmed the presence of mer on macrophages and now report its expression on NK cells, NKT cells, and dendritic cells (DC). We found that DC do not require mer for ingestion of apoptotic cells, as DC from mer-deficient mice phagocytose apoptotic cells normally. Mer was observed in splenic sections on cells outside follicular areas, probably representing DC and macrophages. Mer apparently participates in NKT-cell antigen-induced signaling, as NKT cells from mer-deficient mice evinced much lower cytokine production after in vivo alpha-galactosylceramide stimulation; this defect was intrinsic to the mer-deficient NKT cells. Taken together, these studies show mer expression on cells of the innate immune system. Mer, through its binding of lipid antigens, may not only mediate ingestion of apoptotic cells, but also signal events in NK cells, NKT cells, and DC.


Issues of infant feeding for postnatal prevention of human T-cell leukemia/lymphoma virus type-1 mother-to-child transmission.
Nationwide antenatal human T-cell leukemia/lymphoma virus type-1 (HTLV-1) antibody screening has been conducted in Japan. The purpose of our study was to clarify the issues related to feeding options to prevent postnatal mother-to-child transmission. Of the pregnant carriers at 92 facilities in Japan between 2012 and 2015, 735 were followed prospectively. Among the children born to them, 313 (42.6%) children were followed up to the age of 3 and tested for HTLV-1 antibodies. The mother-to-child transmission rate was calculated for each feeding option selected before birth. Among the 313 pregnant carriers, 55.0, 35.1, 6.1, and 3.8% selected short-term breast-feeding (≤3 months), exclusive formula feeding, frozen-thawed breast-milk feeding, and longer-term breast-feeding, respectively. Despite short-term breast-feeding, 8-18% of the mothers continued breast-feeding for 4-6 months. The mother-to-child transmission rate with short-term breast-feeding was 2.3% (4/172), and its risk ratio compared with that of exclusive formula feeding was not significantly different (0.365; 95% CI: 0.116-1.145). Because of the small number of children who were fed by frozen-thawed breast-milk, their mother-to-child transmission rate was not statistically reliable. Pregnant HTLV-1 carriers tended to select short-term breast-feeding in Japan. While short-term breast-feeding was not always easy to wean within 3 months, it may be a viable option for preventing postnatal mother-to-child transmission because the vertical transmission rate with short-term breast-feeding was not significantly higher than that with exclusive formula feeding. Increasing the follow-up rates for children born to pregnant carriers may provide clearer evidence of preventative effects by short-term breast-feeding and frozen-thawed breast-milk feeding.


Structure-function relationships in scorpion neurotoxins. Identification of the supperreactive lysine residue in toxin I of Androctonus australis Hector.
In a previous article (Habersetzer-Rochat, C. and Sampieri, R. (1976) Biochemistry 15, 2254--2261) it was demonstrated that the toxin I of the North African Scorpion Androctonus australis Hector was inactivated after reaction with iodoacetate; the toxicity loss in mice was correlated with the carboxymethylation of one superreactive residue. In the present work, alkylation of toxin I was performed with iodo[14C]-acetate. Hence, it was possible, after reduction, S-methylation and chymotryptic hydrolysis of this toxin, to isolate the peptide containing the labelled lysine residue. By automatic Edman degradation, this residue was identified as being the penultimate lysine at position 56 in the primary sequence. Comparison of three primary structures of scorpion neurotoxins and comparison in different kinds of activity seem to indicate that this lysine residue is mainly important for toxicity in mice.


Influence of the antigen delivery system on immunoglobulin isotype selection and cytokine production in response to influenza A nucleoprotein.
The influence of different antigen delivery systems on antibody isotype and lymphokine profile has been investigated using influenza nucleoprotein as a model antigen system. Mice exposed to live or inactivated influenza virus produced antibody against whole virus or recombinant nucleoprotein (rNP), which was predominantly of the IgG2a isotype. Spleen or lymph node cells from these mice rapidly produced large amounts of interferon-gamma (IFN-gamma), but no detectable interleukin-5 (IL-5) when stimulated in vitro with specific antigen. In contrast, after primary immunization with rNP or p206-229 in different adjuvants (CFA, quil A or alhydrogel), specific antibody was predominantly of the IgG1 isotype and relatively lower amounts of IFN-gamma but no IL-5 were detected following in vitro antigenic stimulation. Secondary immunization, however, resulted in detection of IgG2a antibodies and increased levels of IFN-gamma. IL-5 was only detected after secondary immunization with peptide in adjuvant. Mice infected with aro A- Salmonella typhimurium expressing NP produced antibody of both IgG1 and IgG2a isotypes and large amounts of IFN-gamma and no IL-5, following in vitro antigenic stimulation, and therefore parallelled the pattern seen with whole virus more closely than that seen following primary immunization with protein or peptide in conventional adjuvants. The results suggest that the antigen delivery vehicle influences both quantitative and qualitative differences in the type of immune response elicited, which may be important in determining the potency of protective immunity induced.


Microspectrophotometric studies of Romanowsky stained blood cells. III. The action of methylene blue and azure B.
The performances of two standardized Romanowsky stains (azure B/eosin and azure B/methylene blue/eosin) have been compared with each other and with a methylene blue/eosin stain. Visible-light absorbance spectra of various hematological substrates have been measured. These have been analyzed in terms of the quantities of bound azure B, methylene blue and eosin dimers and monomers, and in terms of the CIE color coordinates. It has been found that the addition of methylene blue to azure B/eosin produces little change in performance, at least using these two analytical methods. Methylene blue/eosin does not produce the purplish colorations typical of the Romanowsky effect. This is due not to differences between the spectra of methylene blue and azure B, but to the fact that methylene blue does not facilitate the binding of eosin to cellular substrates to the same extent as azure B.


Dynamic and reversible DNA methylation changes induced by genome separation and merger of polyploid wheat.
Wheat is a powerful genetic model for studying polyploid evolution and crop domestication. Hexaploid bread wheat was formed by two rounds of interspecific hybridization and polyploidization, processes which are often accompanied by genetic and epigenetic changes, including DNA methylation. However, the extent and effect of such changes during wheat evolution, particularly from tetraploid-to-hexaploid wheat, are currently elusive. Here we report genome-wide DNA methylation landscapes in extracted tetraploid wheat (ETW, AABB), natural hexaploid wheat (NHW, AABBDD), resynthesized hexaploid wheat (RHW, AABBDD), natural tetraploid wheat (NTW, AABB), and diploid (DD). In the endosperm, levels of DNA methylation, especially in CHG (H=A, T, or C) context, were dramatically decreased in the ETW relative to natural hexaploid wheat; hypo-differentially methylated regions (DMRs) (850,832) were 24-fold more than hyper-DMRs (35,111). Interestingly, those demethylated regions in ETW were remethylated in the resynthesized hexaploid wheat after the addition of the D genome. In ETW, hypo-DMRs correlated with gene expression, and TEs were demethylated and activated, which could be silenced in the hexaploid wheat. In NHW, groups of TEs were dispersed in genic regions of three subgenomes, which may regulate the expression of TE-associated genes. Further, hypo-DMRs in ETW were associated with reduced H3K9me2 levels and increased expression of histone variant genes, suggesting concerted epigenetic changes after separation from the hexaploid. Genome merger and separation provoke dynamic and reversible changes in chromatin and DNA methylation. These changes correlate with altered gene expression and TE activity, which may provide insights into polyploid genome and wheat evolution.


Naturalistic driving study on the impact of an aftermarket blind spot monitoring system on the driver's behaviour of heavy goods vehicles and buses on reducing conflicts with pedestrians and cyclists.
The risk being severely or fatally injured in crashes with heavy goods vehicle and buses is much higher compared to other vehicles. Especially vulnerable road users such as pedestrian and cyclists are at high risk. In the European Union 4600 pedestrian and more than 2000 cyclists were killed in 2019. 18% of the fatalities were counted in crashes with heavy goods vehicles or buses. Blind spot situations and driver inattention or distraction are causing and contributing crash factors. Driver assistance systems are intended to support drivers and might have a positive effect on the crash avoidance. The objective of the study is the analysis of the change of driver behaviour in heavy goods vehicles and buses due to a aftermarket blind spot monitoring system. In a naturalistic driving study 15 heavy goods vehicles and five buses were equipped with a blind spot monitoring system and data were collected over a period of two years. The results revealed that the system would reduce the number of warnings with vulnerable road users by one third for heavy goods vehicles and 10% for buses. Up to 200 lives annually could potentially be saved with the analysed system, on the assumption that the collision warnings correlate directly with crashes.


The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores.
To insure an adequate supply of nutrients, omnivores choose among available food sources. This process is exemplified by the well-characterized innate aversion of omnivores to otherwise nutritious foods of imbalanced amino acid content. We report that brain-specific inactivation of GCN2, a ubiquitously expressed protein kinase that phosphorylates translation initiation factor 2 alpha (eIF2alpha) in response to intracellular amino acid deficiency, impairs this aversive response. GCN2 inactivation also diminishes phosphorylated eIF2alpha levels in the mouse anterior piriform cortex following consumption of an imbalanced meal. An ancient intracellular signal transduction pathway responsive to amino acid deficiency thus affects feeding behavior by activating a neuronal circuit that biases consumption against imbalanced food sources.


Prognostic factors and treatment of multiple myeloma: interest of a cyclic sequential chemohormonotherapy combining cyclophosphamide, melphalan, and prednisone.
1. A type 2 therapeutic trial consisting of the administration of monthly cycles of chemohormonotherapy, each cycle combining weekly sequences of mephalan, prednisone, cyclophosphamide, and prednisone, has been achieved in 20 stage II or III myeloma patients. Tolerance of this regimen in treated out-patients was found to be excellent. Preliminary data indicate that the better survival rate in patients treated by this regimen is still not reached at a 30-month follow-up examination by three other nonrandomized control groups of patients receiving continuous therapy with prednisone alone, prednisone + cyclophosphamide, or prednisone + melphalan. 2. Analysis of the main prognostic factors of the four trials indicates that a) IgG-type myelomas are associated with a better prognosis than IgA type; nonexcreting myelomas are associated with the best prognosis, while Bence Jones myelomas are associated with a prognosis as poor as that of the IgA type; b) tumor volume as well as renal insufficiency, at the time of diagnosis, are also prognosis factors; this study confirms the prognostic value of the recently proposed clinical staging system based on these parameters but outlines that 10% of the patients died from a cause not directly related to myeloma plasmocyte proliferation. 3. In conclusion, these results point out: a) the possible advantage of using two alkylating agents instead of one at the beginning of the disease; b) the need to classify multiple myeloma according to prognosis before attempting therapeutic trials.


Modulating the interfacial concentration of gallates to improve the oxidative stability of fish oil-in-water emulsions.
Distributions of a homologous series of gallic acid (GA) derivatives of increasing lipophilicity were determined in stripped fish oil-in-water emulsions. The distribution was determined by employing a kinetic method based on the reaction between the hydrophobic 4-hexadecylbenzenediazonium ions (16-ArN2+) and the antioxidants (AOs), that allows to determine the partition constants between the oil-interfacial, POI, and water-interfacial, PWI, regions of the emulsion. Results showed that the antioxidant activity of gallic acid and its derivatives was positively correlated with the percentage of AO at the interface. The percentage of butyl, octyl and dodecyl gallates in the interfacial region is similar but much higher than that of the other derivatives, showing the highest AO efficiency. When increasing the surfactant fraction, the percentage of all compounds at the interface increased but the emulsion stability decreased due to the dilution of AO at the interface region. Both butyl and octyl gallates were found the most suitable AOs to carry out fish oil-in-water emulsions protection. For maximum effectiveness, butyl and octyl gallate should be used with the lowest emulsifier volume fraction necessary to physically stabilize emulsions.


Antihypertensive activity of some novel pyridinylidene arylurea derivatives in spontaneously hypertensive rats.
3 novel pyridinylidene arylurea derivatives were found to lower arterial pressure in spontaneously hypertensive rats. Their relative oral potency ranged from 6 to 32 times that of guanethidine. The onset of antihypertensive action following their oral administration was less than 1 h and the duration of action ranged from 8 to over 24 h. The antihypertensive activity of the pyridinylidene arylureas was found to be assoicated with depletion of tissue catecholamines. Compound C depleted cardiac norepinephrine with little or no effect on total brain norepinephrine levels. It is suggested that compound C may have useful antihypertensive properties without CNS depressant activity.


Electrode systems for measuring cardiac impedances using optical transmembrane potential sensors and interstitial electrodes--theoretical design.
The cardiac electrical substrate is a challenge to direct measurement of its properties. Optical technology together with the capability to fabricate small electrodes at close spacings opens new possibilities. Here, those possibilities are explored from a theoretical viewpoint. It appears that with careful measurements from a well-designed set of electrodes one can obtain structural conductivities, separating intracellular from interstitial values, and longitudinal from transverse. Resting membrane resistance also can be obtained.


Profiling "flexible" nursing staff: bank nurses in Scotland.
Nurse banks are locally organised "in house" sources of temporary nursing staff. This paper reports on a survey of nurses working on three nurse banks in the National Health Service in Scotland. A total of 203 nurses responded to the survey, which revealed marked differences in the profile of the nurses working on each of the banks, in terms of age, biographical details, career plans and work commitments. Main issues for management revealed by the survey were the need for good communication with temporary staff and high levels of reported dissatisfaction with access to training opportunities. The paper concludes that there is no "standard" model of a nurse bank in the NHS in Scotland and no standard profile of bank nurses.