Sedative effects and cardiorespiratory influences of intravenous flunitrazepam premedication.
Sedative effects and the influence on cardiorespiratory functions of flunitrazepam, 0.015 mg/kg intravenously, were studied in 13 healthy adult volunteers. Immediately after administration, 12 of the 13 subjects responded when their names were called, while one subject required gentle patting on the shoulder to evoke a response. The scores of EEG and electro-oculogram were decreased. Cardiorespiratory changes were mild and not significant clinically. Anterograde amnesia was remarkable. Equilibrium functions were normal at 180 min postdose. Only one subject complained of pain at injection. It was concluded that intravenous injection of 0.015 mg/kg flunitrazepam was an optimal dose for sedation in healthy adults.


Challenges of fluoride pollution in environment: Mechanisms and pathological significance of toxicity - A review.
Fluoride is an important trace element in the living body. A suitable amount of fluoride has a beneficial effect on the body, but disproportionate fluoride entering the body will affect various organs and systems, especially the liver, kidneys, nervous system, endocrine system, reproductive system, bone, and intestinal system. In recent years, with the rapid development of agriculture and industry, fluoride pollution has become one of the important factors of environmental pollution, and fluoride pollution in any form is becoming a serious problem. Although countries around the world have made great breakthroughs in controlling fluoride pollution, however fluorosis still exists. A large amount of fluoride accumulated in animals will not only produce the toxic effects, but it also causes cell damage and affect the normal physiological activities of the body. There is no systematic description of the damage mechanism of fluoride. Therefore, the study on the toxicity mechanism of fluoride is still in progress. This review summarizes the existing information of several molecular mechanisms of the fluoride toxicity comprehensively, aiming to clarify the toxic mechanism of fluoride on various body systems. We have also summerized the pathological changes of those organ systems after fluoride poisoning in order to provide some ideas and solutions to the reader for the prevention and control of modern fluoride pollution.


Men's hostile sexism and biased perceptions of intimate partners: fostering dissatisfaction and negative behavior in close relationships.
Hostile sexism (HS) expresses attitudes that characterize women who challenge men's power as manipulative and subversive. Does endorsing HS negatively bias perceptions of women's behavior and, in turn, create animosity within intimate relationships? Committed heterosexual couples reported on their own behavior and perceptions of their partner's behavior five times across a year (Study 1) and daily for 3 weeks (Study 2). Men who more strongly endorsed HS perceived their partner's behavior as more negative than was justified by their partner's reports. Furthermore, more negative perceptions of the partner's behavior mediated the links between men's HS and feeling more manipulated by their partners, behaving more negatively toward their partners, and lower relationship quality. This indicates that men who endorse HS behave more negatively toward intimate partners and experience lower relationship satisfaction because their antagonistic attitudes toward women in general permeate the way they perceive those partners.


The contribution of interoceptive signals to spatial orientation: A mini-review.
Humans' sensory systems work synergistically to allow us to determine where our head and body are relative to the environment. To date, most research on this topic has focused on the visual and vestibular systems. There has been much less research on the contributions of interoceptive signals to spatial orientation, so the overall picture of how spatial orientation works is incomplete. This gap in the literature is especially problematic for aviation and spaceflight, where spatial disorientation is more likely to occur due to less common gravity conditions (i.e. microgravity and hypergravity) and can lead to fatal errors. In the present manuscript we review and summarize the current literature on this topic. Based upon the available evidence it would seem that interoceptive signals, particularly patterns of fluid/organ displacement, may play a role in sensing where our body is relative to the environment. More research utilizing experimentally induced perturbations to interoceptive receptors is needed before quantitative conclusions regarding the role of these interoceptive receptors can be drawn.


Optimization of the medication-use process for fentanyl patches at a small community hospital.
To describe a community hospital pharmacy department's novel approach to addressing safe use of fentanyl patches in acute and subacute care patients. Beginning in 2017, improvement opportunities were identified within the medication-use process for fentanyl patches at Cleveland Clinic Euclid Hospital. Prescribing was addressed through development of a procedure requiring an opioid status verification by a pharmacist for all fentanyl patch orders. This procedure includes determination of indication, review of prior opioid use, and documentation within the medical record. At baseline in 2017, 11 of 45 fentanyl patches were initiated for acute pain. In the first year of the procedure, 1 of 13 orders was initiated for acute pain, and in the second year 2 of 24 orders for fentanyl patches were initiated for acute pain. With each review, the pharmacy department identified additional safety and clinical education opportunities. Subsequently, inventory and dispensing practices for patches were assessed. The hospital's inventory was decreased and dispensing practices were altered to mitigate accessibility of the patches. This resulted in a decrease of 73.65% in the on-hand quantity from 2018 to 2020. The overall morphine milligram equivalents (MME) per 24 hours of this dosage form available in the hospital were reduced from 56,073.6 MME in 2018 to 13,557.6 MME in 2020 (75.82% decrease). Evaluation of the fentanyl patch medication-use process and pharmacy-driven interventions resulted in an increase in appropriate utilization of fentanyl patches and a decrease in accessible MME of this potent dosage form.


A novel series of benzimidazole NR2B-selective NMDA receptor antagonists.
A series of novel benzimidazoles are discussed as NR2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists. High throughput screening (HTS) efforts identified a number of potent and selective NR2B antagonists such as 1. Exploration of the substituents around the core of this template identified a number of compounds with high potency for NR2B (pIC(50) >7) and good selectivity against the NR2A subunit (pIC(50) <4.3) as defined by FLIPR-Ca(2+) and radioligand binding studies. These agents offer potential for the development of therapeutics for a range of nervous system disorders including chronic pain, neurodegeneration, migraine and major depression.


Analysis of complex protein kinase B signalling pathways in human prostate cancer samples.
To provide a rational basis for targeted treatment approaches in prostate cancer deregulation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) system was analysed. In all, 45 patients with primary localized prostate cancer that underwent radical prostatectomy were included in the present study. Upon scoring of the pathological grade, expression and phosphorylation levels of PKB/Akt and relevant downstream targets were determined in tissue specimens by immunohistochemistry using specific antibodies against PTEN, PKB/Akt, its downstream targets, and the respective phosphorylated proteins. Most patients (>90%) had up-regulated expression and/or phosphorylation of PKB/Akt in the malignant tissue compared with the surrounding benign tissue, with a higher prevalence of increased phosphorylated PKB/Akt in patients with Gleason scores of > or =6 (100%) compared with those with Gleason scores of 4-5 (five of 13 patients), and in particular in patients with clinical progression. Up-regulated phosphorylation of PKB/Akt occurred either in association with loss or inactivation of PTEN or in a PTEN-independent manner. Enhanced phosphorylation levels of the PKB/Akt substrates glycogen synthase kinase 3, the mammalian target of rapamycin or the forkhead transcription factor like 1 (FKHRL1) were found in 29%, 42% and 40% of the tumours, respectively. Of these, only increased phosphorylated-FKHRL1 levels correlated with clinical progression. Interestingly, 80% of patients had a notable overexpression but not phosphorylation of the eucaryotic initiation factor 4E binding protein. Deregulation of p-PKB/Akt is common in localized prostate cancer and has a putative value as predictive marker for disease progression and as therapeutic target. However, as a consequence of the substantial heterogeneity in the expression and phosphorylation levels of relevant PKB/Akt effector pathways, for a rational use of specified inhibitors of the PI3K/PKB system a complex pattern testing of expression and activity of the respective target proteins for prediction of efficacy and prognosis seems mandatory.


Characteristics of binge eating among women in the community seeking treatment for binge eating or weight loss.
This study examined characteristics of binge eating among overweight women in the community seeking treatment for binge eating or weight loss. Five hundred and ninety-two women completed a telephone interview in which binge eating was thoroughly assessed. A large percentage of the sample (84.4%) reported features of binge eating consistent with the Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV) definition of a binge. A significantly higher rate of DSM-IV BED (33.6%) was found compared to previous studies. Eleven percent of the sample denied bingeing/purging (nonbinge eating disorder, NBED) and 55.4% of the sample reported other eating problems such as bingeing or purging. Women with binge eating disorder (BED) had a higher BMI, became overweight earlier, and reported more unhealthy weight control methods than NBED women. BED women also reported more current and past depression and suicidal ideation than NBED women. BED reported more maternal overweight than NBED, but BED and NBED participants did not differ in paternal overweight or parental eating disorders. Future studies should investigate the relationship between binge eating and suicidal ideation to better understand whether depression precedes or follows binge eating.


Sparse autoencoder-based feature extraction from TOF-SIMS image data of human skin structures.
Time-of-flight secondary ion mass spectrometry (TOF-SIMS) is a useful and versatile tool for surface analysis, enabling detailed compositional information to be obtained for the surfaces of diverse samples. Furthermore, in the case of two- or three-dimensional imaging, the measurement sensitivity in the higher molecular weight range can be improved by using a cluster ion source, thus further enriching the TOF-SIMS information. Therefore, appropriate analytical methods are required to interpret this TOF-SIMS data. This study explored the capabilities of a sparse autoencoder, a feature extraction method based on artificial neural networks, to process TOF-SIMS image data. The sparse autoencoder was applied to TOF-SIMS images of human skin keratinocytes to extract the distribution of endogenous intercellular lipids and externally penetrated drugs. The results were compared with those obtained using principal component analysis (PCA) and multivariate curve resolution (MCR), which are conventionally used for extracting features from TOF-SIMS data. This confirmed that the sparse autoencoder matches, and often betters, the feature extraction performance of conventional methods, while also offering greater flexibility.


Protein identification by mass spectrometric analyses of peptides.
The focus of this chapter is the isolation and analysis of subsets of proteins or subproteomes. These methodologies can be applied to address fundamental questions in many areas of biological research. Protocols are provided for common techniques that include protein isolation from mammalian cells and the subsequent identification of peptides derived from endogenous proteins by the action of proteases.


Non-pharmacological interventions for pollen-induced allergic symptoms: Systematic literature review.
Allergic diseases pose a health problem worldwide. Pollen are widespread aeroallergens which can cause symptoms like shortness of breath, cough, itchy eyes, or rhinitis. Apart from preventive measures and pharmacological treatment, also non-pharmacological interventions have been suggested to reduce symptoms. The objective of this work was to review studies investigating the effectiveness of non-pharmacologic interventions to reduce allergic symptoms. PubMed, EMBASE, and CENTRAL were systematically reviewed in July 2018 and April 2020. Several authors worked on the screening of titles, abstracts, and full texts. One author for each literature search performed the data extraction and the risk of bias assessment. Studies were included if they met the inclusion criteria defined by the PECOs. Studies which investigating the effect of non-pharmacologic interventions on patients with allergic rhinitis were included. Twenty-nine studies investigating eleven types of non-pharmacologic interventions to avoid and reduce allergic symptoms due to pollen exposure were included in this review. Out of all studies, seven studies addressed nasal rinsing and 22 included acupuncture, air filtering, artisanal tears, individual allergen avoidance advice, various nasal applications, self-hypnosis, rhinophototherapy, and wraparound sunglasses. Most studies had a high risk of bias and small sample sizes. There were only a few high-quality studies that give hints about the effectiveness of non-pharmacological interventions. For future research, more high-quality studies are required to confirm the effectiveness of simple, safe, and cost-effective interventions.


Sunflower seed oil combined with ginseng stem-leaf saponins as an adjuvant to enhance the immune response elicited by Newcastle disease vaccine in chickens.
The present study was to evaluate the adjuvant effect of sunflower seed oil containing saponins extracted from the stem and leaf of Panax ginseng C.A. Meyer (E515-D) on the immune response induced by an inactivated Newcastle disease virus (NDV) in chickens. The results showed that E515-D promoted significantly higher serum NDV-specific HI and neutralizing antibody responses, IFN-γ and IL-4 levels, and lymphocyte proliferative responses to Con A, LPS, and NDV antigen than the conventional adjuvant Marcol 52. Different adjuvant effect between E515-D and Marcol 52 may be attributed to different genes expressed in two groups. Transcriptome analysis of splenocytes showed that there were 1198 differentially expressed genes (DEGs) with 539 up and 659 down regulated in E515-D group while 1395 DEGs with 697 up and 698 down regulated in Marcol 52 group in comparison with the control group. Analysis of gene ontology (GO) term and kyoto encyclopedia of Genes and Genomes (KEGG) pathways showed that the predominant immune related pathways included "Toll-like receptor signaling pathway", "NOD-like receptor signaling pathway", "C-type lectin receptor signaling pathway", and "Phosphatidylinositol signaling system" in E515-D group while Marcol 52 were "NOD-like receptor signaling pathway", "Phagosome", and "Lysosome", and the most relevant DEGs in E515-D group were STAT1, STAT2, PI3K, and IL-6. Considering the excellent adjuvant activity and vegetable origin, E515-D deserves further study as an adjuvant for vaccines used in food animals.


[Chemical constituents from Daphne acutiloba].
To study the chemical constituents from Daphne acutiloba. The constituents were separated by column chromatography, and their structures were elucidated by spectroscopic data analyses. Fifteen compounds were isolated from the EtOAc extract and identified as wikstroelide M (1), vesiculosin (2), prostratin (3), 7-hydroxy-coumarin (4), 7,8-di-hydroxy-coumarin (5), isodaphnoside (6), daphnorine (7), rutamontine (8), daphnolin (9), daphneticin (10), (+)-pinoresinol-beta-D-glucoside (11), oleodapnone (12), oleodaphnal (13), ergosterol peroxide (14) and cholest-5-en-3beta-ol (15). All the compounds except for 4, 5 and 14 were obtained from the stems of this plant for the first time.


Assessment of right ventricular performance by pulsed Doppler echocardiography in patients after intraatrial repair of aortopulmonary transposition in infancy or childhood.
The purpose of this study was to determine whether measurement of aortic blood flow velocity and acceleration by pulsed Doppler ultrasound can be used to assess the global performance of the systemic right ventricle noninvasively in young patients who have undergone intraatrial repair of aortopulmonary transposition. The effect of age at surgery on right ventricular performance in these patients was also studied. Pulsed Doppler velocity profiles of aortic blood flow were analyzed at a mean age of 5.5 years in 24 patients who had undergone intraatrial repair of aortopulmonary transposition either in early infancy (mean age 3.4 +/- 1.3 weeks) or later (mean age 8.5 +/- 6.5 months). Velocity and acceleration variables in these patients were compared with the same variables in 24 age-matched normal subjects and with the performance of their own right ventricle as assessed by two-dimensional echocardiographic measurement of ejection fraction. The 12 patients who underwent early repair had a higher ejection fraction than did the 12 who underwent later repair (mean +/- SD 0.60 +/- 0.07 versus 0.42 +/- 0.10; p less than 0.001). Aortic flow velocity was similar in all patients. Aortic acceleration was normal in patients after early intraatrial repair of aortopulmonary transposition (20.8 +/- 2.3 m/s2), but was abnormally slow in patients after late repair (11.1 +/- 1.8 m/s2; p less than 0.001), thus suggesting that the latter group had diminished right ventricular performance. Concomitantly, acceleration time and ratio of acceleration time to ejection time were increased in patients after late repair.(ABSTRACT TRUNCATED AT 250 WORDS)


Autophagy Proteins ATG5 and ATG7 Are Essential for the Maintenance of Human CD34(+) Hematopoietic Stem-Progenitor Cells.
Autophagy is a highly regulated catabolic process that involves sequestration and lysosomal degradation of cytosolic components such as damaged organelles and misfolded proteins. While autophagy can be considered to be a general cellular housekeeping process, it has become clear that it may also play cell type-dependent functional roles. In this study, we analyzed the functional importance of autophagy in human hematopoietic stem/progenitor cells (HSPCs), and how this is regulated during differentiation. Western blot-based analysis of LC3-II and p62 levels, as well as flow cytometry-based autophagic vesicle quantification, demonstrated that umbilical cord blood-derived CD34(+) /CD38(-) immature hematopoietic progenitors show a higher autophagic flux than CD34(+) /CD38(+) progenitors and more differentiated myeloid and erythroid cells. This high autophagic flux was critical for maintaining stem and progenitor function since knockdown of autophagy genes ATG5 or ATG7 resulted in reduced HSPC frequencies in vitro as well as in vivo. The reduction in HSPCs was not due to impaired differentiation, but at least in part due to reduced cell cycle progression and increased apoptosis. This is accompanied by increased expression of p53, proapoptotic genes BAX and PUMA, and the cell cycle inhibitor p21, as well as increased levels of cleaved caspase-3 and reactive oxygen species. Taken together, our data demonstrate that autophagy is an important regulatory mechanism for human HSCs and their progeny, reducing cellular stress and promoting survival. Stem Cells 2016;34:1651-1663.


Structural basis of Dscam isoform specificity.
The Dscam gene gives rise to thousands of diverse cell surface receptors thought to provide homophilic and heterophilic recognition specificity for neuronal wiring and immune responses. Mutually exclusive splicing allows for the generation of sequence variability in three immunoglobulin ecto-domains, D2, D3 and D7. We report X-ray structures of the amino-terminal four immunoglobulin domains (D1-D4) of two distinct Dscam isoforms. The structures reveal a horseshoe configuration, with variable residues of D2 and D3 constituting two independent surface epitopes on either side of the receptor. Both isoforms engage in homo-dimerization coupling variable domain D2 with D2, and D3 with D3. These interactions involve symmetric, antiparallel pairing of identical peptide segments from epitope I that are unique to each isoform. Structure-guided mutagenesis and swapping of peptide segments confirm that epitope I, but not epitope II, confers homophilic binding specificity of full-length Dscam receptors. Phylogenetic analysis shows strong selection of matching peptide sequences only for epitope I. We propose that peptide complementarity of variable residues in epitope I of Dscam is essential for homophilic binding specificity.


Baricitinib restrains the immune dysregulation in patients with severe COVID-19.
BACKGROUNDPatients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK/STAT signaling pathways, which can be disabled by small molecules.METHODSWe treated a group of patients (n = 20) with baricitinib according to an off-label use of the drug. The study was designed as an observational, longitudinal trial and approved by the local ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTSWe provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1β, and TNF-α, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO2, fraction of inspired oxygen) ratio.CONCLUSIONThese data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.TRIAL REGISTRATIONClinicalTrials.gov NCT04438629.FUNDINGThis work was supported by the Fondazione Cariverona (ENACT Project) and the Fondazione TIM.


A new subterranean species of Pseudocrangonyx from China with an identification key to all species of the genus (Crustacea, Amphipoda, Pseudocrangonyctidae).
A subterranean species of Pseudocrangonyx elegantulus Hou, sp. n. is described from caves of Wulongdong National Forest Park in Henan Province, China. Pseudocrangonyx elegantulus is characterized by both male and female with calceoli on antenna II; urosomite III dorsal margin without armature; uropod III with peduncle 0.30 times as long as outer ramus and terminal article of the outer ramus a little shorter than adjacent spines; telson cleft 0.27 of its length. Phylogenetic analysis based on 28S and COI sequences supported the species distinctness. A key to the genus Pseudocrangonyx with 22 species and a map of their distributions are provided.


Hyperfractionated split-course whole abdominal radiotherapy for ovarian carcinoma: tolerance and toxicity.
Whole abdominal irradiation after chemotherapy and second look laparotomy for advanced ovarian carcinoma is poorly tolerated because of hematologic toxicity that frequently necessitates interruption or abandonment of treatment. A new treatment strategy using a hyperfractionated split course schedule to deliver a total of 30 Gy in 30 fractions over 6 weeks was designed in an attempt to overcome this problem, while not compromising the tolerance of late reacting normal tissues. Of 23 patients treated between August 1984 and June 1986, only one failed to complete therapy as scheduled. Six patients with gross residual disease also received a limited field boost of 15 Gy in 15 fractions after completion of treatment to the whole abdomen. None of these six patients achieved disease control, and five required surgery for intestinal obstruction with pathologic evidence of radiation bowel injury. Of the 17 patients who received no boost, five developed gut obstructions associated with tumor recurrence and not attributable to irradiation. We conclude that whole abdominal irradiation using the hyperfractionated split course schedule without a boost is safe and feasible but its therapeutic efficacy appears confined to subsets of patients with no visible residual disease at the time of second look laparotomy, or in whom all visible residual tumor can be resected.


Clinical, Social and Demographics Factors Associated with Spiritual Wellbeing in End Stage Renal Disease.
Spiritual health is one of the important aspects of health status that is often neglected. the present study aims to evaluate spiritual wellbeing in end stage renal disease patients undergoing hemodialysis and its relation to sociodemographic and clinical variables. A convenience sample of 183 individuals undergoing hemodialysis was recruited. Measurements were conducted with the following instruments: (a) a sheet containing demographic data and clinical information such as duration of dialysis e.t.c (b) Facit Spiritual Wellbeing Scale (Facit-Sp12). Statistical analysis was contacted with SPSS v.22. Descriptive statistics were initially generated for sample characteristics. Parametric and no-parametric statistics were used for searching the relations between the variables. P values <0.05 were defined as reflecting the acceptable level of statistical significance. From the total of the 183 participants of the study the 69.9% were male and 30.1% female. The age range was from 26 to 88 years old, with mean 61.39 ± 14.11. The subscale "peace" is associated to gender (t = 2.150, p = 0.033), educational level (F = 2.698, p = 0.047) and duration of dialysis (F = 2.969, p = 0.033) and religious beliefs (t = -2.059, p = 0.041). The subscale "faith" is associated to gender (t = -3.428, p = 0.001), age (p = 0.006), number of children (F = 4.347, p = 0.014). Moreover, the subscale "meaning" is associated to age (p = 0.001). Finally its worth to be mentioned that comorbidity is associated to subscales "meaning" (t = -2.071, p = 0.040), "peace" (t = -2.377, p = 0.018) and the overall spiritual wellbeing (t = -1.988, p = 0.048). Social, demographic factors as well as clinical variables such duration of dialysis and comorbidities are affecting spiritual wellbeing in end stage renal disease.


Vasa vasorum in the carotid sinus of atherosclerotic monkeys: implications for baroreceptor function.
The carotid sinus is unusually susceptible to development of severe atherosclerotic lesions. The purposes of this study were to examine effects of atherosclerosis on blood flow through vasa vasorum in the carotid sinus and to examine responses to humoral stimuli. Blood flow to vasa in the carotid sinus was measured with microspheres in 8 normal and 9 atherosclerotic cynomolgus monkeys. Blood flow to vasa in intima-media (in ml/min per 100 g) was 0.5 +/- 0.3 (mean +/- SE) in normal and 21 +/- 5 in atherosclerotic monkeys (P less than 0.05). Flow to adventitial vasa was 37 +/- 5 in normal monkeys and 50 +/- 7 in atherosclerotic monkeys (P greater than 0.05). Infusion of phenylephrine did not affect blood flow in normal or atherosclerotic monkeys. Infusion of serotonin did not affect blood flow to vasa in normal monkeys, but decreased flow to vasa in both intima-media and adventitia of atherosclerotic monkeys. In normal media, histological examination demonstrated the presence of a few vasa vasorum, which penetrated from adventitia. In atherosclerotic monkeys, medial vasa were much more frequent. Thus, (1) atherosclerosis produces marked increases in blood flow through vasa in intima-media of the carotid sinus, probably as a consequence of proliferation of vasa, and (2) in atherosclerotic monkeys, vasa constrict in response to serotonin. Based on these findings, we speculate that when serotonin is released as platelets aggregate at plaques in the carotid artery, serotonin may be delivered through vasa to nerves in the carotid sinus and thereby affect baroreceptor function.


Transitory and permanent visual field defects induced by occipital lobe seizures.
Visual field defects are rarely associated with epilepsy. We report two patients with a long history of cryptogenetic occipital epilepsy. Both patients suffer complex partial crises accompanied by concentric reduction of the visual field followed, in the first one, by a prolonged left homonymous hemianopsia, and in the second one, by a permanent right inferior quadrantopsia. Occipital and occipito-temporal epileptic activity has been registered between seizures in both patients, and in one patient also during the seizure itself. Differential diagnosis has been considered, especially with migraine.


Empirical Evidence on the Reliability of Lateral Supramalleolar Flap over Reverse Sural Flap for Local Soft Tissue Coverage of Dorsum of the Foot and Ankle Defects.
Background Soft tissue coverage of the distal foot and ankle region has been an area of debate due to the paucity of local flap options. To provide empirical evidence on the reliability of an underreported local alternative for foot and ankle defects, we aim to compare the lateral supramalleolar flap (LSMF) to the reverse sural flap (RSF). Methods During 2016-2019, 48 patients were divided randomly into two equal groups, LSMF and RSF groups respectively. The patients' demographic, surgical, and clinical outcome details were recorded and analyzed. Results Flap necrosis was found in five patients in the group treated with RSF and none in the LSMF group. The mean total number of stages in RSF group was significantly higher than in LSMF group ( p < 0.05). The mean operative time for patients in LSMF group was 85.8 ± 18.5 and 54.2 ± 11.2 in RSF group ( p < 0.05). Five patients in the RSF group needed additional procedures following flap complications. Nine patients in the LSMF group reported satisfaction outcomes to be "excellent," five patients reported "good" whereas, in the RSF group, 14 patients reported "excellent," 5 reported "good," 3 reported "fair," and 2 reported "poor" outcomes. Compared to the RSF (46.4 ± 4.3) group, the LSMF group had significantly better foot function indices (34.03 ± 3.9). Conclusion The lateral supramalleolar flap for foot and ankle defects offers better results, reduced complications as well a lesser number of stages and secondary procedures over the traditionally used reverse sural flap.


The early development and physiology of Xenopus laevis tadpole lateral line system.
Xenopus laevis has a lateral line mechanosensory system throughout its full life cycle, and a previous study on prefeeding stage tadpoles revealed that it may play a role in motor responses to both water suction and water jets. Here, we investigated the physiology of the anterior lateral line system in newly hatched tadpoles and the motor outputs induced by its activation in response to brief suction stimuli. High-speed videoing showed tadpoles tended to turn and swim away when strong suction was applied close to the head. The lateral line neuromasts were revealed by using DASPEI staining, and their inactivation with neomycin eliminated tadpole motor responses to suction. In immobilized preparations, suction or electrically stimulating the anterior lateral line nerve reliably initiated swimming but the motor nerve discharges implicating turning was observed only occasionally. The same stimulation applied during ongoing fictive swimming produced a halting response. The anterior lateral line nerve showed spontaneous afferent discharges at rest and increased activity during stimulation. Efferent activities were only recorded during tadpole fictive swimming and were largely synchronous with the ipsilateral motor nerve discharges. Finally, calcium imaging identified neurons with fluorescence increase time-locked with suction stimulation in the hindbrain and midbrain. A cluster of neurons at the entry point of the anterior lateral line nerve in the dorsolateral hindbrain had the shortest latency in their responses, supporting their potential sensory interneuron identity. Future studies need to reveal how the lateral line sensory information is processed by the central circuit to determine tadpole motor behavior.NEW & NOTEWORTHY We studied Xenopus tadpole motor responses to anterior lateral line stimulation using high-speed videos, electrophysiology and calcium imaging. Activating the lateral line reliably started swimming. At high stimulation intensities, turning was observed behaviorally but suitable motor nerve discharges were seen only occasionally in immobilized tadpoles. Suction applied during swimming produced a halting response. We analyzed afferent and efferent activities of the tadpole anterior lateral line nerve and located sensory interneurons using calcium imaging.


Dietary Uptake and Depuration Kinetics of Perfluorooctane Sulfonate, Perfluorooctanoic Acid, and Hexafluoropropylene Oxide Dimer Acid (GenX) in a Benthic Fish.
Per- and poly-fluoroalkyl substances (PFAS) are ubiquitously distributed throughout aquatic environments and can bioaccumulate in organisms. We examined dietary uptake and depuration of a mixture of 3 PFAS: perfluorooctanoic acid (PFOA; C8 HF15 O2 ), perfluorooctane sulfonate (PFOS; C8 HF17 SO3 ), and hexafluoropropylene oxide dimer acid (HPFO-DA; C6 HF11 O3 ; trade name GenX). Benthic fish (blue spot gobies, Pseudogobius sp.) were fed contaminated food (nominal dose 500 ng g-1 ) daily for a 21-d uptake period, followed by a 42-d depuration period. The compounds PFOA, linear-PFOS (linear PFOS), and total PFOS (sum of linear and branched PFOS) were detected in freeze-dried fish, whereas GenX was not, indicating either a lack of uptake or rapid elimination (<24 h). Depuration rates (d-1 ) were 0.150 (PFOA), 0.045 (linear-PFOS), and 0.042 (linear+branched-PFOS) with corresponding biological half-lives of 5.9, 15, and 16 d, respectively. The PFOS isomers were eliminated differently, resulting in enrichment of linear-PFOS (70-90%) throughout the depuration period. The present study is the first reported study of GenX dietary bioaccumulation potential in fish, and the first dietary study to investigate uptake and depuration of multiple PFASs simultaneously, allowing us to determine that whereas PFOA and PFOS accumulated as expected, GenX, administered in the same way, did not appear to bioaccumulate. Environ Toxicol Chem 2020;39:595-603. © 2019 SETAC.


On fitness in structured metapopulations.
In this paper we derive a general expression measuring fitness in general structured metapopulation models. We apply the theory to a model structured by local population size and in which local dynamics is explicitly modelled. In particular, we calculate the evolutionarily stable dispersal strategy for individuals that can assess the local population density in the case where only dispersal is subject to evolutionary control but all other model in gredients are assumed fixed. We show that there exists a threshold size such that at ESS everyone should stay as long as the population size is below the threshold and everyone should disperse immediately as the population size reaches the threshold.


Absolute configuration for 1,n-glycols: a nonempirical approach to long-range stereochemical determination.
The absolute configurations of 1,n-glycols (n = 2-12, 16) bearing two chiral centers were rapidly determined via exciton-coupled circular dichroism (ECCD) using a tris(pentafluorophenyl)porphyrin (TPFP porphyrin) tweezer system in a nonempirical fashion devoid of chemical derivatization. A unique "side-on" approach of the porphyrin tweezer relative to the diol guest molecule is suggested as the mode of complexation.


Psychophysically derived visual mechanisms in turtle. II--Spatial properties.
Visual mechanisms isolated in Pseudemys by the two-color threshold technique of Stiles show peak wavelength sensitivities at 650 nm (red light) and 540 nm (green light). Ricco critical areas were measured for the two test wavelengths under three conditions: dark, moderate and intense backgrounds. As expected, critical spatial areas decreased with light adaptation. Under dark adaptation only rods and red-sensitive cones were operative, and one photon per 12 rods was sufficient for green-light threshold, as was one photon per four red-sensitive cones for red-light threshold. Rods apparently pool their information among the several receptors within the threshold area. Under light adaptation, rods were not functional and thresholds were determined by red-sensitive and green-sensitive cones alone. Cones did not share information over many receptors, requiring close to one photon per receptor to function at threshold.


[HPV vaccination is important for dermatologists].
The quadrivalent prophylactic HPV vaccination against HPV types 6, 11, 16 and 18 is not only highly effective in preventing HPV 16 and 18-associated cervical cancer, precancerous cervical lesions and high-grade precancerous vulvar and vaginal lesions but also against HPV 6 and 11-associated genital warts. Therefore, HPV-vaccination clearly belongs to the dermatologists' field of responsibility. A survey among 770 German dermatologists showed broad acceptance of the HPV vaccination; two-thirds of the persons asked would recommend the vaccination to their patients, regardless of reimbursement or STIKO recommendation, if they are convinced of the medical benefit. The survey also showed that HPV vaccination has not yet been fully established among dermatologists. Taking the high efficacy of the quadrivalent HPV vaccine into account, dermatologists should actively offer the HPV vaccination to their patients. The current AWMF-S3-guideline "Impfprävention HPV-assoziierter Neoplasien"can be used as a decision-making basis.


Isobolographic analysis of the interactions between midazolam and propofol at GABA(A) receptors in embryonic mouse neurons.
Clinical studies suggest that midazolam and propofol interact synergistically to induce hypnosis, but these drugs do not interact synergistically to prevent movement in response to noxious stimuli. The mechanisms underlying these interactions are not certain but may occur at the level of the gamma-aminobutyric acid A (GABA(A)) receptor. The authors evaluated the interactions between propofol and midazolam in modulating GABA(A) receptor activity in embryonic hippocampal neurons. The effects of midazolam and propofol on peak current evoked by submaximal concentrations of GABA were studied using the patch clamp method. Isobolographic analysis was undertaken by constructing concentration-response curves for midazolam and propofol alone and then evaluating the potency of combinations of midazolam and propofol. In other experiments, the concentration of GABA was increased and flurazepam was substituted for midazolam. Isobolographic analysis confirmed that midazolam and propofol interact synergistically to enhance currents evoked by low concentrations of GABA (1 microM). However, when the concentration of GABA was increased to 3 microM, the interaction was additive. The interaction between flurazepam and propofol was also additive for enhancement of currents evoked by 3 microM GABA. The interaction between midazolam and propofol was critically dependent on the concentration of GABA: Synergism was evident at low concentrations of GABA, but an additive interaction was apparent when the concentration of GABA was increased. Changes in GABA(A) receptor function may underlie the synergistic interaction between propofol and midazolam for clinical effects such as hypnosis. The clinical implication of the results is that the benefits of synergism observed at one concentration ratio of these drugs may not be apparent at another.


Changes produced by CT scanning in the outlook of severe head injury.
This is a study of the changes that have occurred in the field of severe head injury since the advent of CT scanning, comparing two homogeneous series of patients selected by clinical status (Glasgow Coma Scale less than or equal to 8), namely a series of 1,000 cases admitted to our Department between 1973 and 1976, already published in this Journal, and one of 385 cases cared for between 1979 and 1980, when CT scanning had become generally available. The two series of patients compare very closely in many respects, particularly in the incidence of surgical cases. In the more recent series the overall outcome was better both in surgical and in non-surgical cases. Among patients in the CT scan series the incidence of brain contusion associated with haematoma was greater than that of pure subdural haematomas. In non-surgical patients the CT scan, unlike cerebral angiography, afforded better identification of traumatic lesions and the grouping of patients into homogeneous categories correlating with a given outcome. On admission, cerebral angiography and CT scanning were equally effective in detecting lesions of surgical import; later in the course of the illness, however, CT scanning proved far more effective in detecting changes, with fully 15% of the patients being referred for surgery in the light of repeat CT scan findings as opposed to only 4% undergoing surgery on the indications of repeat angiography. Also, in the new series the mean interval from injury to surgery was shorter, with 64% of patients being operated on within 6 hours of the injury.(ABSTRACT TRUNCATED AT 250 WORDS)


MtCOPT2 is a Cu+ transporter specifically expressed in Medicago truncatula mycorrhizal roots.
Arbuscular mycorrhizal fungi are critical participants in plant nutrition in natural ecosystems and in sustainable agriculture. A large proportion of the phosphorus, nitrogen, sulfur, and transition metal elements that the host plant requires are obtained from the soil by the fungal mycelium and released at the arbuscules in exchange for photosynthates. While many of the plant transporters responsible for obtaining macronutrients at the periarbuscular space have been characterized, the identities of those mediating transition metal uptake remain unknown. In this work, MtCOPT2 has been identified as the only member of the copper transporter family COPT in the model legume Medicago truncatula to be specifically expressed in mycorrhizal roots. Fusing a C-terminal GFP tag to MtCOPT2 expressed under its own promoter showed a distribution pattern that corresponds with arbuscule distribution in the roots. When expressed in tobacco leaves, MtCOPT2-GFP co-localizes with a plasma membrane marker. MtCOPT2 is intimately related to the rhizobial nodule-specific MtCOPT1, which is suggestive of a shared evolutionary lineage that links transition metal nutrition in the two main root endosymbioses in legumes.


New technologies and trends in sterilization and disinfection.
Continued improvements in low-temperature sterilization systems have resulted in reduced processing times and expanded capabilities for instrument reprocessing. As the relationship of environmental surface contamination and health care-associated infections has become more defined, area disinfection systems and antimicrobial surface technologies have emerged as new strategies for disinfection of surfaces.


Herpetiform pemphigus induced by penicillamine.
A patient with arthritis is described who developed a dermatitis herpetiformis-like rash after 8 months of D-penicillamine therapy and which cleared soon after the drug was discontinued. The histopathological findings were compatible with a diagnosis of pemphigus, showing intra-epidermal vesicles and spongiosis but no acantholysis. Intercellular antibody was detected by indirect immunofluorescence at the onset of the eruption (titre 1 in 160) and also found in serum taken prior to penicillamine treatment (titre 1 in 20). It is now well known that D-penicillamine can induce pemphigus. The findings reported here suggest the possibility that the patient was predisposed to develop the eruption before the drug was given.


Expression of the K74 Killer Toxin from Saccharomyces paradoxus Is Modulated by the Toxin-Encoding M74 Double-Stranded RNA 5' Untranslated Terminal Region.
Yeast killer toxins are widely distributed in nature, conferring a competitive advantage to the producer yeasts over nonkiller ones when nutrients are scarce. Most of these toxins are encoded on double-stranded RNAs (dsRNAs) generically called M. L-A members of the viral family Totiviridae act as helper viruses to maintain M, providing the virion proteins that separately encapsidate and replicate L-A and M genomes. M genomes are organized in three regions, a 5' region coding the preprotoxin, followed by an internal poly(A) stretch and a 3' noncoding region. In this work, we report the characterization of K74 toxin encoded on M74 dsRNA from Saccharomyces paradoxus Q74.4. In M74, there is a 5' upstream sequence of 141 nucleotides (nt), which contains regulatory signals for internal translation of the preprotoxin open reading frame (ORF) at the second AUG codon. The first AUG close to the 5' end is not functional. For K74 analysis, M74 viruses were first introduced into laboratory strains of Saccharomyces cerevisiae. We show here that the mature toxin is an α/β heterodimer linked by disulfide bonds. Though the toxin (or preprotoxin) confers immunity to the carrier, cells with increased K74 loads have a sick phenotype that may lead to cell death. Thus, a fine-tuning of K74 production by the upstream regulatory sequence is essential for the host cell to benefit from the toxin it produces and, at the same time, to safely avoid damage by an excess of toxin. IMPORTANCE Killer yeasts produce toxins to which they are immune by mechanisms not well understood. This self-immunity, however, is compromised in certain strains, which secrete an excess of toxin, leading to sick cells or suicidal phenotypes. Thus, a fine-tuning of toxin production has to be achieved to reach a balance between the beneficial effect of toxin production and the stress imposed on the host metabolism. K74 toxin from S. paradoxus is very active against Saccharomyces uvarum, among other yeasts, but an excess of toxin production is deleterious for the host. Here, we report that the presence of a 5' 141-nt upstream sequence downregulates K74 toxin precursor translation, decreasing toxin levels 3- to 5-fold. Thus, this is a special case of translation regulation performed by sequences on the M74 genome itself, which have been presumably incorporated into the viral RNA during evolution for that purpose.


Combination of adenosine A1 and A2A receptor blocking agents induces caffeine-like locomotor stimulation in mice.
The spontaneous locomotor activity of C57BL/6J mice was examined, using an automated detection system based on infra-red beams, after administration of caffeine (3-30 mg/kg, i.p.), the adenosine A(2A) receptor selective antagonist SCH 58261 (0.312-2.5 mg/kg, i.p.) and the A(1) selective antagonist DPCPX (1.25-5 mg/kg, i.p.). SCH 58261 failed to influence motor activity in mice habituated to the test environment. DPCPX produced a small increase in motility and locomotion (significant at the dose of 5.0 mg/kg), much weaker than that produced by caffeine. Combined administration of DPCPX (1.2 mg/kg, i.p.) and SCH 58261 (1.2 mg/kg, i.p.) produced stimulation of motility and locomotion comparable with the effect of caffeine (15 mg/kg, i.p.). In contrast to motility and locomotion, rearing counts were not significantly influenced by DPCPX, SCH 58261, their combination, or by caffeine. Caffeine (15 mg/kg, i.p.) caused an increase in NGFI-A mRNA (an immediate early gene was chosen as an index of neuronal activation) in the piriform cortex 4 h after injection. This effect was reproduced by the combination of A(1) and A(2A) receptor antagonist. It is hypothesised that the stimulatory effect of low doses of caffeine in C57BL/6J mice is due to concomitant blockade of both A(1) and A(2A) adenosine receptors.


[A comparative radioisotope study of calcium metabolism in bone and teeth of rats (author's transl)].
Investigations with bone-seeking radionuclides (47Ca, 99mTc-PP, 113Sn) in rats of different age demonstrated a true accumulation in teeth as compared to bone. Blood flow was evaluated by 99mTcO4 and 51Cr-Albumin. Differences of accumulation depended on the isotopes used and on the age of the animals.


Precise Mesoscopic Model Providing Insights into Polymerization-Induced Self-Assembly.
Self-assembly of copolymer is an important approach to obtain multifarious nanostructures. Polymerization-induced self-assembly (PISA) is a recently developed and powerful copolymer self-assembly strategy. However, some researchers have reported a different morphology prepared by PISA and the traditional copolymer self-assembly using the same copolymer system. In this work, to explore the mystery, we develop a precise mesoscopic dissipative particle dynamics (DPD) model to reveal insights into the PISA of poly(4-vinylpyridine)-b-polystyrene (P4VP-b-PS). It is observed that P4VP-b-PS nanotubes can be obtained via TSA rather than PISA, which is consistent with reported experimental results. By carefully investigating the dynamics of PISA under specific solvent and monomer conditions and different polymerization rates, we propose that combining excessive monomers with multistep PISA can help to enhance the morphological regulation ability of PISA and retain a high solid content simultaneously. The findings in this study not only provide a precise modeling method for investigating copolymer self-assembly but also serve as a rational guide for future studies toward optimization of the PISA strategy.


Structure-function relationships in the rat brainstem subnucleus interpolaris: II. Low and high threshold trigeminal primary afferents.
Prior studies indicate that vibrissa, guard hair, hairy skin, mucosa, and nociceptive trigeminal primary afferents give rise to morphologically distinct terminal arbors in the medullary dorsal horn. The present study describes the extent to which similar structure-function relationships exist in the rostrally adjacent subnucleus interpolaris (SpVi). Seventy-three axons were physiologically characterized and visualized by standard intra-axonal HRP labeling techniques. They responded to guard hair (GH) or vibrissa (VIB) deflection; gentle pressure applied to hairy skin (HS), glabrous skin (GS), lingual mucosa (LM), or an incisor (PER); or a noxious pinch of the face (NOX). Response latencies to trigeminal ganglion shocks were equivalent for all categories with low threshold receptive fields (mean = 0.44 ms), and these were significantly shorter than those of fibers with high threshold NOX receptive fields (mean = 0.88 ms). All axons gave off transversely oriented collaterals into SpVi with rostrocaudal discontinuities in their arbors. Collaterals were topographically organized. Axons innervating the rostral mouth and face terminated medially, and those that supplied the caudal face innervated successively more lateral SpVi. The dorsal face was represented in the ventral SpVi, whereas the ventral face and mouth were represented more dorsally. This transverse topography extended largely throughout the rostrocaudal extent of SpVi. VIB, GH, GS, and LM collaterals had similar configurations with circumscribed arbors. HS, PER, and NOX arbors had a "stringy" shape without a clear terminal focus, save for the fact that PER and NOX collaterals often terminated in rostrally displaced substantia gelatinosa at the level of the caudal SpVi. Analysis of variance, considering only those data from mystacial VIB, GH, and HS fibers, indicated significant differences for all of the following measures: number of collaterals, number of boutons per collateral, arbor area, arbor circumference, and arbor circularity (form factor). A similar analysis, considering all fiber types, indicated significant differences for only the following measures: number of collaterals, arbor area, and arbor circumference. Individual group comparisons between the more heavily sampled functional categories indicated that GH afferents had significantly fewer collaterals, fewer boutons per collateral, smaller arbor area, shorter arbor circumference, and more circular arbors than those of HS axons. VIB fibers tended to fall between GH and HS afferents with respect to number of collaterals, arbor area, circumference, and circularity. The remaining functional groups were not as orderly.(ABSTRACT TRUNCATED AT 400 WORDS)


Medical treatment with misoprostol for early failure of pregnancies after assisted reproductive technology: a promising treatment option.
To assess the success rate of misoprostol to induce abortion in early pregnancy failure and to define the factors associated with success of treatment. Prospective study. University-affiliated tertiary medical center. Two hundred twenty women with the diagnosis of blighted ovum or missed abortion with a crown-rump length (CRL) up to 25 mm (<9 w). Treatment protocol included two doses of 800 microg misoprostol given vaginally and orally in intervals of 24 to 72 hours. Failure was defined as surgical intervention because of retained gestational sac, severe pain or bleeding, or suspected retained products of gestation after menstruation. The treatment was successful in 77.2% (170/220) of the patients. Success rate was 72.5% (121/167) for pregnancies achieved spontaneously and 92.4% (49/53) among women who conceived after assisted reproductive technology (relative risk = 3.65: 95% confidence interval 1.378 to 9.667). Multivariate analysis showed that the risk of failure of medical abortion increased significantly for patients who had had at least five previous pregnancies (of them, three or more abortions) as compared with patients with one or two previous pregnancies only, and for those who conceived spontaneously as compared with pregnancies after ovulation induction. Medical treatment in early missed abortion is recommended especially for women with low gravidity and for those who conceived after assisted reproductive technology.


Immunology in the clinic review series; focus on type 1 diabetes and viruses: enterovirus, thymus and type 1 diabetes pathogenesis.
Thymus dysfunction, especially immune suppression, is frequently associated with various virus infections. Whether viruses may disturb the thymus function and play a role in the pathogenesis of autoimmune diseases is an open issue. Enteroviruses, especially Coxsackievirus B4 (CV-B4), have been largely suggested as potential inducers or aggravating factors of type 1 diabetes (T1D) pathogenesis in genetically predisposed individuals. Several pathogenic mechanisms of enterovirus-induced T1D have been suggested. One of these mechanisms is the impairment of central self-tolerance due to viral infections. Coxsackievirus-B4 is able to infect murine thymus in vitro and in vivo and to infect human thymus in vitro. Thymic epithelial cells and thymocytes are targets of infection with this virus, and several abnormalities, especially disturbance of maturation/differentiation processes, were observed. Altogether, these data suggest that CV-B infection of thymus may be involved in the pathogenesis of T1D. Further investigations are needed to explore this hypothesis.


The effect of iron supplementation on maternal iron deficiency anemia does not differ by baseline anemia type among Tanzanian pregnant women without severe iron deficiency anemia.
Whether anemia type modifies the risk of pregnancy and newborn outcomes and the effectiveness of iron supplementation is unclear. We examined the association of iron deficiency anemia (IDA) and non-iron deficiency anemia (NIDA) on the risks of these outcomes and the extent to which anemia type modifies the impact of prenatal iron supplementation. This was a secondary analysis of a placebo-controlled trial of iron supplementation among 1450 HIV-negative women in Tanzania. Eligibility criteria included gestational age < 27 weeks, hemoglobin > 85 g/L, and ferritin > 12 µg/L. Individuals were categorized as non-anemia, IDA or NIDA using hemoglobin, ferritin and CRP. Analyses were conducted using regression models and likelihood ratio tests. Compared to the non-anemia group, delivery hemoglobin was lower by 15 g/L (95% CI 10.9, 19.3) in the baseline IDA group, and 7.3 g/L (95% CI 3.1, 11.5) in the baseline NIDA group. The RRs of anemia severity, iron deficiency, placental malaria, stillbirths, perinatal mortality, birthweight, and preterm birth were not different among women in the baseline NIDA group (vs. non-anemia) compared to the baseline IDA group (vs. non-anemia). The difference in the mean delivery hemoglobin for iron supplementation and placebo arms was 8 g/L (95% CI 6, 11) in the non-anemia group, 7 g/L (95% CI 2, 13) in the NIDA group, and 16 g/L (95% CI 10, 22) in the IDA group. Iron supplementation is effective even among pregnant women with NIDA. NCT01119612 (May 7, 2010).


Nuclear location of phosphoglycerate mutase BB isozyme in rat tissues.
We have previously reported (Ureña et al. Eur. J. Cell Biol. 1990) that in skeletal muscle, type MM phosphoglycerate mutase isozyme is present in the nucleus as well as in the cytosol. To determine whether type BB phosphoglycerate mutase isozyme is also present in nucleus, the subcellular location of this isozyme was studied in different rat tissues by cell fractionation and immunogold techniques. With the aid of high affinity-purified anti-phosphoglycerate mutase BB isozyme antibodies, the isozyme was located in the nucleus of neuronal, astroglial and liver cells but not in the nucleus of oligodendroglial and endothelial cells. Biochemical studies on purified nuclear fractions also demonstrated the presence of phosphoglycerate mutase activity in the nucleus. Both immunocytochemical and biochemical techniques showed that nuclear phosphoglycerate mutase-specific activity depended on the type of cell.


Role of Resection in Glioblastoma Management.
Whenever possible, maximal safe resection is the first intervention for management of glioblastoma. Resection offers tissue for diagnosis, decompression of the brain, cytoreduction, and has been associated with prolonged survival in numerous retrospective studies. In this review, we provide a critical overview of the literature associating glioblastoma resection with survival. We discuss techniques that enhance extent of resection, and the role of clinical and surgeon-variables. At last, we analyze the covariates and confounders that might influence the relationship between extent of resection and survival for glioblastoma, as these might ultimately also influence outcomes and other therapeutic interventions tested in trials.


Effects of rapeseed meal on laying hens (Gallus domesticus) in relation to fatty liver-haemorrhagic syndrome and egg taint.
Fatty liver-haemorrhagic syndrome (FLHS) occurred in the controls and was modified in hens that received a diet containing 10 per cent rapeseed meal. This diet increased the extent and severity of the hepatic haemorrhage without affecting the reticulin content of the liver but decreased the body weight and liver lipid levels and so weakened the correlation between these parameters and haemorrhage score found in FLHS. Plasma aspartate transaminase and beta-glucuronidase activities tended to increase with the score. The rapeseed meal diet also produced thyroid hypertrophy and since this was greater in the hens that produced tainted eggs and was positively correlated with the trimethylamine (TMA) content of the eggs it was postulated that rapeseed meal goitrogens may be involved as secondary factors in producing the disturbance in TMA metabolism that causes the egg taint. This abnormality was associated with a reduction in the soluble protein content of the liver, which reflected a decrease in TMA oxidase activity, but was not related to hepatic haemorrhage, steatosis or reticulolysis, or to lipid levels and the activities of lysosomal enzymes and transaminases in the plasma.


Investigation of the relationship of the number, localization, and displacement of rib fractures with intrathoracic structures and abdominal solid organ complications using computed tomography.
This study aimed at evaluating the fracture properties, intrathoracic structures, and abdominal solid organ complications in patients with traumatic rib fractures. Chest CT images of 305 patients were retrospectively evaluated to determine the number and level of rib fractures and measure the magnitude of displacement. The relationship of rib fractures and displacement patterns with intrathoracic structures and abdominal solid organ complications was investigated. The fractures were most located in the fifth, sixth, and seventh ribs. The mean age of the patients with displaced fractures was statistically significantly higher than the non-displaced fracture group with pneumothorax, hemothorax or lung injury. RibScore was statistically significantly higher in patients with pneumothorax, hemothorax, and lung parenchyma injury, as well as those with liver, spleen, and kidney injury. Hepatic, splenic, and renal injuries were markedly higher in patients with displaced fractures, but this was not statistically significant. Spleen and kidney injuries were statistically significantly more frequent among the patients with the fractures of the 10th to 12th ribs. The rib fracture displacement cut-off values for pneumothorax, hemothorax, and lung injury were found to be 2.18 mm, 2.32 mm, and 2.82 mm, respectively. The presence of a displaced rib fracture is a strong predictor of intrathoracic complications. A more careful intrathoracic evaluation of rib fractures with more than 2 mm displacement will contribute to patient management.


Trastuzumab-based chemotherapy modulates systemic redox homeostasis in women with HER2-positive breast cancer.
Trastuzumab is an immunotargeting therapeutic against breast tumors with amplification of the human epithelial growth factor receptor 2 (HER2). HER2 patients naturally exhibit disruption in the pro-oxidant inflammatory profiling; however, the impact of trastuzumab-based chemotherapy in modulating this process is still unknown. Here we determined the systemic pro-inflammatory profile of women diagnosed with HER2-amplified tumors, undergoing trastuzumab-based chemotherapy (TZ), and compared the results with that of healthy controls (CTR) and untreated patients with HER2-amplified breast cancer (CA). The plasmatic inflammatory profile was assessed by evaluating pro-oxidant parameters such as lipid peroxidation, total antioxidant capacity (TRAP), levels of advanced oxidation protein products (AOPPs), nitric oxide (NO), C-reactive protein (CRP), and total thiol content. Markers of cardiac damage were also assessed. Our findings showed increased NO levels in TZ than that in either CA or CTR groups. Furthermore, TZ augmented TRAP and reduced total thiol than that of the CA group. Our data also revealed that AOPP levels were significantly higher in the TZ than the CA group. AOPP and the MB fraction of creatine-kinase (CKMB) levels were positively correlated in TZ patients. These findings suggest that trastuzumab-associated chemotherapy can modulate the pro-inflammatory markers of HER2-positive breast cancer patients to the levels found in healthy controls.


The pharmacokinetics of carbamazepine.
The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters: kabs = 0.176 +/- 0.209 h-1; k = 0.0203 +/- 0.0055 h-1; T1/2 = 37.5 +/- 13.1 h; VD = 0.825 +/- 0.1041 . KG-1; Clearance = 0.0163 +/- 0.0061 1 . kg-1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.


[Radio-chemotherapy in the treatment of non-operable brain tumors in children].
Twenty-seven pediatric patients (less than 13 years of age) with inoperable primary brain tumors, treated with combined radiotherapy and chemotherapy or radiotherapy alone between January 1976 and December 1987 have been reviewed. Overall survival for all patients and for patients with brain-stem tumors was 49% and 43%, respectively. An increased risk of infection was associated with adjuvant chemotherapy. However, there were no toxicity that resulted in death.


Ozone Quantification by Selected Ion Flow Tube Mass Spectrometry: Influence of Humidity and Manufacturing Gas of Ozone Generator.
The quantification of ozone by SIFT-MS was investigated in conditions suitable with an industrial emission context (high ozone demand, dry air/oxygen as the manufacturing gas of the ozone generator, and high humidity levels beyond saturation at room conditions). Ozone reacts with four negative precursor ions available in the SIFT-MS device (NO2-, O2-, HO-, and O-), each precursor ion having its specific domain of linearity. For a high ozone concentration range, only NO2- and O2- have resulted in a linear behavior (between 1 and 100 ppmv of O3 for NO2-, between 1 and 50 ppmv of O3 for O2-). No water interference was identified during ozone measurements by SIFT-MS using NO2- and O2- precursor ions, even with extreme humidity levels. The presence of nitrogen oxide contaminants (due to the use of dry air as the manufacturing gas of the ozone generator) affected the ozone quantification by SIFT-MS. It is critical for NO2- precursor ions, whose rate constant varied as a function of NO2 concentrations. With O2- precursor ion, ozone was successfully measured in the presence of nitrogen oxides; however, the secondary chemistry must be taken into account.


Differential inactivation of plant lauric acid omega- and in-chain-hydroxylases by terminally unsaturated fatty acids.
The microsomal fraction from Vicia sativa L. cv. Septimane contains a cytochrome P-450-dependent lauric acid omega-hydroxylase that is inactivated in a time-dependent, pseudo-first-order manner when the microsomes are incubated with 11-dodecynoic acid. The rate constant for the inactivation is approximately 4.3-4.8 X 10(-3) s-1. In contrast, the olefinic analog 11-dodecenoic acid is primarily a time-independent inhibitor of the omega-hydroxylase. 1-Aminobenzotriazole, 3-phenoxy-1-propyne, and 3-(2,4-dichlorophenoxy)-1-propyne, mechanism-based inactivators of cinnamic acid 4-hydroxylase, and 9-decenoic acid, a mechanism-based inactivator of the lauric acid in-chain hydroxylase, are at best poor inactivators of the omega-hydroxylase. Conversely, cinnamic acid 4-hydroxylase is only slightly affected by concentrations of 11-dodecynoic acid that completely inactivate the omega-hydroxylase. 11-Dodecynoic acid is thus a potent, relatively specific, inactivator of the V. sativa lauric acid omega-hydroxylase.


Thermodynamically consistent determination of free energies and rates in kinetic cycle models.
Kinetic and thermodynamic models of biological systems are commonly used to connect microscopic features to system function in a bottom-up multiscale approach. The parameters of such models-free energy differences for equilibrium properties and in general rates for equilibrium and out-of-equilibrium observables-have to be measured by different experiments or calculated from multiple computer simulations. All such parameters necessarily come with uncertainties so that when they are naively combined in a full model of the process of interest, they will generally violate fundamental statistical mechanical equalities, namely detailed balance and an equality of forward/backward rate products in cycles due to Hill. If left uncorrected, such models can produce arbitrary outputs that are physically inconsistent. Here, we develop a maximum likelihood approach (named multibind) based on the so-called potential graph to combine kinetic or thermodynamic measurements to yield state-resolved models that are thermodynamically consistent while being most consistent with the provided data and their uncertainties. We demonstrate the approach with two theoretical models, a generic two-proton binding site and a simplified model of a sodium/proton antiporter. We also describe an algorithm to use the multibind approach to solve the inverse problem of determining microscopic quantities from macroscopic measurements and, as an example, we predict the microscopic pKa values and protonation states of a small organic molecule from 1D NMR data. The multibind approach is applicable to any thermodynamic or kinetic model that describes a system as transitions between well-defined states with associated free energy differences or rates between these states. A Python package multibind, which implements the approach described here, is made publicly available under the MIT Open Source license.


Harnessing mitochondrial metabolism and drug resistance in non-small cell lung cancer and beyond by blocking heat-shock proteins.
Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the predominant histological subtype. Despite the emergence of targeted and immune-based therapies that have considerably improved the clinical outcomes of selected patients, the overall NSCLC survival rate remains poor. NSCLC patients experience clinical relapse mainly because of chemoresistance. One promising therapeutic approach is targeting specific molecular vulnerabilities that are associated with the metabolic reprogramming of cancer cells. This strategy relies on evidence that cancer cells rewire their metabolism to sustain their uncontrolled growth as well as invasive and metastatic properties, promoting adaptive resistance to chemo-radiotherapy. A critical component of this malignant transformation is the increased dependency on high levels of heat shock proteins (HSPs), which support the elevated protein folding demand and quality control of misfolded oncoproteins. Here, we provide an overview of the literature on metabolism reprogramming, deregulation of mitochondrion and on the role of HSPs in promoting malignancy in lung and other cancer types. A particular focus is dedicated to the role of mitochondrial HSP60 (HSPD1) in NSCLC metabolism and drug resistance for the potential development of new resistance-defying anti-HSP drugs.


Diagnostic and intraoperative immunoscintigraphy in ovarian cancer.
A new strategy for tumor detection using immunoscintigraphic techniques was used in an attempt to improve the diagnostic potential of conventional external immunoscintigraphy. Twelve patients who were strongly suspected to either suffer from primary or recurrent ovarian cancer were investigated as follows: radioimmuno-scintigraphy (RIS) by means of radiolabelled antibodies was performed in all patients prior to operation (first or second look). During the operative procedure, which always took place immediately after completion of the diagnostic RIS, a hand-held gamma-ray detection probe, especially developed for this purpose was used for the purpose of identifying radiolabelled tumor sites intra-operatively in the open abdomen. In 10 out of 12 of the investigated patients, Radioisotope-Assisted Surgery (RAS) could be performed successfully. The count rates in cancer sites ranged from 150-250 cts per 6 s vs. 30-50 cts per 6 s in normal tissues. While the presence of malignant-tumor sites could always be predicted by conventional RIS, RAS failed twice, but revealed more accurate information concerning the real extent of the disease.


Surveillance of suspected adverse reactions to natural health products in Italy.
Natural health products are promoted to the public as equally or more effective and less toxic than conventional drugs. However, some 'natural' medicines, and in particular some herbal medicines, are known to have adverse effects. The Italian Pharmacovigilance System, in charge of the Italian Medicines Agency, collects spontaneous reports only for registered drugs. The awareness of the need of surveillance of the safety of natural health products has stimulated the implementation of a suspected adverse reaction reporting system in Italy. The system has been set up by the Italian National Institute of Health. An ad hoc reporting form can be downloaded from different institutional web sites. Voluntary reports of suspected adverse reactions are sent to the National Institute of Health and are evaluated by a multidisciplinary group of experts. From April 2002 to March 2007, 233 spontaneous reports of suspected adverse reactions to natural health products were collected. A large proportion of suspected adverse reactions were serious: hospitalization was reported in 35% of forms; 6% reported life threatening clinical events and two fatal events were notified. About 50% of suspected adverse reactions were related to gastrointestinal, skin, psychiatric and nervous system disorders. Mainly herbal products (66%) were involved. Twenty-one cases of hepatitis of various seriousness were reported. Twenty-one reports were associated with 27 homeopathic preparations, mostly preparations containing mixtures of substances. Fourteen reports regarded suspected reactions to products containing propolis. Safety and efficacy of 'natural' medicines have not been thoroughly investigated. It is important to improve communication with the public on safety issues. Encouraging spontaneous reporting can contribute to improve awareness among health personnel and patients about the benefit-harm profile of these remedies.


Integrating computational and mixture-based screening of combinatorial libraries.
Mixture-based synthetic combinatorial library (MB-SCL) screening is a well-established experimental approach for rapidly retrieving structure-activity relationships (SAR) and identifying hits. Virtual screening is also a powerful approach that is increasingly being used in drug discovery programs and has a growing number of successful applications. However, limited efforts have been made to integrate both techniques. To this end, we combined experimental data from a MB-SCL of bicyclic guanidines screened against the κ-opioid receptor and molecular similarity methods. The activity data and similarity analyses were integrated in a biometric analysis-similarity map. Such a map allows the molecules to be categorized as actives, activity cliffs, low similarity to the reference compounds, or missed hits. A compound with IC(50) = 309 nM was found in the "missed hits" region, showing that active compounds can be retrieved from a MS-SCL via computational approaches. The strategy presented in this work is general and is envisioned as a general-purpose approach that can be applied to other MB-SCLs.


Measurement of arterial time-activity curve by monitoring continuously drawn arterial blood with an external detector: errors and corrections.
Accurate description of the arterial time-activity curve (ATAC) is of paramount importance in quantitative determination of the regional cerebral blood flow (rCBF) using positron tomography following bolus i.v. injection of 0-15 labeled water. Frequent manual sampling from an arterial catheter does not permit sampling in less than 5-sec intervals and runs the risk of missing the arrival time or the peak count. A continuous ATAC monitoring system has been developed. This system consists of a single bismuth germinate detector in a lead shield and a constant-flow aspirator. The arterial blood was drawn continuously from a catheter within the brachial artery into an extended tube and its activity was monitored by the detector as the detector time-activity curve (DTAC). Comparison with the manual sampling from the contralateral brachial artery in the same run revealed that the DTAC differed from the manual sampling not only in delayed arrival but also in the shape of the curve, which was dispersed because of viscosity and the width of the detector field of view. However, deconvolution of DTAC using the experimentally obtained system step response provided an accurate arterial time course, which successfully filled in the gaps of the manual sampling. Moreover, water and blood showed different dispersion in the step response, suggesting that the system function should be determined using blood or a fluid of similar hydrodynamic nature.


Bortezomib inhibited the progression of diffuse large B-cell lymphoma via targeting miR-198.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, which is an aggressive malignancy with high variance of clinical features and response to the treatment. The proteasome inhibitor bortezomib (BTZ) has been demonstrated to suppress the progression of DLBCL, however, the underlying molecular mechanisms by which BTZ regulates the growth of DLBCL cells remain largely unknown. Increasing evidence has suggested that microRNAs (miRNAs) are novel targets of anti-cancer drugs to modulate the progression of cancers. Here, we showed BTZ treatment significantly inhibited the proliferation of DLBCL CRL-2630 cells. Mechanistically, exposure of BTZ up-regulated the expression of miR-198 in DLBCL cells. Depletion of miR-198 significantly reversed the inhibitory effect of BTZ on the proliferation of CRL-2630 cells. To further characterize the involvement of miR-198 in BTZ-induced growth defects of CRL-2630 cells, the downstream targets of miR-198 were predicted with the bioinformatics tools. The results showed that miR-198 bound the 3'-untranslated region (UTR) of the high mobility group AT-hook 1 (HMGA1) and suppressed the expression of HMGA1 in DLBCL cells. Consistently, BTZ treatment decreased the level of HMAG1 and inhibited the migration of DLBCL cells. Our results provided the possible mechanism by which BTZ suppressed the growth of DLBCL cells.


The depressed P cycle contributes to the acquisition of ampicillin resistance in Edwardsiella piscicida.
Antibiotic-resistant bacteria are an increasingly serious threat to human health and aquaculture. To further explore bacterial antibiotic resistance mechanism, iTRAQ is used to identify a differential proteome in ampicillin-resistant LTB4 (LTB4-RAMP), a strain of Edwardsiella piscicida. A total of 102 differentially proteins with 50 upregulation and 52 downregulation are identified. Since many of these changes are related to metabolism, interactive pathways explorer(iPath) is used to understand a global differentially metabolic response in LTB4-RAMP. This analysis identifies a global depressed metabolic modulation as the most characteristic feature of LTB4-RAMP. Lower membrane potential and ATP in LTB4-RAMP than control support that the central carbon metabolism and energy metabolism are reduced. Since the pyruvate cycle (the P cycle) plays a key role in the central carbon metabolism and energy metabolism, further investigation focuses on the P cycle and shows that expression of genes and activity of enzymes in the P cycle are decreased in LTB4-RAMP. These results support the conclusion that the depressed P cycle contributes to the acquisition of ampicillin resistance in E.piscicida. These findings indicate that the combination of proteomics and iPath analysis can provide a global metabolic profile, which helps us better understand the correlation between ampicillin resistance and cellular metabolism. SIGNIFICANCE: The present study uses iTRAQ to explore ampicillin resistance mechanism in Edwardsiella piscicida and finds many of these differential abundances of proteins are related to metabolism. IPath further identifies a global depressed metabolic modulation and characterizes the reduced pyruvate cycle as the most characteristic feature of the ampicillin-resistant E. piscicida, which is supported by reduced expression of genes and activity of enzymes in the pyruvate cycle. Consisitently, lower membrane potential and ATP are detetced. These results reveal the metabolic mechanism of ampicillin resistance and provide a solid proof to revert the resistance by reprogramming metabolomics.


An enquiry into the mechanism by which substance P facilitates the phasic longitudinal contractions of the rabbit ileum.
1. The effect of substance P on the phasic longitudinal contractions of the isolated rabbit ileum has been investigated. The contractions were recorded isotonically. Substance P in concentrations below those which cause tonic contraction (0.2-2 nM) increased the height of the phasic contractions in a concentration-dependent fashion without affecting their frequency (8-12/min).2. The effect of substance P was inhibited by verapamil, ouabain, noradrenaline, and isoprenaline, but was unaffected by tetrodotoxin, atropine, D-2-ala,5-metenkephalin, somatostatin, and vasoactive intestinal polypeptide.3. Tetraethylammonium, which blocks voltage-dependent K(+) channels, enhanced the phasic contractile activity of the rabbit ileum in a manner quite similar to substance P, but the maximal response to tetraethylammonium was larger than that to substance P.4. The effect of matched concentrations of substance P and tetraethylammonium, which enhanced the phasic contractions to a similar extent, was investigated at various concentrations of K(+), Na(+), Ca(2+) and Cl(-) in the bathing medium. Both substance P and tetraethylammonium lost their ability to enhance the phasic contractions when K(+) was omitted from the medium or when its concentration therein was increased by a factor of 4, or when the NaCl concentration was reduced to less than 10%. The relative increase in phasic contractile activity evoked by substance P was smaller than that evoked by tetraethylammonium when more than 90% of the Cl(-) was replaced with propionate.5. Noradrenaline, in a concentration which just abolished the spontaneous phasic contractions (200-300 nM), reduced the enhancing effect of substance P on the phasic activity by 40-50%, but did not influence the effect of tetraethylammonium.6. These results indicate that substance P enhances the phasic longitudinal contractions of the isolated rabbit ileum by a direct action on the smooth muscle cells and that this effect is brought about by facilitation of the myogenically controlled action potential discharges in the ileum. Circumstantial evidence suggests that the underlying ionic mechanism of action of substance P is a decrease in K(+) and Cl(-) conductances.


A New Visual Trap for Rhagoletis cerasi (L.) (Diptera: Tephritidae).
The European cherry fruit fly, Rhagoletis cerasi (L.) (Diptera: Tephritidae), is the most important pest of sweet cherries in Europe. The aim of our experiments was to develop a new, cost-efficient, lead chromate-free and more eco-friendly trap for monitoring and mass trapping of R. cerasi. Five different-colored yellow panels and three different trap shapes were compared to a standard Rebell(®) amarillo trap in three experimental orchards in 2012. Trap color F, with a strong increase in reflectance at 500-550 nm and a secondary peak in the UV-region at 300-400 nm, captured significantly more flies than the standard Rebell(®) amarillo trap. Yellow traps with increased reflectance in the blue region (400-500 nm) were least attractive. Trap shape was of minor importance, as long as the object was three-dimensional and visible from all directions. Based on economic and practical considerations, a cylinder-shaped trap "UFA-Samen Kirschenfliegenfalle" was developed for commercial use and is currently under on-farm evaluation.


The incidence rate and characteristics of clinically diagnosed defecatory disorders in the community.
Defecatory disorders (DD) are defined by clinical and objective features of impaired rectal evacuation. The epidemiology of DD in the population is unknown, partly because many constipated patients do not undergo anorectal tests. Our objectives were to estimate the incidence rate and clinical features of DD in the community. We reviewed the medical records of all patients older than 16 years in Olmsted County, MN, who had constipation and underwent anorectal manometry from 1999 through 2008. Criteria for diagnosing DD were constipation for 6 months or longer and one of the following: (i) abnormal rectal balloon expulsion test; (ii) reduced or increased perineal descent; or (iii) two or more abnormal features with defecography or surface electromyography. Of 11 112 constipated patients, 516 had undergone anorectal tests; 245 of these (209 women, 36 men) had a DD. The mean (±SD) age at diagnosis was 44 years (±18) among women and 49 years (±19) among men. The overall age- and sex-adjusted incidence rate per 100 000 person-years was 19.3 (95% CI: 16.8-21.8). The age-adjusted incidence per 100 000 person-years was greater (p < 0.0001) in women (31.8, 95% CI: 27.4-36.1) than in men (6.6, 95% CI: 4.4-8.9). Prior to the diagnosis of DD, nearly 30% of patients had irritable bowel syndrome (IBS), 48% had a psychiatric diagnosis, 18% had a history of abuse, and 21% reported urinary and/or fecal incontinence. Among constipated patients, DD are fourfold more common in women than men and often associated with IBS and psychiatric diagnoses.


The complex of band 3 protein of the human erythrocyte membrane and glyceraldehyde-3-phosphate dehydrogenase: stoichiometry and competition by aldolase.
The cytoplasmic domain of band 3, the main intrinsic protein of the erythrocyte membrane, possesses binding sites for a variety of other proteins of the membrane and the cytoplasm, including the glycolytic enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and aldolase. We have studied the stoichiometry of the complexes of human band 3 protein and GAPDH and the competition by aldolase for the binding sites. In addition, we have tried to verify the existence of mixed band 3/GAPDH/aldolase complexes, which could represent the nucleus of a putative glycolytic multienzyme complex on the erythrocyte membrane. The technique applied was analytical ultracentrifugation, in particular sedimentation equilibrium analysis, on mixtures of detergent-solubilized band 3 and dye-labelled GAPDH, in part of the experiments supplemented by aldolase. The results obtained were analogous to those reported for the binding of hemoglobin, aldolase and band 4.1 to band 3: (1) the predominant or even sole band 3 oligomer forming the binding site is the tetramer. (2) The band 3 tetramer can bind up to four tetramers of GAPDH. (3) The band 3/GAPDH complexes are unstable. (4) Artificially stabilized band 3 dimers also represent GAPDH binding sites. In addition it was found that aldolase competes with GAPDH for binding to the band 3 tetramer, and that ternary complexes of band 3 tetramers, GAPDH and aldolase do exist.


Evaluation of the time-dependent antiproliferative activity and liver microsome stability of 3 phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as promising CYP1A1-dependent antimicrotubule prodrugs.
In this study, the antiproliferative activity of 3 phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) was assessed in a time-dependent manner together with their hepatic stability and metabolism using human, mouse and rat liver microsomes. CEU-818, -820 and -913 were selected as promising hit compounds. Their antiproliferative activity on human breast carcinoma MCF-7 cells was evaluated using escalating concentrations of drugs at 24, 36 and 48 h and the sulforhodamine B assay. Their hepatic stability was evaluated by HPLC-UV of extracts obtained from human, mouse and rat liver microsomes. The antiproliferative activity of PAIB-SOs is concentration and time-dependent and requires between 24 and 36 h of contact with MCF-7 cells to detect a significant antiproliferative activity. PAIB-SOs stability in microsomes usually decreases following this order: human ≈ (rat > mouse). The CEU-913 exhibits the longest half-life in rat and human liver microsomes while the CEU-820 exhibits the longest half-life in mouse liver microsomes. Our in vitro results suggest that PAIB-SOs should have a minimum contact time of 24 h with the tumour to trigger significant antitumoural activity. The activity of mouse liver microsomes towards PAIB-SOs is higher than rat microsomes and tends to be higher than human liver microsomes.


Genome-wide detection of CNVs in Chinese indigenous sheep with different types of tails using ovine high-density 600K SNP arrays.
Chinese indigenous sheep can be classified into three types based on tail morphology: fat-tailed, fat-rumped, and thin-tailed sheep, of which the typical breeds are large-tailed Han sheep, Altay sheep, and Tibetan sheep, respectively. To unravel the genetic mechanisms underlying the phenotypic differences among Chinese indigenous sheep with tails of three different types, we used ovine high-density 600K SNP arrays to detect genome-wide copy number variation (CNV). In large-tailed Han sheep, Altay sheep, and Tibetan sheep, 371, 301, and 66 CNV regions (CNVRs) with lengths of 71.35 Mb, 51.65 Mb, and 10.56 Mb, respectively, were identified on autosomal chromosomes. Ten CNVRs were randomly chosen for confirmation, of which eight were successfully validated. The detected CNVRs harboured 3130 genes, including genes associated with fat deposition, such as PPARA, RXRA, KLF11, ADD1, FASN, PPP1CA, PDGFA, and PEX6. Moreover, multilevel bioinformatics analyses of the detected candidate genes were significantly enriched for involvement in fat deposition, GTPase regulator, and peptide receptor activities. This is the first high-resolution sheep CNV map for Chinese indigenous sheep breeds with three types of tails. Our results provide valuable information that will support investigations of genomic structural variation underlying traits of interest in sheep.


Neurogenesis of glutamic acid decarboxylase immunoreactive cells in the hippocampus of the mouse. I: Regio superior and regio inferior.
The neurogenetic gradients of neurons showing glutamic acid decarboxylase (GAD) immunoreactivity were determined in the regio superior and in the regio inferior of the mouse hippocampus. Pregnant C57Bl mice received pulse injections of (3H)thymidine from E11 through E17 (E0 being the day of mating). Distributions of (3H)thymidine-labeled, GAD-positive neurons in the different strata of the hippocampus proper were recorded in adult animals. GAD-positive neurons in this region are generated prenatally. Radial gradients of neurogenesis of GAD-positive cells are characterized by two main features: 1) with the exception of the stratum lacunosum-moleculare and its interface with the stratum radiatum, GAD-positive neurons of the plexiform strata are generated before those destined for the pyramidal layer; 2) within the pyramidal layer, GAD-positive cells are positioned according to an inside-out sequence. In the transverse axis, neurogenesis of GAD-positive cells follows a regio inferior to regio superior gradient. This gradient is due to prolonged neurogenesis of GAD-positive cells for the pyramidal layer in the regio superior. Given the selective laminar disposition of the GABAergic interneurons in the hippocampus, the present authors explored whether or not the diverse types of these interneurons could have specific birth dates and concluded that no relationship exists between birth dates and adult phenotypes of GAD-immunoreactive cells in the mouse hippocampus proper.


Effect of aerobic exercise on cardiotoxic outcomes in women with breast cancer undergoing anthracycline or trastuzumab treatment: a systematic review and meta-analysis.
We aimed to assess the impact of aerobic exercise (AE) on parameters related to cardiotoxicity in breast cancer (BC) patients receiving anthracycline or trastuzumab. We performed a systematic review and meta-analysis of comparative studies on AE via the screening of standard databases from their inception to January 18, 2022. The risk of bias was assessed qualitatively using the domains outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Data were analyzed quantitatively using fixed effects meta-analysis and subgroup analysis in RevMan software. Notable outcomes included imaging outcomes of cardiotoxicity, cardiorespiratory fitness, and cardiac biomarkers. A meta-analysis of the pooled evidence obtained from seven studies revealed that AE significantly increased peak oxygen consumption (VO2 peak) and E/A values, compared to the values observed during usual care. Moreover, AE was safe and feasible, and was associated with a lower risk of adverse effects, a higher participation rate, and better results, when combined with resistance exercise. In BC patients receiving anthracyclines or trastuzumab, the effects of AE on the levels of cardiotoxicity were mixed; the diastolic functions and VO2 peak values were improved, biomarkers were not affected, and the overall improvements in the levels of cardiotoxicity were promising, despite the use of different exercise parameters.


Towards an ontological politics of drug policy: Intervening through policy, evidence and method.
Increasing attention has been paid to matters of ontology, and its accompanying politics, in the drug policy field. In this commentary, we consider what an 'ontological politics' might mean for how we think about what drug policy is and what it might become, as well as for how we think about (and do) research in drug policy. Thinking ontopolitically questions the tacitly accepted status of 'drug problems', calls into question the realist presumptions which underpin much drug policy analysis, and provokes thinking about what counts as 'evidence' and the 'evidence-based policy' paradigm itself. We call attention to the inventive possibilities of method when grappling with the challenges thrown forth by the ontological turn, with a renewed focus on practice and relations. An ontological politics disrupts consensual claims and draws critical attention to objects that might otherwise appear 'finished' or 'ready-made', not least the things we call 'drugs' and 'drug policy'. Working with 'drug policy multiples' invites new thinking and dialogue to provoke an ethico-political mode of intervention in the field of drug policy and drugs research.


From rare disorders of immunity to common determinants of infection: Following the mechanistic thread.
The immense interindividual clinical variability during any infection is a long-standing enigma. Inborn errors of IFN-γ and IFN-α/β immunity underlying rare infections with weakly virulent mycobacteria and seasonal influenza virus have inspired studies of two common infections: tuberculosis and COVID-19. A TYK2 genotype impairing IFN-γ production accounts for about 1% of tuberculosis cases, and autoantibodies neutralizing IFN-α/β account for about 15% of critical COVID-19 cases. The discovery of inborn errors and mechanisms underlying rare infections drove the identification of common monogenic or autoimmune determinants of related common infections. This "rare-to-common" genetic and mechanistic approach to infectious diseases may be of heuristic value.


Systemic and Splanchnic Lipopolysaccharide and Endothelin-1 Plasma Levels in Liver Cirrhosis before and after Transjugular Intrahepatic Portosystemic Shunt.
Lipopolysaccharide (LPS) and endothelin- (ET-) 1 may aggravate portal hypertension by increasing intrahepatic resistance and splanchnic blood flow. In the portal vein, after TIPS shunting, LPS and ET-1 were significantly decreased. Our study suggests that TIPS can benefit cirrhotic patients not only in high hemodynamics related variceal bleeding but also in intestinal bacterial translocation associated complications such as endotoxemia.


A populational connection distribution map for the whole brain white matter reveals ordered cortical wiring in the space of white matter.
The white matter in the brain is composed of neural fibers that wire the cortical and subcortical brain systems. Considering the complexity in terms of interconnections of many neural populations within the narrow space surrounded by the folding walls of the gray matter, the brain requires a certain way of structured wiring. To explore the three-dimensional organization of wiring in an accessible manner, we focused on voxel-level wiring patterns in the white matter according to cortical distributions in which each voxel mediates the wiring. We constructed a voxel-wise connection distribution map from the whole white matter voxels to 360 cortical regions using probabilistic tractography of the 100 diffusion imaging data in the Human Connectome Project. We then explored the spatial organization of the fiber bundles at the white matter voxels in terms of the maximal and second maximal cortical connection labels and the local gradient and entropy of cortical connection density using the population connection distribution map. We presented dominant cortical connection labels, local gradient, and connection entropy for the most representative white matter regions, including the internal capsule, external capsule, corpus callosum, cingulum bundle, and uncinate fascicles, most of which were introduced in the current study. Those major tracts showed a gradient organization of connection distributions for individual voxels. This organized pattern, as reflected in the whole brain connection distribution map, could be established to optimize wiring in the entire brain within the physical space of the white matter.