Does evolution of iteroparous and semelparous reproduction call for spatially structured systems?
A persistent question in the evolution of life histories is the fitness trade-off between reproducing only once (semelparity) in a lifetime or reproducing repeated times in different seasons (iteroparity). The problem can be formulated into a research agenda by assuming that one reproductive strategy is resident (has already evolved) and by asking whether invasion (evolution) of an alternative reproductive strategy is possible. For a spatially nonstructured system, Bulmer (1994) derived the relationship v + PA < 1 (PA is adult survival; vbS and bS are offspring numbers for iteroparous and semelparous breeding strategies, respectively) at which semelparous population cannot be invaded by an iteroparous mutant. When the inequality is changed to v + PA > 1, invasion of a semelparous mutant is not possible. From the inequalities, it is easy to see that possibilities for evolutionary establishment of a novel reproductive strategy are rather narrow. We extended the evolutionary scenario into a spatially structured system with dispersal linkage among the subunits. In this domain, a rare reproductive strategy can easily invade a population dominated by a resident reproductive strategy. The parameter space enabling invasion is far more generous with spatially structured evolutionary scenarios than in a spatially nonstructured system.


Bactericidal activity of human serum against strains of Klebsiella from different sources.
One hundred and eighty strains of Klebsiella were tested for sensitivity to pooled normal human serum, capsular type and faecal coliform reaction. Strains of K. pneumoniae isolated from clinical infections were more likely to be serum resistant than those from the gut flora or environmental sources. For K. oxytoca strains, there was no significant correlation between serum sensitivity and source of isolation. Of 60 strains of K. oxytoca tested, 19 (32%) were serum resistant, as were 27 (23%) of 120 strains of K. pneumoniae. Strains of K. pneumoniae from human sources gave positive reactions in the faecal coliform test more frequently than strains from environmental sources. There was no correlation between a positive faecal coliform reaction and resistance to the bactericidal effect of human serum. Strains of capsular type K21 were isolated more frequently from clinical infections and were more often serum resistant than other strains. Serum resistance appears to be a virulence factor in strains of K. pneumoniae but does not account for the difference in pathogenicity between K. pneumoniae and K. oxytoca.


Phosphorylation and desensitization of neurokinin-1 receptor expressed in epithelial cells.
A rat kidney epithelial cell line expressing the rat neurokinin-1 receptor (NK-1 R) was used to investigate the relationship between receptor phosphorylation and desensitization. Substance P (SP) maximally stimulated cellular inositol 1,4,5-trisphosphate (IP3) production 14-fold within 3 s, after which cellular IP3 levels rapidly diminished to near basal levels in the continuing presence of SP. SP also caused concentration-dependent phosphorylation of the NK-1R, and this effect was blocked by a receptor antagonist. Stimulation with 100 nM SP for as little as 2 s resulted in 90% desensitization of the receptor to restimulation by SP, and near-maximal receptor phosphorylation was observed at 5 s. Receptor desensitization was not affected by agents that affect protein kinase A. Phorbol 12-myristate 13-acetate (PMA) also caused phosphorylation and desensitization of the receptor but with slower kinetics and to a lesser extent than SP. PMA- but not SP-induced NK-1 R desensitization and phosphorylation were abolished by the protein kinase C inhibitor bisindolylmaleimide 1. The concentration-response curves for SP-stimulated IP3 signaling and desensitization were similar, but the curve for NK-1R phosphorylation was shifted to the right and was steeper, suggesting that the relationship between desensitization and phosphorylation is complex. These results show that both rapid homologous and rapid heterologous NK-1R desensitizations may be mediated by receptor phosphorylation but occur via distinct mechanisms with different kinetics and efficacies.


Awareness-driven behavior changes can shift the shape of epidemics away from peaks and toward plateaus, shoulders, and oscillations.
The COVID-19 pandemic has caused more than 1,000,000 reported deaths globally, of which more than 200,000 have been reported in the United States as of October 1, 2020. Public health interventions have had significant impacts in reducing transmission and in averting even more deaths. Nonetheless, in many jurisdictions, the decline of cases and fatalities after apparent epidemic peaks has not been rapid. Instead, the asymmetric decline in cases appears, in most cases, to be consistent with plateau- or shoulder-like phenomena-a qualitative observation reinforced by a symmetry analysis of US state-level fatality data. Here we explore a model of fatality-driven awareness in which individual protective measures increase with death rates. In this model, fast increases to the peak are often followed by plateaus, shoulders, and lag-driven oscillations. The asymmetric shape of model-predicted incidence and fatality curves is consistent with observations from many jurisdictions. Yet, in contrast to model predictions, we find that population-level mobility metrics usually increased from low levels before fatalities reached an initial peak. We show that incorporating fatigue and long-term behavior change can reconcile the apparent premature relaxation of mobility reductions and help understand when post-peak dynamics are likely to lead to a resurgence of cases.


Caregiving demands in parents of children with cancer: psychometric validation of the Care of My Child with Cancer questionnaire.
A comprehensive evaluation of the psychometric properties of Care of My Child With Cancer (CMCC) was performed in a sample of 411 parents of children undergoing treatment of cancer at five Canadian pediatric oncology centers. Psychometric tests used to assess data quality, targeting, reliability, and construct validity demonstrated that the CMCC is a scientific sound measure. The CMCC will be helpful for assessing increasing parental responsibility for caregiving tasks associated with cancer care.


Incidence trends of pediatric onset inflammatory bowel disease in the years 2000-2009 in Saxony, Germany-first results of the Saxon Pediatric IBD Registry.
In developed countries, the incidence of inflammatory bowel disease (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) is increasing. Therefore, we aimed to investigate the incidence rates and trends over time in the population of children and adolescents in one of the federal states of Germany, in Saxony. Over the 10-year period 2000-2009 all 31 children's hospitals and pediatric gastroenterologists, respectively in Saxony reported all IBD patients up to 15 years of age to the Saxon Pediatric IBD Registry. The completeness of the registry was estimated as 96.7% by independent surveys in the years 2005-2009. Incidence rates were presented as age-standardized incidence rates (ASR) regarding New European Standard Population 1990 per 100,000 person-years (PY) with 95% confidence intervals [CI]. Joinpoint and linear regression was used for trend analyses. 344 patients with confirmed IBD between 2000-2009 were included in the epidemiological evaluation: 212 (61.6%) patients with CD, 122 (35.6%) with UC and 10 (2.9%) with unclassified IBD (IBD-U). The ASR per 100,000 PY over the whole observation period was 7.2 [6.4-7.9] for IBD, 4.4 [3.8-5.0] for CD, 2.6 [2.1-3.0] for UC and 0.2 [0.1-0.3] for IBD-U. For IBD, the ASR per 100,000 PY increased from 4.6 [2.8-6.3] in 2000 to 10.5 [7.5-13.6] in 2009. The incidence trend analysis of ASRs using the joinpoint regression confirmed a significant increase of IBD as well as UC. The mean age at first diagnosis decreased significantly during the observation period from 11.5 (11.0-13.4) in 2000 to 9.6 (5.1-13.5) years in 2009. The median of the diagnostic latency among IBD patients was 3 months. The incidence of IBD in children and adolescents in Saxony was slightly higher than the average of other countries in the same time period and followed the trend towards a general increase of IBD. The age at diagnosis was subject to a very unfavorable downward trend.


Central and peripheral pain generators in women with chronic pelvic pain: patient centered assessment and treatment.
Women with chronic pelvic pain (CPP) often present without obvious cause on imaging studies, laboratory values or physical exam. Dysfunctional sensory processing in the central nervous system (CNS) may explain pain of unclear origin. Central sensitization (CS), a mechanism of centrally mediated pain, describes this abnormal processing of sensory information. Women with CPP often present with several seemingly unrelated symptoms. This can be explained by co-existing chronic pain syndromes occurring in the same patient. Central sensitization occurs in all of these pain syndromes, also described as dysfunctional pain syndromes, and thus may explain why several often occur in the same patient. Six of the most common pain disorders that co-exist in CPP include endometriosis, painful bladder syndrome/interstitial cysitis, vulvodynia, myofascial pain/ pelvic floor hypertonus, irritable bowel syndrome, and primary dysmenorrhea. Central pain generators, (pain originating from CS) and peripheral pain generators, (pain from local tissue damage), can both occur in each of these six conditions. These pain generators will be described. Chronic pain, specifically dysfunctional sensory processing, is recognized as a systemic disease process like diabetes to be managed as opposed to a local problem to be "fixed" or cured. A multi-disciplinary approach to assessment and treatment with a focus on improving emotional, physical and social functioning instead of focusing strictly on pain reduction is more effective in decreasing disability. This is best achieved by determining the patient's needs and perspective through a patient-centered approach. Algorithms for such an approach to assessment and treatment are outlined.


Humanized VB22B minibody for human Mpl stimulates human megakaryopoiesis but does not enhance platelet aggregation.
Thrombopoietin stimulates megakaryopoiesis and platelet production by binding to its receptor, Mpl, on hematopoietic progenitor cells. Previously, a murine VB22B minibody for Mpl was shown to stimulate megakaryocyte colony formation in vitro and increase the platelet count in cynomolgus monkeys. In this study, we directly compared the effects of a humanized VB22B minibody (huVB22B) with those of thrombopoietin and eltrombopag under the hypothesis that Mpl agonists might have different biological effects on megakaryopoiesis, platelet production, intracellular signal transduction, and platelet function. Human bone marrow-derived CD34(+) cells were used for colony formation assays and proplatelet formation assays in vitro. The DNA ploidy in megakaryocytes was analyzed by flow cytometry. Phosphorylation of signal transducers and activators of transcription and mitogen-activated protein kinase was detected by Western blotting using specific antibodies. The effects of the Mpl agonists on platelet aggregation were analyzed by aggregometry using human platelets. HuVB22B was as potent as thrombopoietin and eltrombopag in its ability to form mature megakaryocytes using human CD34(+) cells in vitro. It did not affect granulocyte-macrophage or erythroid colony formation. HuVB22B increased the number of proplatelet-forming megakaryocytes more efficiently than thrombopoietin or eltrombopag. Despite stronger phosphorylation of signal transducers and activators of transcription and mitogen-activated protein kinase compared with thrombopoietin in human platelets, huVB22B did not enhance adenosine diphosphate- or collagen-induced platelet aggregation. Eltrombopag did not enhance agonist-induced platelet aggregation. We found that huVB22B, eltrombopag, and thrombopoietin have different effects on megakaryopoiesis, platelet function, and intracellular signaling. The precise mechanisms for these different biological effects regarding stimulation through the same receptor, Mpl, remain to be elucidated.


Permutation Disalignment Index as an Indirect, EEG-Based, Measure of Brain Connectivity in MCI and AD Patients.
In this work, we introduce Permutation Disalignment Index (PDI) as a novel nonlinear, amplitude independent, robust to noise metric of coupling strength between time series, with the aim of applying it to electroencephalographic (EEG) signals recorded longitudinally from Alzheimer's Disease (AD) and Mild Cognitive Impaired (MCI) patients. The goal is to indirectly estimate the connectivity between the cortical areas, through the quantification of the coupling strength between the corresponding EEG signals, in order to find a possible matching with the disease's progression. PDI is first defined and tested on simulated interacting dynamic systems. PDI is then applied to real EEG recorded from 8 amnestic MCI subjects and 7 AD patients, who were longitudinally evaluated at time [Formula: see text]0 and 3 months later (time [Formula: see text]1). At time [Formula: see text]1, 5 out of 8 MCI patients were still diagnosed MCI (stable MCI) whereas the remaining 3 exhibited a conversion from MCI to AD (prodromal AD). PDI was compared to the Spectral Coherence and the Dissimilarity Index. Limited to the size of the analyzed dataset, both Coherence and PDI resulted sensitive to the conversion from MCI to AD, even though only PDI resulted specific. In particular, the intrasubject variability study showed that the three patients who converted to AD exhibited a significantly ([Formula: see text]) increased PDI (reduced coupling strength) in delta and theta bands. As regards Coherence, even though it significantly decreased in the three converted patients, in delta and theta bands, such a behavior was also detectable in one stable MCI patient, in delta band, thus making Coherence not specific. From the Dissimilarity Index point of view, the converted MCI showed no peculiar behavior. PDI significantly increased, in delta and theta bands, specifically in the MCI subjects who converted to AD. The increase of PDI reflects a reduced coupling strength among the brain areas, which is consistent with the expected connectivity reduction associated to AD progression.


Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.
Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.


Assessing humoral and cell-mediated immune response in Hawaiian green turtles, Chelonia mydas.
Seven immature green turtles, Chelonia mydas, captured from Kaneohe Bay on the island of Oahu were used to evaluate methods for assessing their immune response. Two turtles each were immunized intramuscularly with egg white lysozyme (EWL) in Freund's complete adjuvant, Gerbu, or ISA-70; a seventh turtle was immunized with saline only and served as a control. Humoral immune response was measured with an indirect enzyme linked immunosorbent assay (ELISA). Cell-mediated immune response was measured using in vitro cell proliferation assays (CPA) using whole blood or peripheral blood mononuclear cells (PBM) cultured with concanavalin A (ConA), phytohaemagglutinin (PHA), or soluble egg EWL antigen. All turtles, except for one immunized with Gerbu and the control, produced a detectable humoral immune response by 6 weeks which persisted for at least 14 weeks after a single immunization. All turtles produced an anamnestic humoral immune response after secondary immunization. Antigen specific cell-mediated immune response in PBM was seen in all turtles either after primary or secondary immunization, but it was not as consistent as humoral immune response; antigen specific cell-mediated immune response in whole blood was rarely seen. Mononuclear cells had significantly higher stimulation indices than whole blood regardless of adjuvant, however, results with whole blood had lower variability. Both Gerbu and ISA-70 appeared to potentiate the cell-mediated immune response when PBM or whole blood were cultured with PHA. This is the first time cell proliferation assays have been compared between whole blood and PBM for reptiles. This is also the first demonstration of antigen specific cell-mediated response in reptiles. Cell proliferation assays allowed us to evaluate the cell-mediated immune response of green turtles. However, CPA may be less reliable than ELISA for detecting antigen specific immune response. Either of the three adjuvants appears suitable to safely elicit a detectable immune response in green turtles.


Biodegradable Dual-Network Cellulosic Composite Bioplastic Metafilm for Plastic Substitute.
With the escalating environmental and health concerns over petroleum-based plastics, sustainable and biodegradable cellulosic materials are a promising alternative to plastics, yet remain unsatisfied properties such as fragility, inflammability and water sensitivity for practical usage. Herein, we present a novel dual-network design strategy to address these limitations and fabricate a high-performance cellulosic composite bioplastic metafilm with the exceptional mechanical toughness (23.5 MJ m-3 ), flame retardance, and solvent resistance by in situ growth of cyclotriphosphazene-bridged organosilica network within bacterial cellulose matrix. The phosphorus, nitrogen-containing organosilica network, verified by the experimental and theoretical results, plays a triple action on significantly enhancing tensile strength, toughness, flame retardance and water resistance of composite bioplastic metafilm. Furthermore, cellulosic bioplastic composite metafilm demonstrates a higher maximum usage temperature (245 °C), lower thermal expansion coefficient (15.19 ppm °C-1 ), and better solvent resistance than traditional plastics, good biocompatibility and natural biodegradation. Moreover, the composite bioplastic metafilm have a good transparency of average 74 % and a high haze over 80 %, which can serve as an outstanding substrate substitute for commercial polyethylene terephthalate film to address the demand of flexible ITO films. This work paves a creative way to design and manufacture the competitive bioplastic composite to replace daily-used plastics.


Blind evaluation of the microwave-accelerated metal-enhanced fluorescence ultrarapid and sensitive Chlamydia trachomatis test by use of clinical samples.
Accurate point-of-care (POC) diagnostic tests for Chlamydia trachomatis infection are urgently needed for the rapid treatment of patients. In a blind comparative study, we evaluated microwave-accelerated metal-enhanced fluorescence (MAMEF) assays for ultrafast and sensitive detection of C. trachomatis DNA from vaginal swabs. The results of two distinct MAMEF assays were compared to those of nucleic acid amplification tests (NAATs). The first assay targeted the C. trachomatis 16S rRNA gene, and the second assay targeted the C. trachomatis cryptic plasmid. Using pure C. trachomatis, the MAMEF assays detected as few as 10 inclusion-forming units/ml of C. trachomatis in less than 9 min, including DNA extraction and detection. A total of 257 dry vaginal swabs from 245 female adolescents aged 14 to 22 years were analyzed. Swabs were eluted with water, the solutions were lysed to release and to fragment genomic DNA, and MAMEF-based DNA detection was performed. The prevalence of C. trachomatis by NAATs was 17.5%. Of the 45 samples that were C. trachomatis positive and the 212 samples that were C. trachomatis negative by NAATs, 33/45 and 197/212 were correctly identified by the MAMEF assays if both assays were required to be positive (sensitivity, 73.3%; specificity, 92.9%). Using the plasmid-based assay alone, 37/45 C. trachomatis-positive and 197/212 C. trachomatis-negative samples were detected (sensitivity, 82.2%; specificity, 92.9%). Using the 16S rRNA assay alone, 34/45 C. trachomatis-positive and 197/212 C. trachomatis-negative samples were detected (sensitivity, 75.5%; specificity, 92.9%). The overall rates of agreement with NAAT results for the individual 16S rRNA and cryptic plasmid assays were 89.5% and 91.0%, respectively. Given the sensitivity, specificity, and rapid detection of the plasmid-based assay, the plasmid-based MAMEF assay appears to be suited for clinical POC testing.


Bright, Mechanosensitive Upconversion with Cubic-Phase Heteroepitaxial Core-Shell Nanoparticles.
Lanthanide-doped nanoparticles are an emerging class of optical sensors, exhibiting sharp emission peaks, high signal-to-noise ratio, photostability, and a ratiometric color response to stress. The same centrosymmetric crystal field environment that allows for high mechanosensitivity in the cubic-phase (α), however, contributes to low upconversion quantum yield (UCQY). In this work, we engineer brighter mechanosensitive upconverters using a core-shell geometry. Sub-25 nm α-NaYF4:Yb,Er cores are shelled with an optically inert surface passivation layer of ∼4.5 nm thickness. Using different shell materials, including NaGdF4, NaYF4, and NaLuF4, we study how compressive to tensile strain influences the nanoparticles' imaging and sensing properties. All core-shell nanoparticles exhibit enhanced UCQY, up to 0.14% at 150 W/cm2, which rivals the efficiency of unshelled hexagonal-phase (β) nanoparticles. Additionally, strain at the core-shell interface can tune mechanosensitivity. In particular, the compressive Gd shell results in the largest color response from yellow-green to orange or, quantitatively, a change in the red to green ratio of 12.2 ± 1.2% per GPa. For all samples, the ratiometric readouts are consistent over three pressure cycles from ambient to 5 GPa. Therefore, heteroepitaxial shelling significantly improves signal brightness without compromising the core's mechano-sensing capabilities and further, promotes core-shell cubic-phase nanoparticles as upcoming in vivo and in situ optical sensors.


Catastrophizing and pain in arthritis, fibromyalgia, and other rheumatic diseases.
Pain is among the most frequently reported, bothersome, and disabling symptoms described by patients with osteoarthritis, rheumatoid arthritis, fibromyalgia, and other musculoskeletal conditions. This review describes a growing body of literature relating catastrophizing, a set of cognitive and emotional processes encompassing magnification of pain-related stimuli, feelings of helplessness, and a generally pessimistic orientation, to the experience of pain and pain-related sequelae across several rheumatic diseases. We reviewed published articles in which pain-related catastrophizing was assessed in the context of one or more rheumatic conditions. Because much of the available information on catastrophizing is derived from the more general chronic pain literature, seminal studies in other disease states were also considered. Catastrophizing is positively related, in both cross-sectional and prospective studies across different musculoskeletal conditions, to the reported severity of pain, affective distress, muscle and joint tenderness, pain-related disability, poor outcomes of pain treatment, and, potentially, to inflammatory disease activity. Moreover, these associations generally persist after controlling for symptoms of depression. There appear to be multiple mechanisms by which catastrophizing exerts its harmful effects, from maladaptive influences on the social environment to direct amplification of the central nervous system's processing of pain. Catastrophizing is a critically important variable in understanding the experience of pain in rheumatologic disorders as well as other chronic pain conditions. Pain-related catastrophizing may be an important target for both psychosocial and pharmacologic treatment of pain.


Linear IgA bullous dermatosis v dermatitis herpetiformis. Quantitative measurements of dermoepidermal alterations.
Linear IgA bullous dermatosis (LAD), also known as "atypical dermatitis herpetiformis," is a disorder that is distinct from classic dermatitis herpetiformis (DH). In eight patients with DH and six with LAD, quantitative assessment of a variety of histopathologic variables was made. The number of rete tips with neutrophils in basal vacuoles and the length of the epidermal basement membrane zone (BMZ) associated with these findings were greater in LAD than DH. The number of microabscesses of neutrophils in the dermal papillae and the length of epidermal BMZ associated with them were greater in DH than in LAD. By using the number of microabscesses and the number of rete tips with neutrophils in basal vacuoles in a probability model, we found by retrospective analysis that a correct diagnosis could be made for LAD in 75% of biopsy specimens with a probability of 97% and in all cases of DH with a probability of 92%. Using this model, we made no misdiagnoses. This is the first diagnostic probability model in dermatopathology that expresses a confidence level in diagnosis.


Experimental radiotherapy-induced enteritis: a probiotic interventional study.
Acute radiation of the small intestine causes an immediate and potentially reversible effect on the sensitive regenerative epithelium of the intestinal mucosa while markedly altering the overall intestinal ecosystem. The aim of the present study was test a novel probiotic mixture formulation (Microflorana-F) in an experimental model of acute radiation enteritis with particular interest in endotoxinemia and bacterial translocation. Male Wistar rats allocated to three groups were fed for 7 days with: (A) a standard balanced diet; (B) a standard diet with the addition of 1 mL t.i.d. of Microflorana-F and (C) the same probiotic but after heat inactivation. Under ketamine anesthesia, abdominal irradiation was performed at a single dose rate of 20 Gy. Sham-radiated healthy rats served as a control (D). Standard food and active/inactive probiotic supplementation schedule was maintained throughout the study period. When they were killed 14 days later a midline laparotomy and a medium sternotomy was carried out. The mesenteric lymph nodes, whole spleen and liver samples as well as blood, the portal vein and bile samples were cultured. Endotoxinemia was also measured. Early deaths (1 week) occurred mostly in rats fed standard food or inactivated probiotic. The endotoxin level significantly increased in irradiated rats fed standard food and inactivated probiotic while supplementation with the active form of the probiotic mixture significantly improved such parameters (P < 0.05). After radiation injury, mesenteric lymph nodes and portal blood were the samples most frequently yielding bacterial growth. Treatment with only the active form of probiotic significantly reduced the incidence of bacterial contamination in all samples. These data suggest that the manipulation of gut ecosystem by biologically effective probiotic preparations might be a worthwhile therapeutic and preventive tool in radiation-induced enteritis.


Mechanisms involved in fibrin formation.
That the role of thrombin in the conversion of fibrinogen to fibrin is essentially enzymatic, is established not only by the minute amounts of thrombin which are effective but also by the complete independence of fibrin yields and thrombin concentrations over a very wide range of thrombin dilutions and clotting times. The thrombin-fibrinogen reaction, in the phase beyond the "latent period" at least, seems fundamentally "first order." Technical requirements of the experiments leading to these conclusions include: (1) a highly purified (e.g. 97 per cent "clottable") fibrinogen, (2) absence of traces of thrombic impurities in the fibrinogen, (3) absence of fibrinolytic protease contaminant of the thrombin and the fibrinogen, and (4) sufficient stability of the thrombin even at very high dilutions. Four conditions affecting thrombin stability have been investigated. Fibrin yields are not significantly modified by numerous experimental circumstances that influence the clotting time, such as (1) temperature, (2) pH, (3) non-specific salt action due to electrical (ionic) charges, which alter the Coulomb forces involved in the fibrillar aggregation, (4) specific ion effects, whether clot-accelerating (e.g. Ca(++)) or clot-inhibitory (e.g. Fe(CN)(6)''''), (5) occluding (adsorptive) colloids, which have a "fibrinoplastic" action, e.g. (a) acacia and probably (b) fibrinogen which has been mildly "denatured" by salt-heating, acidification, etc. The data with which several European workers have attempted to substantiate the idea of a two-stage thrombin-fibrinogen reaction with an intermediary "profibrin" (allegedly partly "denatured") have been reanalyzed with controls which lead us to very different conclusions, viz. (1) denaturation and fibrin formation are independent; (2) partial denaturation is "fibrinoplastic" (see above); and (3) conditions of strong salinity and acid pH (5.1) usually do not completely prevent the thrombin-fibrinogen reaction but merely prolong the "latent" phase and lessen the time required for completion of essentially the same reaction (fibrin polymerization) when more favorable clotting conditions are restored. Thus, our experiments advance the modern concepts concerning the coagulation mechanisms along lines that, for the most part, agree with those of the Harvard physical chemists, and we oppose the European views concerning a two-stage reaction, "profibrin," and "the denaturase theory" of clotting.


[Turkey's publication output in cardiovascular medicine declined in 2010 both in quantity and quality].
The performance of Turkey's institutions was evaluated regarding publication output in cardiovascular medicine in 2010 based on data of the Web of Knowledge. Only articles in full-text and reviews that appeared in source publications covered by Science Citation Index CD Edition were included. A fractional count system was used for items published jointly with a foreign or noncardiological Turkish institution. Turkey's publications numbered as low as 121, representing more than one-fourth decline, and her share of world publication decreased from 8.2 to 6.1 per mille, to a level below that of before 2001. Ninety-five articles originated from adult cardiology. The median impact factor also declined to 1.60, by one-fifth compared with the previous year; half of the publications appeared in periodicals with an impact factor of 1.15-2.60. Among medical institutions with highest productivity, Gülhane Military Medical Academy, Siyami Ersek Cardiovascular Surgery Center, Türkiye Yüksek İhtisas Hospital, and Kartal Koşuyolu Education and Research Hospital as well as Erciyes University and Cerrahpaşa medical faculties ranked in front. Authorities need to be aware that Turkey's science and, in particular, cardiology are losing prestige and should take new serious measures.


Cubitus Valgus with Tardy Ulnar Nerve Palsy - Functional Outcome of Milch Osteotomy without Anterior Transposition of Ulnar Nerve.
To assess the results of Milch osteotomy in terms of deformity correction and functional outcome in the absence of ulnar nerve transposition. Nine patients with cubitus valgus deformity greater than 20° with tardy ulnar nerve palsy (TUNP) operated between 2012 and 2017 were evaluated. Correction by Milch osteotomy and fixation was done in each case, without osteosynthesis of the non-union lateral condyle humerus or transposition of the ulnar nerve. At one year post-operatively, carrying angle, elbow function (Mayo Elbow Performance Score) and ulnar nerve symptoms were assessed. The mean carrying angle pre-operatively was 30.8° on the affected side which improved to a mean of 8.3° postoperatively with an average correction of 22.5°. The mean elbow flexion pre-operatively was 129.4° which improved to 133.3° post-operatively. The mean preoperative MEP score was 76.7 which improved to a mean of 92.2 post-operatively (p < 0.01). TUNP recovered completely in all the patients. Milch osteotomy is an effective procedure for cubitus valgus deformity correction and its associated tardy ulnar nerve palsy without a decrease in elbow ROM. Correction of even severe valgus deformities without concurrent anterior transposition of the ulnar nerve is likely to improve ulnar nerve symptoms.


The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis.
Mutations in palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme that removes fatty acyl groups from cysteine residues in modified proteins, cause the fatal inherited neurodegenerative disorder infantile neuronal ceroid lipofuscinosis. The accumulation of undigested substrates leads to the formation of neuronal storage bodies that are associated with the clinical symptoms. Less severe forms of PPT1 deficiency have been found recently that are caused by a distinct set of PPT1 mutations, some of which retain a small amount of thioesterase activity. We have determined the crystal structure of PPT1 with and without bound palmitate by using multiwavelength anomalous diffraction phasing. The structure reveals an alpha/beta-hydrolase fold with a catalytic triad composed of Ser115-His289-Asp233 and provides insights into the structural basis for the phenotypes associated with PPT1 mutations.


Molecular detection and characterization of carnivore parvoviruses in free-ranging Eurasian otters (Lutra lutra) in southern Italy.
The most important Italian population of the Eurasian otter (Lutra lutra) occurs in the southern part of the peninsula with two isolated sub-populations of about 250 adult individuals. The Eurasian otter is considered to be near threatened and it is a fully protected species. The aims of this study were to investigate for the first time the occurrence and characterize the parvoviruses included in the species Carnivore protoparvovirus 1 in seven carcasses of road-killed Eurasian otters from the southern Italy. Carnivore protoparvovirus 1 are responsible for acute gastroenteritis and leukopenia in pets and free-ranging carnivores. Initial screening of tissue samples by real-time PCR revealed CPV/FPV DNA in tissue samples of five Eurasian otters; three of them, showed co-infections by both CPV and FPV. Among the five positive Eurasian otters, we successfully obtained six DNA sequences from four individuals including two CPV-2a, one CPV-2b, one CPV-2c, and two FPV sequences. Comparison of these sequences with 250 VP2 gene sequences deposited in the GenBank database, showed 10 nt differences resulting in two synonymous and eight non-synonymous substitutions. On the basis of these results, two sequences here found were characterized as new CPV-2a, one was characterized as new CPV-2b variant, and one was characterized as FPV-like mutant. The last two sequences belong to a FPV and CPV-2c strain respectively. Carnivore protoparvovirus 1 is reported for the first time in the Eurasian otter showing high infection value in southern Italy. Occurrence of this infection should be studied further to understand its possible pathogenicity and virulence to the fragile and isolate Eurasian otter population which live in southern Italy.


Efficacy of combining GMX1777 with radiation therapy for human head and neck carcinoma.
Rapidly metabolizing tumor cells have elevated levels of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD(+) biosynthesis, which serves as an important substrate for proteins involved in DNA repair. GMX1777, which inhibits nicotinamide phosphoribosyltransferase, was evaluated in two human head and neck cancer models in combination with radiotherapy. Effects of GMX1777-mediated radiosensitization were examined via metabolic and cytotoxicity assays in vitro; mechanism of action, in vivo antitumor efficacy, and radiosensitization were also investigated. IC(50) values of GMX1777 for FaDu and C666-1 cells were 10 and 5 nmol/L, respectively, which interacted synergistically with radiotherapy. GMX1777 induced a rapid decline in intracellular NAD(+) followed by ATP reduction associated with significant cytotoxicity. These metabolic changes were slightly increased with the addition of radiotherapy, although poly(ADP-ribose) polymerase activity was significantly reduced when GMX1777 was combined with radiotherapy, thereby accounting for the synergistic cytotoxicity of these two modalities. Systemic GMX1777 administration with local tumor radiotherapy caused complete disappearance of FaDu and C666-1 tumors for 50 and 20 days, respectively. There was also significant reduction in tumor vascularity, particularly for the more sensitive FaDu model. [(18)F]FDG-positron emission tomography/computed tomography images showed reduction in [(18)F]FDG uptake after GMX1777 administration, showing decreased glucose metabolism in vivo. Our data represent the first report showing that GMX1777 plus radiotherapy is an effective therapeutic strategy for head and neck cancer, mediated via pleiotropic effects of inhibition of DNA repair and tumor angiogenesis, while sparing normal tissues. Therefore, GMX1777 combined with radiotherapy definitely warrants clinical evaluation in human head and neck cancer patients.


Deterministic risk assessment of firefighting water additives to terrestrial organisms.
Firefighting water additives are used to increase the rate at which fires can be extinguished. The majority of ecotoxicological research has focused on firefighting formulations containing perfluorinated compounds as additives, due to the persistence and bioaccumulative nature of the perfluorinated constituents. A number of relatively new additives have come on the market to replace the products containing perfluorinated compounds. The potential effect of these new additives on the environment has been largely unstudied. This study investigated the toxicity of six firefighting water additives: Eco-Gel™, ThermoGel 200L™, FireAde™, Fire-Brake™, Novacool Foam™, and F-500™ to terrestrial biota. Terrestrial organisms could be exposed to firefighting water additives through leaching into soil and/or runoff following a firefighting event or through direct aerial application during a forest fire. Toxicity to three plant species was assessed through seedling germination and emergence tests: Fagopyrum esculentum (buckwheat), Raphanus raphanistrum subsp. sativus (radish), and Rudbeckia hirta (black-eyed Susan). The effects of firefighting water additives on three soil invertebrates, the collembolan Folsomia candida, the earthworms Eisenia andrei, and Dendrodrilus rubidus, were also investigated using static acute tests to estimate EC50/LC50s. The concentration that resulted in a 50% reduction in survival (LC50) for the acute toxicity tests conducted with F. candida ranged from 3 (Eco-Gel) to 0.175% (Novacool) by volume. Comparatively, the acute toxicity of two firefighting water additives to D. rubidus could not be determined, as a 50% reduction in survival was not observed. A number of firefighting water additives were found to pose a hazard to terrestrial organisms based on a worst-case exposure scenario of direct application at the greatest recommended application rate for a class A fire (e.g., wood, paper). The firefighting water additive F-500 was found to pose a hazard (HQ ≥ 1) for all species tested, except for the acute test conducted with D. rubidus. Comparatively, Eco-Gel posed a hazard for only the acute and chronic tests with F. candida. This study represents the first comparative deterministic risk assessment of firefighting water additives to terrestrial ecosystems.


[Bilharziasis and bladder cancer. A case report].
In our setting, the association between bilharziasis and bladder cancer is uncommon. However, the presence of recurrent haematuria in a patient from an endemic area of bilharziasis (east of Africa and Middle East), is highly suspicious of this disease. Lack of an adequate treatment by using anthelminthic drugs during the acute phase of disease, might lead to the onset of chronic bladder lesions and, on occasion, bladder cancer, of the epidermoid type in the majority of cases. Because of the high mortality and aggressivity of this type of cancer, an early diagnosis and appropriate treatment of acute lesions is mandatory. We report a 40-year-old black male from Senegal, presenting chronic bladder schistosomiasis and infiltrative epidermoid carcinoma of the bladder, diagnosed and treated in our department by palliative cystectomy.


Torture and its neurological sequelae.
Refugees and asylum seekers continue to enter the United States and the European Union in record numbers. Some have estimated that between 5-35% of all refugees have suffered torture in their countries of origin. Although general practitioners and specialized physicians are likely to encounter victims of torture as patients, few providers are familiar with the health problems that may affect this patient population. :To provide neurologists, neurosurgeons, and rehabilitation medicine physicians with basic knowledge about survivors of torture that can help in the diagnosis, treatment, and referral of such patients. A MEDLINE (1966-October 2001) search using keywords torture and sequelae (nervous system diseases and brain injuries) was conducted. Other data sources included books, reference lists, online resources and expert opinion. :Forms of torture that may affect the nervous system include beatings, gunshot wounds, stab wounds, asphyxiation, prolonged suspension and electrocution. Victims of torture commonly experience neurological symptoms such as headaches, vertigo, loss of consciousness and dizziness during and after torture. A successful and meaningful clinical interaction with a survivor of torture includes avoiding retraumatization, building trust, spelling out any limits on confidentiality, and above anything else, establishing empathy with the patient. Neurological sequelae of torture can be devastating physically and psychologically. The treatment of these neurological conditions does not differ from other patient populations. However, the clinical approach is unique and must focus on avoiding retraumatization and helping the victim reintegrate into society as quickly as possible.


Hot-press molded poly(methyl methacrylate) matrix for solid-state dye lasers.
A hot-press molding method was used to fabricate dye-doped poly(methyl methacrylate) (PMMA) slabs. Three rhodamine dyes, Rh640 (ClO(4)), Rh6G(ClO(4)), and Rh6G (Cl), were impregnated into the PMMA matrix first by dissolving the dye and granular PMMA in a solvent mixture of chloroform and methanol and then heating the mixture in vacuo at 175 degrees C to obtain a spongy preform. The powdered preform was molded into slabs at 175 degrees C and at <1 mbar, to eliminate the formation of bubbles in the slabs. We annealed the slabs for several hours to improve its optical homogeneity and hence its lasing efficiency. When pumped by a 1.5-mJ nitrogen laser, we obtained peak lasing efficiencies of 8% and 7.8%, respectively, for Rh6G (ClO(4)) and Rh640 (ClO(4)) in PMMA matrices. The lasing efficiency of Rh6G (ClO(4))-doped PMMA suffered a reduction rate of 0.012%/shot compared with 0.15%/shot for Rh640 (ClO(4))-doped PMMA. In contrast, Rh6G (Cl) in a hot-press molded PMMA slab suffered thermal bleaching that resulted in a low lasing efficiency of <1%; this can be explained by its absorption and fluorescence characteristics.


Magnolol supplementation alleviates diquat-induced oxidative stress via PI3K-Akt in broiler chickens.
This experiment was conducted to investigate the effects of magnolol on the oxidative parameters and jejunum injury induced by diquat in broiler chickens. This test adopts a 2 × 2 factors design, a total of 288 one-day-old male AA broiler chicks randomly allocated to four groups, consisting of six replicates of 12 birds each, which was then denoted as CON group, diquat (DIQ) group (16 mg/kg BW diquat was injected into birds at the age of 21 days), magnolol (MAG) group (basic bird diet supplemented with 300 mg/kg magnolol), and MAG + DIQ group. At 21 days of age, broilers in the DIQ group and the MAG + DIQ group were intraperitoneally injected with 16 mg/kg BW diquat. Results showed that diet supplementing with MAG could alleviate the decrease of ADG to a certain extent after exposure to DIQ. Addition of magnolol to the diet alleviated the decrease of ADG during injection, antioxidant enzymes, and gene expression and increased the markers of oxidative damage induced by diquat induction. Magnolol supplement reversed the increase of apoptotic cells in the diquat-induced chicken jejunum. RNA sequencing showed that PI3K-Akt, calcium, and NF-kappa B signaling pathways were the main enrichment pathways between the DIQ group and the MAG + DIQ group. Our findings revealed that magnolol may improve antioxidant enzyme activity and expression of related genes through the PI3K-Akt pathway to alleviate oxidative stress.


The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis.
Classic anti-glomerular basement membrane (GBM) disease presents with rapidly progressive glomerulonephritis (GN) with or without pulmonary hemorrhage. On biopsy typical disease displays bright polytypic linear GBM staining for IgG by immunofluorescence and diffuse crescentic/necrotizing GN on light microscopy. Here, we studied 20 patients with atypical anti-GBM nephritis typified by bright linear GBM staining for immunoglobulins but without a diffuse crescentic phenotype. Patients had hematuria, proteinuria, and mild renal insufficiency, without pulmonary hemorrhage. Light microscopy showed endocapillary proliferative GN in 9 patients, mesangial proliferative GN in 6, membranoproliferative GN in 3, and focal segmental glomerulosclerosis with mesangial hypercellularity in 2. Eight of the 20 showed features of microangiopathy. Crescents/necrosis were absent in 12 and were focal in 8 patients. Bright linear GBM staining for IgG was seen in 17 patients, IgM in 2, and IgA in 1 patient, which was polytypic in 10 patients and monotypic in 10 patients. No circulating α3NC1 antibodies were detected by commercial ELISA. The 1-year patient and renal survival rates were 93% and 85%, respectively. Thus, atypical anti-GBM nephritis is a rare variant of anti-GBM disease characterized clinically by an indolent course, no pulmonary involvement, and undetectable circulating α3NC1 antibodies. Further studies are needed to characterize the molecular architecture of GBM autoantigens in these patients and establish optimal therapy.


The effect of respiratory care department management of a blood gas analyzer on the appropriateness of arterial blood gas utilization.
We investigated the effects of establishing a blood gas analysis service controlled by respiratory care practitioners (RCPs) on the appropriateness of arterial blood gas (ABG) sampling. An ABG analyzer was placed outside the surgical intensive care unit (SICU) and only RCPs were permitted to process samples on it. In 1-month and 1-year follow-up audits of appropriateness of ABG analysis, the nursing staff improved from 42% appropriate to 73% appropriate in both follow-up periods. RCPs maintained a high degree of appropriateness in all periods (90%, 87%, and 91%), although the percentage of the total ABGs performed by RCPs increased. Additional benefits included a better mutual understanding of each caregiver's role and work load, more collaboration among caregiver groups, and caregiver's perception of improved patient care.


Energy window stochastic density functional theory.
Linear scaling density functional theory is important for understanding electronic structure properties of nanometer scale systems. Recently developed stochastic density functional theory can achieve linear or even sublinear scaling for various electronic properties without relying on the sparsity of the density matrix. The basic idea relies on projecting stochastic orbitals onto the occupied space by expanding the Fermi-Dirac operator and repeating this for Nχ stochastic orbitals. Often, a large number of stochastic orbitals are required to reduce the statistical fluctuations (which scale as Nχ -1/2) below a tolerable threshold. In this work, we introduce a new stochastic density functional theory that can efficiently reduce the statistical fluctuations for certain observable and can also be integrated with an embedded fragmentation scheme. The approach is based on dividing the occupied space into energy windows and projecting the stochastic orbitals with a single expansion onto all windows simultaneously. This allows for a significant reduction of the noise as illustrated for bulk silicon with a large supercell. We also provide theoretical analysis to rationalize why the noise can be reduced only for a certain class of ground state properties, such as the forces and electron density.


Size and genomic location of the pMGA multigene family of Mycoplasma gallisepticum.
The pMGA multigene family encodes variant copies of the cell surface haemagglutinin of Mycoplasma gallisepticum. Quantitative Southern blotting, using an oligonucleotide probe complementary to a region conserved in the leader sequence of all known pMGA genes, was used to estimate the number of members of the family in the genome of seven strains of M. gallisepticum. The number of copies estimated to be present in the genome varied from 32 in strain F to 70 in strain R, indicating that the pMGA gene family may be second in size only to the tRNA family among prokaryotes. If all members of the pMGA family are of similar length to those which have been characterized, a minimum of 79 kb (7.7%) of the genome of strain S6, 82 kb (8.2%) of PG31 and 168 kb (16%) of the genome of strain R is dedicated to encoding variants of the same haemagglutinin. The GAA repeat motif identified in the intergenic region between all characterized pMGA genes appeared to be a feature common to most, if not all, pMGA genes, and furthermore probably exclusive to them. The genomic locations of members of the pMGA family were determined by PFGE and Southern blot hybridization of M. gallisepticum strain S6. The hybridizing regions were localized to four separate regions on the chromosome. The pMGA genes are likely to be predominantly arranged as tandem repeats within these regions, similar to the restricted regions for which the genomic sequence has been determined.


Anticancer activity of novel unnatural synthetic isoprenoids.
The KRAS oncogene has a high prevalence in solid malignancies. Targeting KRAS and inappropriate activation of the MAPK pathway with novel drugs is of interest. This study developed and screened a library of compounds designed to inhibit KRAS signaling by altering prenyl function. To screen a library of novel farnesyl analogs for their anticancer activity in human lung cancer and breast cancer cell lines. To evaluate if the designed and actual pharmacology are congruent. Sixty-seven novel compounds were tested and 70% of them screened positive for activity in at least one cell line. Two active compounds inhibited phosphorylation of MAP kinase consistent with KRAS inhibition. Although 47 of the 67 novel agents screened positive for activity, none of them were highly potent. However, targeting RAS with compounds that compete with farnesyl and geranylgeranyl modification of the protein remains viable and further work is already underway to create second generation molecules.


Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: randomised clinical trial.
Plasmodium falciparum resistance has rendered chloroquine monotherapy ineffective in much of Africa, but data on alternative regimens are limited. We compared chloroquine+sulfadoxine-pyrimethamine, amodiaquine+sulfadoxine-pyrimethamine, and amodiaquine+artesunate for treatment of uncomplicated malaria in Kampala, Uganda. Of 1017 consecutive patients aged 6 months to 10 years with uncomplicated malaria who were screened, 418 were randomised to receive: chloroquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine, single dose); amodiaquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine; or amodiaquine and artesunate (4 mg/kg daily for 3 days). Primary efficacy outcomes were 28-day clinical failure risks, adjusted and unadjusted by genotyping to distinguish new infection and recrudescence. The primary safety endpoint was incidence of serious adverse events during follow-up. Analysis was intention to treat and per protocol. 18 patients were excluded before enrollment. Of those enrolled, 384 of 400 (96%) were assigned an efficacy outcome and 396 (99%) were assessed for safety. Risk of 28-day clinical treatment failure was significantly higher with chloroquine+sulfadoxine-pyrimethamine (44/125 [35%]) than with amodiaquine+sulfadoxine-pyrimethamine (12/129 [9%]; risk difference 26% [95% CI 16-36]; p<0.0001) or amodiaquine+artesunate (3/130 [2%]; 33% [24-42]; p<0.0001). The greater risk of clinical treatment failure with amodiaquine+sulfadoxine-pyrimethamine was balanced by a lower risk of new infection, resulting in a similar need for retreatment over 28 days for amodiaquine+sulfadoxine-pyrimethamine (17/129 [13%]) and amodiaquine+artesunate (16/130 [12%]; p=0.854). Serious adverse events were uncommon with all regimens. Risk of treatment failure with chloroquine+sulfadoxine-pyrimethamine was unacceptably high. Combinations of amodiaquine and sulfadoxine-pyrimethamine or artesunate were significantly more efficacious, and each regimen could be an appropriate alternative for treatment of uncomplicated malaria in Africa.


Effect of food safety training on behavior change of food handlers: A case of orange-fleshed sweetpotato purée processing in Kenya.
Sweetpotato purée processing is new to Kenya and a rapidly growing value addition activity among informal, small, and medium-sized food enterprises (SMEs) in sub-Saharan Africa (SSA). Inadequate knowledge of food safety and poor hygiene practices by food handlers, low level of compliance with Good Manufacturing Practices (GMPs), and microbial contamination are major food safety challenges in orange-fleshed sweetpotato (OFSP) purée processing in Kenya. The extent of food safety training in enhancing food safety in rural-based SMEs and food processing environments has not been fully investigated. This study aimed at evaluating the impact of food safety training on food safety knowledge and hygiene practices of food handlers and in control of microbial contamination in OFSP purée processing in Kenya. Pre- and post-food safety training assessments were conducted to determine food handler's (N = 14) knowledge and practices on food safety. Food, water, and swab samples (n = 62) from the processing environment were collected before and two months after the training and analyzed for food hygiene indicator microorganisms. The findings indicate a significant (p < 0.05) improvement in overall food safety knowledge and practices of food handlers after the training. Poor knowledge scores were exhibited on aspects of cross-contamination, cleaning, and sanitation but these significantly (p < 0.05) improved after the training. Similarly, microbial counts on food equipment surfaces, installations, personnel hands, and in the final product (OFSP purée) significantly (p < 0.05) declined to acceptable levels after the food safety training. Total counts, yeasts and molds, S. aureus, Enterobacteriaceae, and total coliforms counts in the packaged OFSP purée were 2.6, 1.8, 1.5, 1.9, and 1.2 LOG CFU/g respectively hence suitable for its current application as an ingredient in baked products. The findings from this study indicate food safety training as an appropriate tool for improving food handler's knowledge and hygiene practices as well as enhancing microbial safety and quality of processed foods in SMEs if necessary food safety support resources are provided.


Stifle osteochondritis dissecans in snow leopards (Uncia uncia).
Three snow leopard (Uncia uncia) cubs, female and male siblings and an unrelated female, had lameness attributed to osteochondritis dissecans (OCD) lesions noted at 6, 8, and 10 mo of age, respectively. All cubs were diagnosed with OCD via radiographs. The sibling cubs both had lesions of the right lateral femoral condyles, while the unrelated cub had bilateral lesions of the lateral femoral condyles. Subsequently, OCD was confirmed in all three cases during surgical correction of the lateral femoral condyle lesions via lateral stifle arthrotomies, flap removal, and debridement of the defect sites. Histopathology also supported the diagnosis of OCD. Postoperatively, the sibling cubs developed seromas at the incision sites and mild lameness, which resolved within a month. To date, two cubs have been orthopedically sound, while one of the sibling cubs has developed mild osteoarthritis. OCD has rarely been reported in domestic felids, and to the authors' knowledge these are the first reported cases of OCD in nondomestic felids.


Structural requirements for porphyrin inhibition of the hemin-controlled protein kinase and maintenance of protein synthesis in reticulocytes.
The role of hemin in the maintenance of protein synthesis in reticulocyte lysates was examined by comparing the effects of various porphyrins and metalloporphyrins on the protein kinase activity of the hemin-controlled repressor and on protein synthesis. The porphyrin requirements for maintenance of protein synthesis were relatively specific. Iron and cobalt metalloporphyrins sustained protein synthesis whereas other metalloporphyrins, metal-deficient porphyrins, and non-porphyrin precursor and degradation products of protoporphyrin IX were ineffective. These same compounds were examined for their effectiveness in inhibiting the protein kinase activity of the hemin-controlled repressor with initiation factor 2 (eIF-2). Most of the metalloporphyrins and porphyrins tested were inhibitory. The presence of the iron atom in the porphyrin was not essential for inhibition, but the maintenance of the integrity of the porphyrin ring was imperative. The porphyrins which inhibited the hemin-regulated protein kinase contained vinyl groups or ethyl groups, or were protonated in the 2- and 4-positions of the porphyrin ring, whereas those with bulky or acidic groups in these positions were ineffective. Precursor and degradation products of protoporphyrin IX and synthetic porphyrins modified at other positions had no effect on the enzyme. Both hemin and protoporphyrin IX inhibited phosphorylation of eIF-2 exogenously added to a reticulocyte lysate; however, hemin sustained protein synthesis in the lysate, whereas protoporphyrin IX did not. These results suggest that regulation of the protein kinase phosphorylating the alpha subunit of eIF-2 is not the only point at which hemin modulates protein synthesis in reticulocytes and reticulocyte lysates, since a correlation between inhibition of protein synthesis, inhibition of protein kinase activity, and phosphorylation of eIF-2 is not observed with all porphyrins.


Comparison of Methods Study between a Photonic Crystal Biosensor and Certified ELISA to Measure Biomarkers of Iron Deficiency in Chronic Kidney Disease Patients.
The total analytical error of a photonic crystal (PC) biosensor in the determination of ferritin and soluble transferrin receptor (sTfR) as biomarkers of iron deficiency anemia in chronic kidney disease (CKD) patients was evaluated against certified ELISAs. Antigens were extracted from sera of CKD patients using functionalized iron-oxide nanoparticles (fAb-IONs) followed by magnetic separation. Immuno-complexes were recognized by complementary detection Ab affixed to the PC biosensor surface, and their signals were followed using the BIND instrument. Quantification was conducted against actual protein standards. Total calculated error (TEcalc) was estimated based on systematic (SE) and random error (RE) and compared against total allowed error (TEa) based on established quality specifications. Both detection platforms showed adequate linearity, specificity, and sensitivity for biomarkers. Means, SD, and CV were similar between biomarkers for both detection platforms. Compared to ELISA, inherent imprecision was higher on the PC biosensor for ferritin, but not for sTfR. High SE or RE in the PC biosensor when measuring either biomarker resulted in TEcalc higher than the TEa. This did not influence the diagnostic ability of the PC biosensor to discriminate CKD patients with low iron stores. The performance of the PC biosensor is similar to certified ELISAs; however, optimization is required to reduce TEcalc.


The Opportunities and Challenges of Pragmatic Randomized Trials Using a Specialized Software: CloudTrials Project.
Pragmatic randomized trials are essential to improve knowledge of real world clinical practice. Pragmatic trials design reflect routine clinical care, which have advantages to initiate and conduct, compared to classical clinical trials. Trials help to: engage bedside clinicians, increase efficiency of patient recruitment and follow up, minimize loss to follow up and include technological patient reported outcomes. The objective is to describe the opportunities and challenges designing a specialized software to administrate pragmatic randomized trials.


Real-Time Magnetic Navigation of a Rotating Colloidal Microswarm Under Ultrasound Guidance.
Untethered microrobots hold great promise for applications in biomedical field including targeted delivery, biosensing, and microsurgery. A major challenge of using microrobots to perform in vivo tasks is the real-time localization and motion control using medical imaging technologies. Here we report real-time magnetic navigation of a paramagnetic nanoparticle-based microswarm under ultrasound guidance. A three-axis Helmholtz electromagnetic coil system integrated with an ultrasound imaging system is developed for generation, actuation, and closed-loop control of the microswarm. The magnetite nanoparticle-based microswarm is generated and navigated using rotating magnetic fields. In order to localize the microswarm in real time, the dynamic imaging contrast has been analyzed and exploited in image process to increase the signal-to-noise ratio. Moreover, imaging of the microswarm at different depths are experimentally studied and analyzed, and the minimal dose of nanoparticles for localizing a microswarm at different depths is ex vivo investigated. For real-time navigating the microswarm in a confined environment, a PI control scheme is designed. Image differencing-based processing increases the signal-to-noise ratio, and the microswarm can be ex vivo localized at depth of 2.2-7.8 cm. Experimental results show that the microswarm is able to be real-time navigated along a planned path in a channel, and the average steady-state error is 0.27 mm ( ∼ 33.7% of the body length). The colloidal microswarm is real-time localized and navigated using ultrasound feedback, which shows great potential for biomedical applications that require real-time noninvasive tracking.


Using multiple measurements of tissue to estimate subject- and cell-type-specific gene expression.
Patterns of gene expression, quantified at the level of tissue or cells, can inform on etiology of disease. There are now rich resources for tissue-level (bulk) gene expression data, which have been collected from thousands of subjects, and resources involving single-cell RNA-sequencing (scRNA-seq) data are expanding rapidly. The latter yields cell type information, although the data can be noisy and typically are derived from a small number of subjects. Complementing these approaches, we develop a method to estimate subject- and cell-type-specific (CTS) gene expression from tissue using an empirical Bayes method that borrows information across multiple measurements of the same tissue per subject (e.g. multiple regions of the brain). Analyzing expression data from multiple brain regions from the Genotype-Tissue Expression project (GTEx) reveals CTS expression, which then permits downstream analyses, such as identification of CTS expression Quantitative Trait Loci (eQTL). We implement this method as an R package MIND, hosted on https://github.com/randel/MIND. Supplementary data are available at Bioinformatics online.


Primary Care's Historic Role in Vaccination and Potential Role in COVID-19 Immunization Programs.
Coronavirus disease 2019 (COVID-19) pandemic recovery will require a broad and coordinated effort for infection testing, immunity determination, and vaccination. With the advent of several COVID-19 vaccines, the dissemination and delivery of COVID-19 immunization across the nation is of concern. Previous immunization delivery patterns may reveal important components of a comprehensive and sustainable effort to immunize everyone in the nation. The delivery of vaccinations were enumerated by provider type using 2017 Medicare Part B Fee-For-Service data and the 2013-2017 Medical Expenditure Panel Survey. The delivery of these services was examined at the service, physician, and visit level. In 2017 Medicare Part B Fee-For-Service, primary care physicians provided the largest share of services for vaccinations (46%), followed closely by mass immunizers (45%), then nurse practitioners/physician assistants (NP/PAs) (5%). The Medical Expenditure Panel Survey showed that primary care physicians provided most clinical visits for vaccination (54% of all visits). Primary care physicians have played a crucial role in delivery of vaccinations to the US population, including the elderly, between 2012-2017. These findings indicate primary care practices may be a crucial element of vaccine counseling and delivery in the upcoming COVID-19 recovery and immunization efforts in the United States.


Neoadjuvant Chemotherapy is Associated With Decreased Survival in Early-Stage Gastric Cancer.
Although randomized controlled trials on neoadjuvant chemotherapy for gastric cancer have included some T1-staged tumors, overall survival (OS) has not been analyzed for this subset. Due to the low negative predictive value of clinical staging and the benefits of neoadjuvant chemotherapy for locally advanced disease, identifying patient groups with early-stage gastric cancer that may benefit from neoadjuvant chemotherapy is of merit. The objective of this study was to evaluate the relationship between OS and sequence of surgical therapy for clinical T1 gastric cancer. The 2017 National Cancer Database was used to compare patients who had surgery-first and those who received neoadjuvant chemotherapy for T1-stage gastric cancer. OS was analyzed using a parametric regression survival-time model adjusted for covariates. The effects of these covariates on OS based on surgical sequence were examined. 11,219 patients were included, of which 10,191 underwent surgery as their first or only treatment. When adjusted for covariates, neoadjuvant chemotherapy followed by curative-intent surgery was significantly associated with increased risk of death (HR 1.15, 95% CI 1.01-1.31, P = .030). In multivariate analysis, clinical N0 stage, non-minorities, and patients with high socioeconomic status had improved OS if they did not have neoadjuvant chemotherapy and instead had upfront surgery. Neoadjuvant chemotherapy is associated with decreased OS for early-stage gastric adenocarcinoma, even for patients with clinically positive nodal disease. In addition, the lack of survival improvement with a surgery-first approach in patients with disparities deserves further study.


Rehabilitation management of low back pain - it's time to pull it all together!
In the past, rehabilitation research initiatives for low back pain (LBP) have targeted outcome enhancement through personalized treatment approaches, namely through classification systems (CS). Although the use of CS has enhanced outcomes, common management practices have not changed, the prevalence of LBP is still high, and only selected patients meet the CS profile, namely those with a nociceptive context. Similarly, although practice guidelines propose some level of organization and occasionally a timeline of care provision, each mainly provides best practice for isolated treatment approaches. Moreover, there is no theoretical framework that has been proposed that guides the rehabilitation management process of mechanical LBP. In this commentary, we propose a model constituted of five domains (nociceptive drivers, nervous system dysfunction drivers, comorbidities drivers, cognitive-emotional drivers, and contextual drivers) grounded as mechanisms driving pain and/or disability in LBP. Each domain is linked to the International Classification of Functioning, Disability and Health, where once a patient is deemed suitable for rehabilitation, the clinician assesses elements of each domain in order to identify where the relative treatment efforts should be focused. This theoretical model is designed to provide a more comprehensive management overview, by appreciating the relative contribution of each domain driving pain and disability. Considering that the multiple domains driving pain and disability, and their interaction, requires a model that is comprehensive enough to identify and address each related issue, we consider that the proposed model has several positive implications for rehabilitation of this painful and highly prevalent musculoskeletal disorder.


SURGICAL INTERVENTION IN PATIENTS WITH IDIOPATHIC INFLAMMATORY BOWEL DISEASE AND PERIANAL DISEASE.
Aim: The aim of the study was to investigate the incidence of IBD in gastrointestinal surgery patients and record the disease's characteristics and treatment. Materials and Methods: A search was carried out in the archives of the gastroenterology clinics of the University General Hospital of Ioannina and the General Hospital of Ioannina "G. Hatzikosta" in Greece. All cases of operated patients from 1980 to 2018 were examined. The duration of the study was 4 months. Data were analyzed with the SPSS program, v.28. Results: The total sample consisted of 1464 patients (n=1464). Most of them (915-62.5%) came from the University General Hospital of Ioannina, while the rest (549-37.5%) came from the GHI hospital "G. Hatzikosta". The mean age of the patients was 47 years (M=47.26, SD=17.34, Min=<1 month, Max=95 years). From the total sample, 58 patients (4%) suffered from IBD; most were men (42-72.41%). Their mean age was approximately 50 years (M=49.63, SD=16.48, Min=25 years, Max=77 years, range=52 years) and most belonged to the age groups of 31-40 years (11 patients- 19.6%) and 21-30 years and 61-70 years (10 patients-17.9%). The perianal disease was present in 43.1% (25 patients). The most frequent type of operation was fistula resection, ligation, curettage-biopsy (24.1%) and opening-drainage (22.4%-13 patients) and the most frequent type of anesthesia was general anesthesia (93.1%-54 patients). Conclusions: This long-term study of the patients' data followed up over time showed that the possibility of surgery in patients with IBD is mitigated through systematic monitoring and multifaceted therapeutic treatment.The perianal disease which appeared more often in men shows that it can be diagnosed early and at an early stage and with the new minimally invasive techniques the patient with IBD can be treated with a better quality of life.


Remote electron and energy transfer sensitized photoisomerization of encapsulated stilbenes.
Excited state chemistry and physics of molecules, in addition to their inherent electronic and steric features, depend on their immediate microenvironments. This study explores the influence of an organic capsule, slightly larger than the reactant molecule itself, on the excited state chemistry of the encapsulated molecule. Results presented here show that the confined molecule, in fact, is not isolated and can be manipulated from outside even without direct physical interaction. Examples where communication between a confined molecule and a free molecule present outside is brought about through electronic and energy transfer processes are presented. Geometric isomerization of octa acid encapsulated stilbenes induced by energy and electron transfer by cationic sensitizers that attach themselves to the anionic capsule is examined. The fact that isomerization occurs when the sensitizer present outside is excited illustrates that the reactant and sensitizer are communicating across the molecular wall of the capsule. Ability to remotely activate a confined molecule opens up new opportunities to bring about reactions of confined radical ions and triplet excited molecules generated via long distance energy and electron transfer processes.


Twenty years' experience with the Swiss data registry for assisted reproductive medicine: outcomes, key trends and recommendations for improved practice.
The impact of assisted reproductive technology (ART) on Swiss demography was quantified. From 1993 to 2012 the number of deliveries, including multiples, generated by ART was compared with overall delivery numbers. Swiss experts in ART collaborated in a consensus to increase successful outcomes, to reduce the incidence of complications of ART and to validate recommendations through statistical review of available data. Data generated between 1993 and 2012 and published by the Federal Office of Statistics (BfS) were compared with the Swiss database on ART (FIVNAT-CH) as organised by the Swiss Society of Reproductive Medicine (SGRM). From these analyses a panel of Swiss experts in ART extracted recommendations to improve current practice, to prevent complications related to ART and to recommend changes in current Swiss legislation dealing with ART. Since 1993 the age of women giving birth rose together with the number of women asking for ART. This demographic trend was reflected in a rise in the number of deliveries generated by ART (in 2012: 2.2%) and the proportion of multiple births (in 2012: 17.6%). The outcome of ART was most negatively influenced by the age of the treated patient. The number of retrieved oocytes decisively impacted the likelihood of delivery, the risk of multiple births and the incidence of ovarian hyperstimulation syndrome. Optimal ovarian stimulation should be designed for the retrieval of 10 to 15 oocytes per treatment. Swiss legislation should enable and stimulate a policy of elective single embryo transfer to avoid multiple births.


GABAA receptors containing ρ1 subunits contribute to in vivo effects of ethanol in mice.
GABAA receptors consisting of ρ1, ρ2, or ρ3 subunits in homo- or hetero-pentamers have been studied mainly in retina but are detected in many brain regions. Receptors formed from ρ1 are inhibited by low ethanol concentrations, and family-based association analyses have linked ρ subunit genes with alcohol dependence. We determined if genetic deletion of ρ1 in mice altered in vivo ethanol effects. Null mutant male mice showed reduced ethanol consumption and preference in a two-bottle choice test with no differences in preference for saccharin or quinine. Null mutant mice of both sexes demonstrated longer duration of ethanol-induced loss of righting reflex (LORR), and males were more sensitive to ethanol-induced motor sedation. In contrast, ρ1 null mice showed faster recovery from acute motor incoordination produced by ethanol. Null mutant females were less sensitive to ethanol-induced development of conditioned taste aversion. Measurement of mRNA levels in cerebellum showed that deletion of ρ1 did not change expression of ρ2, α2, or α6 GABAA receptor subunits. (S)-4-amino-cyclopent-1-enyl butylphosphinic acid ("ρ1" antagonist), when administered to wild type mice, mimicked the changes that ethanol induced in ρ1 null mice (LORR and rotarod tests), but the ρ1 antagonist did not produce these effects in ρ1 null mice. In contrast, (R)-4-amino-cyclopent-1-enyl butylphosphinic acid ("ρ2" antagonist) did not change ethanol actions in wild type but produced effects in mice lacking ρ1 that were opposite of the effects of deleting (or inhibiting) ρ1. These results suggest that ρ1 has a predominant role in two in vivo effects of ethanol, and a role for ρ2 may be revealed when ρ1 is deleted. We also found that ethanol produces similar inhibition of function of recombinant ρ1 and ρ2 receptors. These data indicate that ethanol action on GABAA receptors containing ρ1/ρ2 subunits may be important for specific effects of ethanol in vivo.


Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer.
To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases. Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies. Foreign language papers were included. Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity. 95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted > or = 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates. In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.


Central Nomega-nitro-L-arginine methyl ester does not influence lithium-induced c-Fos and conditioned taste aversion.
LiCl at doses sufficient to induce conditioned taste aversion (CTA) causes c-Fos expression in the brain regions implicated in CTA formation. It has been reported that nitric oxide (NO) may play a role in CTA learning and LiCl increases both the synthesis and activity of NO synthase (NOS) in the brain. In this study, we examined the effect of central Nomega-nitro-L- arginine methyl ester (L-NAME) on the brain c-Fos expression and CTA learning induced by lithium in rats. In the results, intracerebroventricular L-NAME given prior to lithium did not change either the lithium-induced CTA or c-Fos in the relevant brain regions. This suggests that the brain NO system may not be involved in the neuronal activation during lithium-induced CTA formation.


Th17 Cells Participate in Thy1.1 Glomerulonephritis Which Is Ameliorated by Tacrolimus.
Thy1.1 glomerulonephritis (Thy1.1 GN) in rats is widely used as an experimental model of mesangial proliferative glomerulonephritis (GN). We previously reported that T-helper (Th) cells were accumulated in glomeruli from the early phase of this model and that not Th2 cells but Th1 cells play an important role in the development of glomerular alterations. Although Th17 is reported to be involved in the pathogenesis of several autoimmune diseases, the role of Th17 cells in the pathogenesis of mesangial alterations in Thy1.1 GN remains unclear. The kinetics of the infiltration of subsets of Th cells and the expression of IL-17 in Thy1.1 GN were analyzed. Next, the localization and the cell types of IL-17 receptor (IL-17R)-positive cells and IL-6-positive cells were analyzed. Then, the effect of tacrolimus on the expressions of Th17-related cytokines in Thy1.1 GN was analyzed. Not only Th1 cells but also Th17 cells were recruited into glomeruli from the early phase of the disease. mRNA expression of IL-17 in glomeruli was elevated. The increased positive expression of IL-17R was detected in the mesangial area, and some of IL-17R-positive cells were co-stained with IL-6. Tacrolimus treatment ameliorated mesangial alterations by suppressing the expressions of Th17-related cytokines such as IL-17 and IL-6. Th17 cells participate in the development of Thy1.1 GN, a mimic of mesangial proliferative GN, and Th17 cells and their related cytokines are pertinent therapeutic targets.


A comparison of the antiemetic efficacy of prochlorperazine and metoclopramide for the treatment of cisplatin-induced emesis: a prospective, randomized, double-blind study.
This study compared high-dose metoclopramide and prochlorperazine for their antiemetic activities in the treatment of patients with solid tumors receiving cisplatin-based cancer chemotherapy, in a prospective, double-blind fashion. Sixty patients were entered in the study, and 28 patients on each regimen were evaluable. For regimen 1, metoclopramide was given intravenously (IV) over 15 minutes at a dose of 2 mg/kg 30 minutes before, 30 minutes after, and three hours after treatment with cisplatin. In regimen 2, prochlorperazine was given IV 30 minutes before and three hours after the cisplatin; a placebo was administered at 30 minutes after cisplatin. There was no statistically significant difference between the two regimens in their antiemetic efficacies during the first three hours. For emesis that occurred from three to 24 hours after administration of cisplatin, prochlorperazine was marginally superior. The median number of emeses in the metoclopramide regimen was 2.5 (range, 0 to 10+) compared to 1.0 (range, 0 to 10+) in the prochlorperazine regimen. This is not a significant difference. The overall incidence of adverse reactions was greater in the metoclopramide regimen, with drowsiness being the most common toxicity for both antiemetic programs. Thus, IV high-dose metoclopramide and prochlorperazine are similar and effective in the management of cisplatin-induced emesis. IV prochlorperazine at 20-mg dosage is surprisingly effective.


Solid-phase processing of U2 snRNA precursors.
HeLa cell cytoplasmic extracts contain both precursors to small nuclear RNA (snRNA) U2 and an activity that is capable of trimming these snRNA precursors to the size of mature U2. The substrate for this RNA processing reaction is the ribonucleoprotein complex containing pre-U2 RNA. To circumvent the difficulty of biochemically isolating pre-U2 ribonucleoprotein (pre-U2 RNP) complexes for use as substrate for the analysis of the processing activity, we have developed a procedure for the processing of pre-U2 RNP complexes that have been immobilized on anti-Sm antibody/protein A-Sepharose columns. When the immobilized [3H]uridine-labeled substrate RNP complexes are incubated at 37 degrees C with unlabeled cytoplasmic extracts from HeLa cells, labeled molecules the size of mature U2 are produced in a linear fashion for up to 3 h. Similar results are obtained when substrate pre-U2 RNPs are immobilized with an anti-2,2,7-trimethylguanosine antibody. Thus, accurate processing of the 3' termini of U2 precursors occurs on the antibody columns. Incubation with buffer alone does not result in the production of mature-sized U2, indicating that the processing activity is not intrinsic to the pre-U2 RNP. Using this assay procedure, we have demonstrated that the processing activity is destroyed by trypsin or by preincubation at 65 degrees C but is resistant to treatment with micrococcal nuclease. These results are compatible with the conclusion that the processing activity is a classical enzyme that does not contain a nuclease-sensitive essential RNA component.


The CONSTANS-like 4 transcription factor, AtCOL4, positively regulates abiotic stress tolerance through an abscisic acid-dependent manner in Arabidopsis.
The precise roles of the B-box zinc finger family of transcription factors in plant stress are poorly understood. Functional analysis was performed on AtCOL4, an Arabidopsis thaliana L. CONSTANS-like 4 protein that is a putative novel transcription factor, and which contains a predicted transcriptional activation domain. Analyses of an AtCOL4 promoter-β-glucuronidase (GUS) construct revealed substantial GUS activity in whole seedlings. The expression of AtCOL4 was strongly induced by abscisic acid (ABA), salt, and osmotic stress. Mutation in atcol4 resulted in increased sensitivity to ABA and salt stress during seed germination and the cotyledon greening process. In contrast, AtCOL4-overexpressing plants were less sensitive to ABA and salt stress compared to the wild type. Interestingly, in the presence of ABA or salt stress, the transcript levels of other ABA biosynthesis and stress-related genes were enhanced induction in AtCOL4-overexpressing and WT plants, rather than in the atcol4 mutant. Thus, AtCOL4 is involved in ABA and salt stress response through the ABA-dependent signaling pathway. Taken together, these findings provide compelling evidence that AtCOL4 is an important regulator for plant tolerance to abiotic stress.


[The effect of the dynamic component in the mechanical deformation of the vessels on the blood supply to the skeletal muscles].
Dynamic and static distension of the cat m. gastrocnemius by 10-20% of initial length induced similar hyperemia provided the same amplitude of the distension and a common impulse of passive strength are preserved. The post-elongation hyperemia did not depend on changes in the blood flow during distension or on increase in the number of dynamic components of the distension. Isolated application of muscle vibration induced post-vibration hyperemia whereas the combination of the 8-24 Hz vibration with continuous distension of the muscle exerted no effect on the parameters of the post-elongation hyperemia.


Identification of multiple transcription start sites in the human insulin-like growth factor-I gene.
We have localized four transcription initiation sites in the human insulin-like growth factor-I (IGF-I) gene. Two transcription start sites were identified which result in a longer and shorter version of the leader derived from the known exon 1 of the IGF-I gene. Transcription starting at the upstream transcription initiation site results in a leader exon 1 of about 1155 nucleotides (nt), whereas transcription starting at the downstream initiation site results in a leader of about 240 nt. The majority of the transcripts initiate at the latter site. We further identified a region in the human IGF-I gene between exons 1 and 2, which shows a high degree of homology with the rat IGF-I leader exon 1B. By means of the polymerase chain reaction (PCR) we detected human IGF-I mRNAs containing this novel leader. The corresponding exon was designated exon 1B according to the rat IGF-I gene terminology. PCR and RNase protection analyses identified two transcription start sites within this alternative leader exon 1B. Transcription initiated at the most upstream start site results in a leader of about 750 nt, whereas transcription starting at the downstream site is heterogeneous, resulting in leaders of 65-75 nt long. No consensus TATA-box or AT-rich regions are present immediately upstream of all four transcription start sites identified, nor are these regions particularly GC-rich. The IGF-I gene is known to be expressed differentially in a tissue- and development-specific fashion. Differential activation of multiple promoters could very well play a crucial role in IGF-I gene regulation.


Metagenomic analysis of the gastric microbiota cultivable from a patient with gastritis concomitant with Barrett's esophagus.
Barrett's esophagus is a distal metaplasia characterized by the transformation of squamous mucosa into columnar mucosa. This esophageal phenotype is a product not only of the chronic reflux of gastric acids, but also by microorganisms that colonize the oral cavity and stomach. Two classes of microbiota can be identified in Barrett's esophagus; microbiota type I is associated with the normal esophagus and type II with an inflamed esophagus. The present study describes the gastric microbiota of a patient with antral gastritis concomitant with Barrett's esophagus absent infection with Helicobacter pylori. Gastric biopsies were obtained following the protocol of Sydney and following ethical practices. The isolates were cultivated under microaerophilic conditions on Columbia Agar supplemented with IsoVitaleX™ and 7% sterile blood. Extracted DNA was sequenced using 454-GS and the results analyzed on the MG-RAST server. Gram negative isolates were found and bacteria resistant to levofloxacin, amoxicillin, tetracycline, erythromycin, and clarithromycin. The phyla Bacteroidetes, Firmicutes, Fusobacteria and Proteobacteria, the genus Bacteroides and the species group Bacteroides fragilis were most abundant. Functionally, the metabolism of carbohydrates, amino acids, and to a lesser extent, the metabolism of cofactors and vitamins were most dominant, and of which the enzymes β-glucosidase (EC 220.127.116.11), β-galactosidase (EC 126.96.36.199) and β-N-acetylhexosaminidase (EC 18.104.22.168) were most dominant. The findings of this study, because they are of only one case may probably suggest a possible pathogenic role, previously undescribed for Bacteroides fragilis, associated with human gastritis when concomitant esophageal pathology exists.


The impact of the COVID-19 pandemic on a recreational rainbow trout (Oncorhynchus mykiss) fishery.
There has been a recent flurry of publications describing the potential effects of the COVID-19 pandemic on both commercial and recreational fisheries. As of yet, studies have only provided insights from researchers or industry experts detailing perceived consequences, or from survey data indicating modifications in angler activity levels and behaviours. Using real recreational fisheries data from an ongoing radio telemetry study (2018-present), we explored changes in the relative exploitation rates of rainbow trout (Oncorhynchus mykiss; Walbaum 1792) in the Saugeen River, Ontario, a tributary to Lake Huron, before compared to during the pandemic. Restrictions on site access that affected the implementation of important management activities that usually support this popular fishery are also discussed. During the initial phase of complete public lock-downs imposed during spring 2020, angler exploitation rates decreased to half that reported prior to the pandemic. Fishway operations were temporarily suspended and hatchery efforts were interrupted. Once restrictions began to ease in fall 2020, there was an eight-fold increase in overall exploitation rate and a four and a half-fold increase in harvest rate compared to seasons prior to the pandemic. While the full impact of the ongoing pandemic on the Lake Huron fishery is not likely to be fully realized for several years, the potential effects on future return run sizes may need to be considered by fisheries managers monitoring trends in population escapement.


An iron(ii) spin-crossover metallacycle from a back-to-back bis-[dipyrazolylpyridine].
The syntheses of 4-mercapto-2,6-di(pyrazol-1-yl)pyridine (bppSH) and bis[2,6-di(pyrazol-1-yl)pyrid-4-yl]disulfide (bppSSbpp) are reported. In contrast to previously published "back-to-back" bis-[2,6-di(pyrazol-1-yl)pyridine] derivatives, which form coordination polymers with transition ions that are usually insoluble, bppSSbpp yields soluble oligomeric complexes with iron(ii) and zinc(ii). Mass spectrometry and DOSY data show that [{Fe(μ-bppSSbpp)}n](2n+) and [{Zn(μ-bppSSbpp)}n](2n+) form tetranuclear metallacycles in nitromethane solution (n = 4), although (1)H NMR and conductivity measurements imply the iron compound may undergo more fragmentation than its zinc congener. Both [{Fe(bppSH)2](2+) and [{Fe(μ-bppSSbpp)}n](2n+) exhibit thermal spin-crossover in CD3NO2 solution, with midpoint temperatures near 245 K. The similarity of these equilibria implies there is little cooperativity between the iron centres in the metallacyclic structures.


Drug dosing in renal disease.
Renal disease alters the effects of many drugs, particularly when active drug moieties are renally cleared. Drug doses should usually be reduced in renal disease in proportion to the predicted reduction in clearance of the active drug moiety. Patient factors to consider in adjusting drug doses include the degree of renal impairment and patient size. Drug factors to consider in adjusting doses include the fraction of the drug excreted unchanged in urine and the drug's therapeutic index. Estimates of renal function are useful to guide dosing of renally cleared drugs with medium therapeutic indices, but are not precise enough to guide dosing of drugs with narrow therapeutic indices. This article discusses principles of drug dose adjustment in renal disease.


Glypican1/2/4/6 and sulfated glycosaminoglycans regulate the patterning of the primary body axis in the cnidarian Nematostella vectensis.
Glypicans are members of the heparan sulfate (HS) subfamily of proteoglycans that can function in cell adhesion, cell crosstalk and as modulators of the major developmental signalling pathways in bilaterians. The evolutionary origin of these multiple functions is not well understood. In this study we investigate the role of glypicans in the embryonic and larval development of the sea anemone Nematostella vectensis, a member of the non-bilaterian clade Cnidaria. Nematostella has two glypican (gpc) genes that are expressed in mutually exclusive ectodermal domains, NvGpc1/2/4/6 in a broad aboral domain, and NvGpc3/5 in narrow oral territory. The endosulfatase NvSulf (an extracellular modifier of HS chains) is expressed in a broad oral domain, partially overlapping with both glypicans. Morpholino-mediated knockdown of NvGpc1/2/4/6 leads to an expansion of the expression domains of aboral marker genes and a reduction of oral markers at gastrula stage, strikingly similar to knockdown of the Wnt receptor NvFrizzled5/8. We further show that treatment with sodium chlorate, an inhibitor of glycosaminoglycan (GAG) sulfation, phenocopies knockdown of NvGpc1/2/4/6 at gastrula stage. At planula stage, knockdown of NvGpc1/2/4/6 and sodium chlorate treatment result in alterations in aboral marker gene expression that suggest additional roles in the fine-tuning of patterning within the aboral domain. These results reveal a role for NvGpc1/2/4/6 and sulfated GAGs in the patterning of the primary body axis in Nematostella and suggest an ancient function in regulating Frizzled-mediated Wnt signalling.


The outcomes of visualization and acupuncture on the quality of life of adult cancer patients receiving chemotherapy.
The use of complementary and alternative medicine (CAM) to treat cancer patients has increased around the world, and its benefits have been described. These therapies represent an important theme in oncology and have been used in parallel with conventional therapies. This study aimed to assess the outcomes of using relaxation with visualization and acupuncture on the quality of life of cancer patients undergoing chemotherapy treatment and to compare these outcomes with patients who did not choose to receive the intervention. Participants chose to be in either the intervention group (IG) or control group (CG). They completed the Quality of Life Questionnaire-Core 30 at the start and end of chemotherapy. The IG was chosen by 38 patients with different types of cancer who completed weekly relaxation with visualization and acupuncture sessions, whereas the CG was composed of 37 patients who did not receive the intervention. Statistically significant results evidenced an increase in global health and emotional and social functions and a decrease in fatigue and loss of appetite for the IG, and an increase in global health for the CG (P< or =.05). A highly significant difference was found when comparing the post-chemotherapy scores of the Quality of Life Questionnaire-Core 30 in the global health domain between the CG and the IG (P< or =.001), indicating positive outcomes of the CAM intervention. Adults with cancer are able to choose between involvement or not with this kind of CAM intervention. Global health could be improved by participating in this type of intervention.