Prognostic implication of aquaporin 1 overexpression in resected lung adenocarcinoma.
Aquaporins (AQPs) are a group of transmembrane water-selective channel proteins thought to play a role in the regulation of water permeability for plasma membranes. Indeed, high AQP levels have been suggested to promote the progression, invasion and metastasis of tumours. Specifically, AQP1 and AQP5 overexpression in lung adenocarcinoma (AC) have been suggested to be involved in molecular mechanisms in lung cancer. The aim of this retrospective cohort single-centre study was to assess both the levels of expression and therein the prognostic significance, regarding outcome of AQP1 and AQP5 in resected AC patients. Patients with histological diagnoses of lung AC submitted to pulmonary resection were included in this cohort study. Tissue microarrays containing cores from 185 ACs were prepared. AQP1 and AQP5 expressions were assessed by immunohistochemistry. Results were scored as either low (Score 0-2) or high (Score 3-9). Clinical data, pathological tumour-node-metastasis staging and follow-up were recorded. Multivariate Cox survival analysis and Fisher's t-test were performed. AQP1 overexpression was detected in 85 (46%) patients, while AQP5 overexpression was observed in 45 (24%) patients. AQP1 did not result being significantly correlated with clinical and pathological parameters, while AQP5 resulted more expressed in AC with mucinous and papillary predominant patterns. Patients with AQP1 overexpression had shorter disease-free survival (P = 0.001) compared with patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter disease-free survival (P = 0.001). Our results evidenced that AQP1 overexpression resulted in a shorter disease-free survival in lung AC patients. Being so, AQP1 overexpression might be an important prognostic marker in lung AC.


Dissection plane of the human vocal fold lamina propria and elastin fibre concentration.
To determine whether a natural plane of dissection occurs in the normal human vocal fold, semi-blunt instruments (Bouchayer laryngeal dissectors) were used to dissect the lamina propria. The depth of the plane of dissection was correlated with the elastin fibre concentration to determine whether the plane occurred at a predictable point in the elastin concentration as it increased between the superficial and middle layers. Eight human larynges were dissected using an operative microscope. The dissection plane consistently occurred between 23-50% depth into the lamina propria. No consistent correlation was found with the elastin fibre concentration. The depth of the plane of dissection has an interesting association with age: dissection planes occurred more superficially in older specimens.


State-of-the-Art Molecular Plant Biology Research in Spain.
Molecular plant biology is the study of the molecular basis of plant life [...].


Growth parameters and attention to faces at 4 to 6 months of age.
Duration of attention to faces and response decrement were studied in 57 full-term infants between 15.1 and 28.5 weeks of age during a health maintenance clinic visit. Six measures of growth, obtained from the medical record, included weight, length, and head circumference at birth, and weight, length, and head circumference at the time of the clinic visit. Correlation analysis revealed that longer average initial fixation time was associated with male sex, shorter birth length, and larger ponderal index. Multiple regression analysis indicated that together these three variables accounted for 17% of the variance in average initial fixation time (p less than 0.05). Length at the time of the health maintenance visit and male sex also were associated with longer average initial fixation time and, together, accounted for 13% of the variance (p less than 0.05). Response decrement was larger in children with larger head circumference at birth, in girls, and in infants with a larger ponderal index at birth. Together, these three variables accounted for 27% of the variance (p less than 0.001). Results suggest that more efficient processing of visual information may be related to neurophysiological maturity at term, and raises the possibility that neurophysiological maturity may account for a substantial portion of the correlation between attention behavior and later intelligence.


The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity.
Recent studies have demonstrated that the signaling activity of the cytosolic pathogen sensor retinoic acid-inducible gene-I (RIG-I) is modulated by a variety of posttranslational modifications (PTMs) to fine-tune the antiviral type I interferon (IFN) response. Whereas K63-linked ubiquitination of the RIG-I caspase activation and recruitment domains (CARDs) catalyzed by TRIM25 or other E3 ligases activates RIG-I, phosphorylation of RIG-I at S8 and T170 represses RIG-I signal transduction by preventing the TRIM25-RIG-I interaction and subsequent RIG-I ubiquitination. While strategies to suppress RIG-I signaling by interfering with its K63-polyubiquitin-dependent activation have been identified for several viruses, evasion mechanisms that directly promote RIG-I phosphorylation to escape antiviral immunity are unknown. Here, we show that the serine/threonine (Ser/Thr) kinase US3 of herpes simplex virus 1 (HSV-1) binds to RIG-I and phosphorylates RIG-I specifically at S8. US3-mediated phosphorylation suppressed TRIM25-mediated RIG-I ubiquitination, RIG-I-MAVS binding, and type I IFN induction. We constructed a mutant HSV-1 encoding a catalytically-inactive US3 protein (K220A) and found that, in contrast to the parental virus, the US3 mutant HSV-1 was unable to phosphorylate RIG-I at S8 and elicited higher levels of type I IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in a RIG-I-dependent manner. Finally, we show that this RIG-I evasion mechanism is conserved among the alphaherpesvirus US3 kinase family. Collectively, our study reveals a novel immune evasion mechanism of herpesviruses in which their US3 kinases phosphorylate the sensor RIG-I to keep it in the signaling-repressed state. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latency in the majority of the human population worldwide. HSV-1 occasionally reactivates to produce infectious virus and to facilitate dissemination. While often remaining subclinical, both primary infection and reactivation occasionally cause debilitating eye diseases, which can lead to blindness, as well as life-threatening encephalitis and newborn infections. To identify new therapeutic targets for HSV-1-induced diseases, it is important to understand the HSV-1-host interactions that may influence infection outcome and disease. Our work uncovered direct phosphorylation of the pathogen sensor RIG-I by alphaherpesvirus-encoded kinases as a novel viral immune escape strategy and also underscores the importance of RNA sensors in surveilling DNA virus infection.


Cytoskeleton involvement during human cytomegalovirus replicative cycle in human embryo fibroblasts.
Several studies indicate that viruses can induce different cytoskeletal modifications. The present investigation examines the possible involvement of human embryo fibroblast cytoskeleton in the replication of human cytomegalovirus (HCMV). Significant cytoskeletal modifications occur in infected cells; specifically, microfilament depolymerization is observed very early during the HCMV replicative cycle, whilst microtubules and intermediate filaments do not undergo any change for longer times after infection. Our data focus, in particular, on microfilament depolymerization, which starts within the first hour of the replicative cycle, and on the significance of this event, as a CMV-induced mechanism to modify the post-transcriptional regulation of cellular gene expression for its own benefit. Among the possible mechanisms exploited by HCMV to induce microfilament modifications, one might involve the cellular ADP-ribosylation activity, which is increased by HCMV very early in the infectious cycle. Experiments carried out on HCMV-infected cells, in the presence of ADP-ribosylation inhibitors, seem to confirm this hypothesis.


Synthesize magnetic ZnFe2O4@C/Cd0.9Zn0.1S catalysts with S-scheme heterojunction to achieve extraordinary hydrogen production efficiency.
Suppressing the electron-hole recombination rate of catalyst legitimately is one of the effective strategies to improve photocatalytic hydrogen evolution. Herein, carbon-coated metal oxide, ZnFe2O4@C (ZFO@C), nanoparticles were synthesized and employed to couple with quadrupedal Cd0.9Zn0.1S (CZS) via an ordinary ultrasonic self-assembly method combined with calcination to form a novel ZFO@C/CZS catalyst with step-scheme (S-scheme) heterojunction. The photocatalytic hydrogen evolution reaction (HER) was conducted to verify the enhanced photoactivity of ZFO@C/CZS. The optimal ZFO@C/CZS exhibits an extraordinary photocatalytic HER rate of 111.3 ± 0.9 mmol g-1 h-1 under visible-light irradiation, corresponding to an apparent quantum efficiency as high as (76.2 ± 0.9)% at 450 nm. Additionally, the as-synthesized ZFO@C/CZS composite exhibits high stability and recyclability. The excellent photocatalytic hydrogen evolution performance should arise from the formed S-scheme heterojunction and the unique ZFO@C core-shell structure, which inhibit electron hole recombination as well as provide more reactive sites. The pathway of S-scheme charge transfer was validated through density functional theory calculations and electrochemical measurements. This work provides a rational strategy for the synthesis of unique magnetic S-scheme heterojunction photocatalysts for water splitting under visible light irradiation.


Effects of exercise in combination with epoetin alfa during high-dose chemotherapy and autologous peripheral blood stem cell transplantation for multiple myeloma.
To determine the effect of aerobic and strength resistance training and epoetin alfa (EPO) therapy on transfusions, stem cell collections, transplantation recovery, and multiple myeloma treatment response. Randomized clinical trial. A myeloma research and therapy center in the south central United States. 135 patients with multiple myeloma, 120 evaluable. Random assignment to exercise or usual care groups. All patients received EPO based on an algorithm. Aerobic capacity, using the six-minute walk test, was assessed prior to induction chemotherapy, prior to stem cell mobilization, and following stem cell collection for all patients and before and after transplantation for patients continuing in the study. Data analysis included analysis of variance to compare other outcome variables by groups. Number of red blood cell and platelet transfusions during transplantation, number of attempts at and total number of days of stem cell collection, time to recovery after transplantation, and response to intensive therapy for multiple myeloma. Recovery and treatment response were not significantly different between groups after transplantation. The exercise group had significantly fewer red blood cell transfusions and fewer attempts at stem cell collection. Serious adverse events were similar in each group. Exercise with prophylactic EPO therapy reduces the number of RBC transfusions and attempts at stem cell collection for patients receiving intensive treatment for multiple myeloma. Exercise is safe and has many physiologic benefits for patients receiving multiple myeloma treatment.


Primary aortic sarcoma in arch and descending aorta: a case report and literature review.
Aortic sarcoma is a rare entity. In this study, we report a case of a 56-year-old man with complaints of pain and numbness of bilateral lower extremities. An endovascular aortic repair was finally adopted to prevent recurrent embolic events. An endo-biopsy was performed and showed aortic sarcoma. Axillary bifemoral and femoro-femoral cross-over bypass surgeries were taken to supply blood to the lower extremities in the 6th month after the first operation. He finally passed away in the 37th month. Aortic sarcoma should be taken into consideration as one of the possible etiologies for massive thrombus in aorta. Palliative surgeries such as bypass, endovascular aortic repair can also be an alternative to treat aortic sarcoma.


Impact of preexisting memory to seasonal A/H1N1 influenza virus on the immune response following vaccination against avian A/H5N1 virus.
Cross-protection against divergent strains of influenza virus is an objective of various vaccination approaches. B cells cross-neutralizing several influenza A heterosubtypes have been isolated from cultured human memory B cells (MBCs) and plasmablasts early after influenza vaccination or infection. However, a systematic assessment of the frequency of MBCs and plasmablasts in the blood of healthy individuals is lacking. Here, we show that under resting conditions about 45% of human adults never vaccinated nor exposed to avian A/H5N1 influenza have detectable circulating MBCs cross-reacting with H5N1. This proportion rises to 63.3% among subjects with a large pool of MBCs specific for seasonal H1N1 (i.e. frequency ≥1% of total IgG MBCs). Moreover, subjects with high baseline frequencies of H1N1-specific MBCs had an expansion of H5N1-specific MBCs producing H5-neutralizing antibodies already after the first dose of an MF59-adjuvanted H5N1 vaccine. These results suggest that H1N1-specific MBCs contain a subset of cells cross-reacting to H5. We propose that a proportion of human adults have a pool of H5/H1 cross-reactive MBCs that contribute to the rapid rise of the antibody response to divergent influenza strains. This may have implications on vaccination strategies aimed at counteracting future influenza pandemics.


Evolution of Th2 responses: characterization of IL-4/13 in sea bass (Dicentrarchus labrax L.) and studies of expression and biological activity.
Th2 immunity is a primary host defence against metazoan pathogens and two of the important cytokines involved in this immune response in mammals are IL-4 and IL-13. Recently the origin and evolution of Th2 immune responses have been investigated in fish where a molecule with relatedness to both IL-4 and IL-13 is present, termed IL-4/13. Different IL-4/13 paralogues (IL-4/13 A and IL-4/13B) exist in teleost fish. In this paper, we have focused on the IL-4/13 isoforms found in the European sea bass (Dicentrarchus labrax L.). Two tandem duplicated but divergent IL-4/13 A isoforms and one IL-4/13B are present, a unique situation compared to other teleosts. These genes were studied in terms of their in vitro and in vivo transcript levels after different treatments and their biological activities after production of the recombinant isoforms. The results show that the presence of these three paralogues is associated with different activities, both in terms of their expression profiles and the ability of the proteins to modulate the expression of immune genes in head kidney leukocytes. It is clear that the initiation and control of type-2 responses in seabass is complex due to the presence of multiple IL-4/13 isoforms with overlapping but distinct activities.


[The relationship between the condition of the brain stem compartments of the acoustic analyzer and rheoencephalography in people who participated in the liquidation of the consequences of the Chernobyl' nuclear plant disaster].
Pure-tone and speech threshold and suprathreshold audiometry, short-latent acoustic evoked potentials (SLAEP) and rheoencephalography (REG) were applied in examination of 67 patients with neurosensory hypoacusis (NSH) aged 21 to 45 years. These patients worked as wreckers in the zone contaminated with radionuclides 5 years and later after the Chernobyl accident. Relationships between functional condition of the truncal structures of the acoustic analyser and cerebral hemodynamics were studied. Correlation analysis has shown that there is close correlation between SLAEP and REG, especially in the vertebrobasillar area of cerebral circulation. The closest relations existed between the duration of the latent period of SLAEP wave V, interpeak interval I-V and rheographic index in the vertebrobasillar system. Combination of SLAEP and REG potentialities opens wide prospects for revelation of the key pathogenetic links for disorders of the acoustic system of unconventional origin, improves quality of these disorders diagnosis, promotes individual approach to therapy of such patients.


Estimating the marginal hazard ratio by simultaneously using a set of propensity score models: A multiply robust approach.
The inverse probability weighted Cox model is frequently used to estimate the marginal hazard ratio. Its validity requires a crucial condition that the propensity score model be correctly specified. To provide protection against misspecification of the propensity score model, we propose a weighted estimation method rooted in the empirical likelihood theory. The proposed estimator is multiply robust in that it is guaranteed to be consistent when a set of postulated propensity score models contains a correctly specified model. Our simulation studies demonstrate satisfactory finite sample performance of the proposed method in terms of consistency and efficiency. We apply the proposed method to compare the risk of postoperative hospitalization between sleeve gastrectomy and Roux-en-Y gastric bypass using data from a large medical claims and billing database. We further extend the development to multisite studies to enable each site to postulate multiple site-specific propensity score models.


Caffeine impairs short-term neurological outcome after concussive head injury in rats.
Adenosine is an endogenous neuroprotective agent that is released during ischemia, hypoxia, epilepsy, and ischemic brain injury. Caffeine is a receptor antagonist for adenosine that might interfere with the neuroprotective effect of adenosine in ischemic-hypoxic conditions. An investigation was undertaken to study the effect of caffeine on neurological function, edema formation, and blood-brain barrier permeability after experimental head injury in rats. Adult female Wistar rats classified into different groups received caffeine intraperitoneally at doses of 0, 50, 100, and 150 mg/kg body weight. Thirty minutes after the caffeine treatment, the animals were subjected to concussive head injury (CHI) administered by a controlled cortical impact device. Neurological severity score was recorded in each rat at 2 hours after CHI. Specific gravity, water content (as an indicator of edema), and blood-brain barrier impairment were analyzed in the cortical tissue surrounding the injury site. The levels of myeloperoxidase and malondialdehyde in the cortical region were measured as indicators of neutrophil infiltration and lipid peroxidation, respectively. A significant increase in righting latency and neurological deficiency after CHI was observed in caffeine-treated rats as compared with untreated animals. Although no deaths occurred in the rats exposed to CHI after pretreatment with saline, pretreatment with caffeine caused significant mortality of animals after trauma in a dose-dependent manner. Caffeine also exacerbated neutrophil infiltration, edema, and disruption of blood-brain barrier in the traumatic cortex. Light microscopy of brain revealed more severe hemorrhage and neuronal degeneration in the injured hemisphere of caffeine-treated rats as compared with rats in the injury-alone group. A significant increase in malondialdehyde in the brain of injured rats treated with caffeine before CHI clearly indicated the role of oxidative stress. Caffeine adversely affects outcome after CHI, possibly as a result of blockade of adenosine receptors. The findings also point toward the involvement of free radical-mediated neuronal damage in caffeine-induced exacerbation of neurotrauma.


A GTP:AMP phosphotransferase, Adk2p, in Saccharomyces cerevisiae. Role of the C terminus in protein folding/stabilization, thermal tolerance, and enzymatic activity.
Adenylate kinases participate in maintaining the homeostasis of cellular nucleotides. Depending on the yeast strains, the GTP:AMP phosphotransferase is encoded by the nuclear gene ADK2 with or without a single base pair deletion/insertion near the 3' end of the open reading frame, and the corresponding protein exists as either Adk2p (short) or Adk2p (long) in the mitochondrial matrix. These two forms are identical except that the three C-terminal residues of Adk2p (short) are changed in Adk2p (long), and the latter contains an additional nine amino acids at the C terminus of the protein. The short form of Adk2p has so far been considered to be inactive (Schricker, R., Magdolen, V., Strobel, G., Bogengruber, E., Breitenbach, M., and Bandlow, W. (1995) J. Biol. Chem. 270, 31103-31110). Using purified proteins, we show that at the physiological temperature for yeast growth (30 degrees C), both short and long forms of Adk2p are enzymatically active. However, in contrast to the short form, Adk2p (long) is quite resistant to thermal inactivation, urea denaturation, and degradation by trypsin. Unfolding of the long form by high concentrations of urea greatly stimulated its import into isolated mitochondria. Using an integration-based gene-swapping approach, we found that regardless of the yeast strains used, the steady state levels of endogenous Adk2p (long) in mitochondria were 5-10-fold lower compared with those of Adk2p (short). Together, these results suggest that the modified C-terminal domain in Adk2p (long) is not essential for enzyme activity, but it contributes to and strengthens protein folding and/or stability and is particularly important for maintaining enzyme activity under stress conditions.


Negative association of the chemokine receptor CCR5 d32 polymorphism with systemic inflammatory response, extra-articular symptoms and joint erosion in rheumatoid arthritis.
Chemokines and their receptors control immune cell migration during infections as well as in autoimmune responses. A 32 bp deletion in the gene of the chemokine receptor CCR5 confers protection against HIV infection, but has also been reported to decrease susceptibility to rheumatoid arthritis (RA). The influence of this deletion variant on the clinical course of this autoimmune disease was investigated. Genotyping for CCR5d32 was performed by PCR and subsequent electrophoretic fragment length determination. For the clinical analysis, the following extra-articular manifestations of RA were documented by the rheumatologist following the patient: presence of rheumatoid nodules, major organ vasculitis, pulmonary fibrosis, serositis or a Raynaud's syndrome. All documented CRP levels were analyzed retrospectively, and the last available hand and feet radiographs were analyzed with regards to the presence or absence of erosive disease. Analysis of the CCR5 polymorphism in 503 RA patients and in 459 age-matched healthy controls revealed a significantly decreased disease susceptibility for carriers of the CCR5d32 deletion (Odds ratio 0.67, P = 0.0437). Within the RA patient cohort, CCR5d32 was significantly less frequent in patients with extra-articular manifestations compared with those with limited, articular disease (13.2% versus 22.8%, P = 0.0374). In addition, the deletion was associated with significantly lower average CRP levels over time (median 8.85 vs. median 14.1, P = 0.0041) and had a protective effect against the development of erosive disease (OR = 0.40, P = 0.0047). Intriguingly, homozygosity for the RA associated DNASE2 -1066 G allele had an additive effect on the disease susceptibility conferred by the wt allele of CCR5 (OR = 2.24, P = 0.0051 for carrier of both RA associated alleles) The presence of CCR5d32 significantly influenced disease susceptibility to and clinical course of RA in a German study population. The protective effect of this deletion, which has been described to lead to a decreased receptor expression in heterozygous patients, underlines the importance of chemokines in the pathogenesis of RA.


The effect of education and counselling on knowledge, attitudes and beliefs about responses to acute myocardial infarction symptoms.
The time that elapses from the onset of symptoms of acute myocardial infarction (AMI) to treatment has a significant effect on mortality and morbidity. This study reports the effectiveness of an education and counselling intervention on knowledge, attitudes and beliefs about AMI symptoms and the appropriate response to symptoms. The intervention was tested in a randomised controlled trial of 200 people with a history of coronary heart disease (CHD). The groups were equivalent at baseline on study outcomes, clinical history and sociodemographic characteristics with the exception of more women in the intervention group (38% vs. 24%). The results of repeated measures ANOVA showed that the intervention resulted in improved knowledge of CHD, AMI symptoms and the appropriate response to symptoms that was sustained to 12 months (p=0.02). There were no differences between groups' attitudes and beliefs over time. It is concluded that a short individual teaching and counselling intervention resulted in improved knowledge of CHD, AMI symptoms and the appropriate response to symptoms in people at risk of AMI sustained to 12 months.


Facial Reanimation by Modified Intraoral Temporalis Tendon Transfer With Ancillary Procedures.
Facial nerve palsy is an exceedingly debilitating condition, incapacitating functional and aesthetic facets of the face. Orthodromic transfer of temporalis muscle is an easy and predictable technique which offers early animation of oral commissure and lower face. A retrospective chart review of 6 patients of facial palsy treated with orthodromic temporalis tendon transfer for facial reanimation is presented. The technique consisted of intra-oral coronoidectomy followed by attachment of fascia lata grafts from the coronoid to the commissure, the upper and lower lips via small cutaneous incisions. Contraction of the temporalis, pulls the fascia lata extensions thereby reanimating the lower face. 4 male and 2 female patients with an age range of 25 to 49 years were treated. Simultaneous fat grafting (2 patients), depressor labi inferioris muscle resection (2 patients) and wedge excision of nasolabial fold (2 patients) was done as ancillary procedures. Post-operative smile evaluation was carried out using the Terzis and Noah facial grading system. Patients were asked to smile with and without biting, and photographs and video were taken. The results were graded from 1 to 5 based on a 5-point scale (ie, poor, fair, moderate, good, and excellent) by an independent observer. The results were excellent in 1 patient (Terzis grading 5/5) and good in the remaining 5 patients (Terzis grading 4/5). Excursion of the oral commissure ranged from 6 to 10 mm. Our experience indicates that temporalis tendon transfer for facial reanimation has a short learning curve and provides early predictable outcome without significant complications. This single-stage, day-care procedure can be easily incorporated by maxillofacial surgeons to expand their surgical spectrum.


Neurofilament light chain levels in serum among a large mixed memory clinic cohort: Confounders and diagnostic usefulness.
Early and accurate diagnosis of neurocognitive disorders including neurodegenerative dementia remains challenging. This study explores the impact of biological factors on serum neurofilament light chain (NfL) levels and clinical usefulness for the detection of neurocognitive disorders in a mixed memory clinic. Serum samples and clinical data were obtained from 1188 patients who underwent diagnostic investigations for memory complaints between January 2018 and September 2019. Serum NfL was measured using single molecule array technology. NfL exhibited a moderate association with age, estimated glomerular filtration rate (eGFR), and Fazekas score. NfL was able to differentiate between patients with neurocognitive disorders and those without with a sensitivity and specificity of 80%. NfL could, however, not distinguish between different dementia etiologies. Serum NfL could aid early diagnostic triage by identifying patients requiring further diagnostic procedures and therefore aid in a more focused use of health-care resources.


The geometry of structural equilibrium.
Building on a long tradition from Maxwell, Rankine, Klein and others, this paper puts forward a geometrical description of structural equilibrium which contains a procedure for the graphic analysis of stress resultants within general three-dimensional frames. The method is a natural generalization of Rankine's reciprocal diagrams for three-dimensional trusses. The vertices and edges of dual abstract 4-polytopes are embedded within dual four-dimensional vector spaces, wherein the oriented area of generalized polygons give all six components (axial and shear forces with torsion and bending moments) of the stress resultants. The relevant quantities may be readily calculated using four-dimensional Clifford algebra. As well as giving access to frame analysis and design, the description resolves a number of long-standing problems with the incompleteness of Rankine's description of three-dimensional trusses. Examples are given of how the procedure may be applied to structures of engineering interest, including an outline of a two-stage procedure for addressing the equilibrium of loaded gridshell rooves.


An E2F1-mediated DNA damage response contributes to the replication of human cytomegalovirus.
DNA damage resulting from intrinsic or extrinsic sources activates DNA damage responses (DDRs) centered on protein kinase signaling cascades. The usual consequences of inducing DDRs include the activation of cell cycle checkpoints together with repair of the damaged DNA or induction of apoptosis. Many DNA viruses elicit host DDRs during infection and some viruses require the DDR for efficient replication. However, the mechanism by which DDRs are activated by viral infection is poorly understood. Human cytomegalovirus (HCMV) infection induces a DDR centered on the activation of ataxia telangiectasia mutated (ATM) protein kinase. Here we show that HCMV replication is compromised in cells with inactivated or depleted ATM and that ATM is essential for the host DDR early during infection. Likewise, a downstream target of ATM phosphorylation, H2AX, also contributes to viral replication. The ATM-dependent DDR is detected as discrete, nuclear γH2AX foci early in infection and can be activated by IE proteins. By 24 hpi, γH2AX is observed primarily in HCMV DNA replication compartments. We identified a role for the E2F1 transcription factor in mediating this DDR and viral replication. E2F1, but not E2F2 or E2F3, promotes the accumulation of γH2AX during HCMV infection or IE protein expression. Moreover, E2F1 expression, but not the expression of E2F2 or E2F3, is required for efficient HCMV replication. These results reveal a novel role for E2F1 in mediating an ATM-dependent DDR that contributes to viral replication. Given that E2F activity is often deregulated by infection with DNA viruses, these observations raise the possibility that an E2F1-mediated mechanism of DDR activation may be conserved among DNA viruses.


Bio-signals Collecting System for Fatigue Level Classification.
Fatigue is a risk factor that reduces quality of life and work efficiency, and threatens safety in a high-risk environment. However, fatigue is not yet precisely defined and is not a quantified concept as it relies on subjective evaluation. The purpose of this study is to manage risks, improve mission efficiency, and prevent accidents through the development of machine learning and deep learning based fatigue level classifier. Acquiring true fatigue levels to train machine learning and deep learning fatigue classifier may play a fundamental role. Aims of this study are to develop a bio-signal collecting device and to establish a protocol for capturing and purifying data for extracting the true fatigue levels accurately. The bio-signal collection system gathered visual, thermal, and vocal signals at the same time for one minute. The true fatigue level of the subjects is classified through the Daily Multidimensional Fatigue Inventory and physiological indicators related to fatigue for screening the subjective factors out. The generated dataset is constructed as a DB along with the true fatigue levels and is provided to the research institutions. In conclusion, this study proposes a research method that collects bio-signals and extracts the true fatigue levels for training machine learning and deep learning based fatigue level classifier to evaluate the fatigue of healthy subjects in multi-levels.


Clinical review: Clinical management of new oral anticoagulants: a structured review with emphasis on the reversal of bleeding complications.
New oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, have been recently approved for primary and secondary prophylaxis of thromboembolic conditions. However, there is no clear strategy for managing and reversing their anticoagulant effects. We aimed to summarize the available evidence for clinical management and reversal of bleeding associated with new oral anticoagulants. Using a systematic review approach, we aimed to identify studies describing reversal strategies for dabigatran, rivaroxaban, and apixaban. The search was conducted using Medline, EMBASE, HealthSTAR, and grey literature. We included laboratory and human studies. We included 23 studies reported in 37 out of 106 potentially relevant references. Four studies were conducted in humans and the rest were in vitro and in vivo studies. The majority of the studies evaluated the use of prothrombinase complex concentrate (PCC), either activated or inactivated, and recombinant activated factor VII (rFVIIa). Other interventions were also identified. Laboratory studies suggest that hemostatic parameters and bleeding might be partially or completely corrected by PCC for rivaroxaban better than dabigatran. Studies in humans suggest that PCC might reverse the effects of rivaroxaban better than dabigatran assessed by hemostatic tests. We were not able to locate studies evaluating the clinical efficacy of these agents. The best available evidence suggests that PCC (activated or inactivated) might be the best option for reversing new anticoagulants. Evidence for rFVIIa is less compelling. There might be differences in the efficacy of reversing agents for different anticoagulants. Studies assessing the clinical efficacy of these reversal agents are urgently needed.


Biogeography of microbial communities in high-latitude ecosystems: Contrasting drivers for methanogens, methanotrophs and global prokaryotes.
Methane-cycling is becoming more important in high-latitude ecosystems as global warming makes permafrost organic carbon increasingly available. We explored 387 samples from three high-latitudes regions (Siberia, Alaska and Patagonia) focusing on mineral/organic soils (wetlands, peatlands, forest), lake/pond sediment and water. Physicochemical, climatic and geographic variables were integrated with 16S rDNA amplicon sequences to determine the structure of the overall microbial communities and of specific methanogenic and methanotrophic guilds. Physicochemistry (especially pH) explained the largest proportion of variation in guild composition, confirming species sorting (i.e., environmental filtering) as a key mechanism in microbial assembly. Geographic distance impacted more strongly beta diversity for (i) methanogens and methanotrophs than the overall prokaryotes and, (ii) the sediment habitat, suggesting that dispersal limitation contributed to shape the communities of methane-cycling microorganisms. Bioindicator taxa characterising different ecological niches (i.e., specific combinations of geographic, climatic and physicochemical variables) were identified, highlighting the importance of Methanoregula as generalist methanogens. Methylocystis and Methylocapsa were key methanotrophs in low pH niches while Methylobacter and Methylomonadaceae in neutral environments. This work gives insight into the present and projected distribution of methane-cycling microbes at high latitudes under climate change predictions, which is crucial for constraining their impact on greenhouse gas budgets.


[Epidemiology, treatment and prevention of attention deficit/hyperactivity disorder: a review].
Attention deficit/hyperactivity disorder (ADHD) is characterized by inattentiveness and/or impulsiveness and hyperactivity, which are unsuited for the developmental stage or age. Although mechanisms leading to the onset of the disease are unclear, this condition seriously hinders childrens' social or learning functions, and recently it was selected as a target disease for a special supporting education program by the Minitry of Education, Culture, Sports, Science and Technology, together with learning disorders and high-functioning pervasive developmental disorders in Japan. In spite of the increasing social interest in ADHD, the epidemiological evidence including data for incidence, prevalence, gender differences, and etiology remain insufficient. In Western countries, as represented by the United States, operational diagnostic criteria such as DSM-IV are widely used and several diagnostic processes using structured interviews have been established. However, the diagnostic criteria have not been consistent even within DSM as shown by DSM-IV and DSM-III-R, and therefore basic epidemiological evidence was not consistent in the previous studies. Regarding the etiology of ADHD, exposure to addictive substances during the pregnancy period caused by maternal smoking or drinking, and familial socioeconomic status are considered important environmental factors. In addition, a family history of mental disorders and polymorphisms of dopamine-related genes such as DRD4 or SLC6A3 have been noted as genetic factors concerning the development of ADHD. However, in Japan, no studies of these subjects or gene-environment interactions have so far been performed. Thus, epidemiological assessment of other than Western populations is needed. In the clinical situation, it is important to grasp the timing of treatment and target problems on the basis of changes of children's ability to control their attention or behavior, and environmental factors associated with growth processes. Especially, comorbidity such as conduct disorder or oppositional defiant disorder is a critical problem. Thus, considering that ADHD is a multifactorial disease, a comprehensive therapic strategy involving medication, education, judicature, and administration should be established for primary and secondary prevention.


Combination chemotherapy in vitro exploiting glutamine metabolism of human glioma and medulloblastoma.
The human glioma-derived cell line D-54 MG and the human medulloblastoma-derived cell line TE-671 have been shown to be sensitive in culture to the pharmacological interference with glutamine metabolism by acivicin, 6-diazo-5-oxo-L-norleucine, and methionine sulfoximine. Using as a guide the multiple contributions of glutamine to the biosynthesis of proteins, purines, and pyrimidines, we now have identified six additional antimetabolites active against these lines in vitro at clinically relevant concentrations. The 50% growth-inhibitory levels of the drugs against D-54 MG in 6-day continuous exposure experiments were: L-asparaginase, 0.057 IU/ml; 5-fluorouracil, 0.5 micrograms/ml; 6-mercaptopurine, 0.8 micrograms/ml; actinomycin D, 0.0007 micrograms/ml; N-phosphonacetyl-L-aspartic acid, 2.3 micrograms/ml; and 5-azacytidine, 0.2 micrograms/ml (3-day exposure. The corresponding 50% growth-inhibitory values in TE-671 were: L-asparaginase, 0.54 IU/ml; 5-fluorouracil, 1.5 micrograms/ml; 6-mercaptopurine, 4.7 micrograms/ml; actinomycin D, 0.00044 micrograms/ml; N-phosphonacetyl-L-aspartic acid, 4.5 micrograms/ml; and 5-azacytidine, 0.49 micrograms/ml. Dipyridamole up to 10 micrograms/ml was inactive against both lines. The isobologram method was used to evaluate the effectiveness of several two-drug combinations which were biochemically designed. The sums of the optimal fractional inhibitory concentrations for the pairs were: acivicin plus L-asparaginase, 0.14; acivicin plus methionine sulfoximine, 0.40; 6-diazo-5-oxo-L-norleucine plus methionine sulfoximine, 0.60; acivicin plus 6-mercaptopurine, 1.0, all in TE-671; and acivicin plus 5-fluorouracil, 0.79, in D-54 MG. Our findings suggest that an antimetabolite regimen exploiting glutamine sensitivity might improve the chemotherapy of some human gliomas and medulloblastomas.


Low-fluence laser-facilitated platelet-rich plasma permeation for treating MRSA-infected wound and photoaging of the skin.
Platelet-rich plasma (PRP) is rich in cytokines and growth factors and is a novel approach for tissue regeneration. It can be used for skin rejuvenation but the large molecular size of the actives limits its topical application. In this study, low-fluence laser-facilitated PRP was delivered to evaluate its effect on absorption through the skin, infection-induced wound, and photoaging. The PRP permeation enhancement was compared for two ablative lasers: fractional (CO2) laser and fully-ablative (Er:YAG) laser. In the Franz cell experiment, pig skin was treated with lasers with superficial ablation followed by the application of recombinant cytokines, growth factors, or PRP. The transport of interferon (IFN)-γ and tumor necrosis factor (TNF)-α was negligible in intact skin and stratum corneum (SC)-stripped skin. Both lasers significantly elevated skin deposition of IFN-γ and TNF-α from PRP, and fully-ablative laser showed a higher penetration enhancement. A similar tendency was found for vascular endothelial growth factor and epidermal growth factor. Er:YAG laser-exposed skin displayed 1.8- and 3.9-fold higher skin deposition of platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-β1 from PRP, respectively. According to the confocal images, both laser interventions led to an extensive and deep distribution of IFN-γ and PDGF-BB in the skin. In the in vivo methicillin-resistant Staphylococcus aureus (MRSA) infection model, CO2 laser- and Er:YAG laser-assisted PRP delivery reduced bacterial load from 1.8 × 106 to 5.9 × 105 and 1.4 × 104 colony-forming units, respectively. The open wound induced by MRSA was closed by the laser-assisted PRP penetration. In the mouse photoaging model, elastin and collagen deposition were fully restored by combined PRP and full-ablative laser but not by PRP alone and PRP combined with fractional laser. Laser-facilitated PRP delivery even with a low fluence setting can be considered a promising strategy for treating some dermatological disorders.


Serum concentrations of steroid hormones during reproduction in the Atlantic stingray, Dasyatis sabina.
The Atlantic stingray, Dasyatis sabina, has a well-defined annual reproductive cycle in Florida. We collected adult specimens over 12 months and evaluated reproductive parameters and serum levels of five steroid hormones, 17beta-estradiol (E2), progesterone (P4), testosterone (T), dihydrotestosterone (DHT), and corticosterone (CS). Female E2 peaked twice, once in mid-March to early April in association with ovulation and again in mid-June to mid-July in association with the enlargement of a second group of ovarian follicles. Female P4 peaked in early March and early April, coincident with the peak in E2. Female DHT was variable but exhibited a pattern not clearly associated with known events in the reproductive cycle. Female T and CS levels did not vary significantly through time. In males, T, DHT, and CS increased progressively through winter and spring, peaking in March when females were ovulating and when copulation probably took place. DHT concentrations were usually at least twice T levels. These three hormones peaked long after the November/December peak in gonadosomatic index. E2 was measurable in males and was highest during the period of testicular development. Male P4 varied in a pattern not clearly associated with known reproductive events.


[Peculiarities of somatic diseases in people of middle and old age survived Leningrad siege at childhood].
The results of a study on peculiarities of development of some diseases in adult peoples survived the Leningrad siege at childhood are presented. The age- and sex-related differences in an incidence and clinical features of diseases are demonstrated. More frequent incidence of severe arterial hypertension, diabetes mellitus type 2, biliar calculite disease, chronic atrophic pangastritis, terminal stage of kidney failure, more early mortality, clinically unfavorable aortal atherosclerosis development, as well as atherosclerosis of coronary, brain and carotid artheria have been revealed. Specific histological and morphometric changes in kidney tissue of the patients at preclinical stage are demonstrated.


Barriers and facilitators to implementation of shared medical appointments in primary care for the management of long-term conditions: a systematic review and synthesis of qualitative studies.
To synthesise the published literature on practitioner, patient and carer views and experiences of shared medical appointments (SMAs) for the management of long-term conditions in primary care. Systematic review of qualitative primary studies. A systematic search was conducted using MEDLINE (Ovid), PsycINFO (Ovid), CINAHL (EBSCOhost), Web of Science, Social Science Premium Collection (Proquest) and Scopus (SciVerse) from database starting dates to June 2019. Practitioner, patient and carer perspectives were coded separately. Deductive coding using a framework approach was followed by thematic analysis and narrative synthesis. Quality assessment was conducted using the Critical Appraisal Skills Programme for qualitative studies. We identified 18 unique studies that reported practitioner (n=11), patient (n=14) and/or carer perspectivs(n=3). Practitioners reported benefits of SMAs including scope for comprehensive patient-led care, peer support, less repetition and improved efficiency compared with 1:1 care. Barriers included administrative challenges and resistance from patients and colleagues, largely due to uncertainties and unclear expectations. Skilled facilitators, tailoring of SMAs to patient groups, leadership support and teamwork were reported to be important for successful delivery. Patients' reported experiences were largely positive with the SMAs considered a supportive environment in which to share and learn about self-care, though the need for good facilitation was recognised. Reports of carer experience were limited but included improved communication between carer and patient. There is insufficient evidence to indicate whether views and experiences vary between staff, medical condition and/or patient characteristics. Participant experiences may be subject to reporting bias. Policies and guidance regarding best practice need to be developed with consideration given to resource requirements. Further research is needed to capture views about wider and co-occurring conditions, to hear from those without SMA experience and to understand which groups of patients and practitioners should be brought together in an SMA for best effect. CRD42019141893.


Repellency Effect of Essential Oils of some Native Plants and Synthetic Repellents against Human Flea, Pulex irritans (Siphonaptera: Pulicidae).
Fleas are important vectors of human and animal disease, and control measures for protection against their bites and flea-borne diseases are necessary. The essential oils (EOs) of four native medicinal plants, Ziziphora tenuiore, Myrtus communis, Achillea wilhelmsii and Mentha piperita were isolated by hydrodistillation technique and analyzed by GC-MC. The repellent activity of EOs and synthetic compounds, DEET and permethrin, were assayed on human subjects against field collected fleas. The effective doses of 50% and 90% of EOs and synthetic compounds were estimated by probit analysis of dose and response regression line. Analysis of EOs revealed about 19 major components. All oils were found to be more repellent (ED50 range= 208-955μg cm-2) than DEET and permethrin (ED50 range= 27-182 × 103μg cm-2). Thyme and myrtle oils showed high repellent activities and among the total detected terpenes, thymol (36.26%) and α-pinene (32.5%) were the major components of those oils respectively. Low repellent potency of DEET and permethrin against fleas might be related to flea olfactory system and further molecular and electrophysiological studies are required to conceive new ideas for the discovery and development of the next generation of repellents. Based on high repellent activity of thyme and myrtle essential oils against Pulex irritans further studies should be staged to develop their appropriate effective formulations. Likewise, field trials should be carried out to evaluate the operational feasibility and dermal toxicity over a long period.


Plant organellar DNA polymerases bypass thymine glycol using two conserved lysine residues.
Plant organelles cope with endogenous DNA damaging agents, byproducts of respiration and photosynthesis, and exogenous agents like ultraviolet light. Plant organellar DNA polymerases (DNAPs) are not phylogenetically related to yeast and metazoan DNAPs and they harbor three insertions not present in any other DNAPs. Plant organellar DNAPs from Arabidopsis thaliana (AtPolIA and AtPolIB) are translesion synthesis (TLS) DNAPs able to bypass abasic sites, a lesion that poses a strong block to replicative polymerases. Besides abasic sites, reactive oxidative species and ionizing radiation react with thymine resulting in thymine glycol (Tg), a DNA adduct that is also a strong block to replication. Here, we report that AtPolIA and AtPolIB bypass Tg by inserting an adenine opposite the lesion and efficiently extend from a Tg-A base pair. The TLS ability of AtPolIB is mapped to two conserved lysine residues: K593 and K866. Residue K593 is situated in insertion 1 and K866 is in insertion 3. With basis on the location of both insertions on a structural model of AtPolIIB, we hypothesize that the two positively charged residues interact to form a clamp around the primer-template. In contrast with nuclear and bacterial replication, where lesion bypass involves an interplay between TLS and replicative DNA polymerases, we postulate that plant organellar DNAPs evolved to exert replicative and TLS activities.


[Global demographic problem and active aging (literature review)].
The article presents an overview of foreign sources devoted to the problems of population aging as a significant phenomenon that has become the most important medical and socio-demographic challenge in the world. The review provides global data on this problem and shows the need for elaborating and implementing active aging strategies, optimizing opportunities for health, participation and safety in order to improve the life quality as people age. The paper employs the method of content analysis of scientific publications retrieved in PubMed database by keywords - «aging», «population aging», «demographic trend», «longevity», and «life expectancy». Scientific publications for the period 2018-2023, WHO and UN materials, statistical data, and popular scientific publications have been studied. The purpose of the review was to analyze trends and global nature of aging based on scientific publications and open sources, and to highlight the most promising areas of the demographic policy on the older adults. In the time of rapid demographic changes, it is extremely important to use all available opportunities that maximize healthy aging with the participation of the older adults. We should remember that aging is a natural process and it is better to accept it, both psychologically and physically, rather than ignore. Healthy aging should become and has become the main principle of life, suggesting a longer healthy life of the older adults, who, in turn, should understand how to accept and implement this principle in their lives.


Hospital preparedness for hazardous materials incidents and treatment of contaminated patients.
Hospital-based facilities providing emergency care in the state of Washington were surveyed to determine their level of preparedness for hazardous materials incidents including the treatment of contaminated patients. Responses to a faxed questionnaire were received from 95 (94%) of the 101 emergency care facilities in Washington State. Only 42 (44%) of the facilities reported the ability to receive any chemically exposed patient. Of the 95 responding emergency care facilities, 39 (41%) had no designated decontamination facilities; 67 (70%) had protocols for handling chemical contamination and possible evacuation from hazardous materials spills, and 52 (55%) had protocols for handling medical facility contamination and possible evacuation from treating chemically contaminated patients. Twelve (13%) facilities had evacuated their emergency department or other part of the hospital for contamination incidents in the past 5 years. Despite the frequent occurrence of hazardous materials incidents, most emergency care facilities in Washington State are not fully prepared to handle contaminated patients and chemical spills. This may have important implications for the care of persons with exposure to hazardous materials and for implementing Joint Commission on Accreditation of Healthcare Organizations standards and federal Occupational Safety and Health Administration regulations.


Isolation and characterization of mutants of the plasmid pKM101 deficient in their ability to enhance mutagenesis and repair.
A screening procedure was developed for identifying mutants of the plasmid pKM101 no longer capable of enhancing mutagenesis. The test was based on the large pKM101-mediated increase in the number of Gal+ papillae observed on colonies of Salmonella typhimurium gal mutants plated on tetrazolium-galactose plates in the presence of a mutagen. The pKM101 mutant plasmids transferred normally, were stably maintained in cells, caused normal levels of ampicillin resistance, and still imparted sensitivity to phage Ike to their hosts. However, the pKM101 mutants had lost the ability to (i) enhance the reversion of both point and frameshift mutations, (ii) protect the cells against killing by UV irradiation, (iii) increase the spontaneous reversion rates of point mutations, (iv) enhance plasmid-mediated reactivation of UV-irradiated phage P22, (v) enhance Weigle reactivation. One pKM101 mutant with different properties from the others was identified by its increased spontaneous mutator effect. It is suggested that pKM101 amplifies the activity of the inducible error-prone repair systems in bacteria and that this is the function of pKM101 in the Ames Salmonella tester strains used for detection of carcinogens as mutagens.


First-principles modeling of the highly dynamical surface structure of a MoS2 catalyst with S-vacancies.
Vacancy sites, e.g., S-vacancies, are essential for the performance of MoS2 catalysts. As earlier studies have revealed that the size and shape of the S-vacancies may affect the catalytic activity, we have studied the behavior and mobility of such vacancies on MoS2 using DFT calculations and kinetic Monte-Carlo (kMC) simulations. The diffusion barriers for the S-vacancies are highly dependent on the immediate environment: isolated single S-vacancies are found to be immobile. In contrast, small nS-vacancies formed from n = 2 to 5 neighboring S-vacancies are often highly dynamic systems that can move within a confined area. Large extended nS-vacancies are generally unstable and transform quickly into alternating patterns of S-atoms and vacancy sites. These results illustrate the importance of recognizing MoS2 (but also other catalysts) as dynamic structures when trying to tune their catalytic performances by introducing specific defect structures.


Receptor-specific signaling for both the alternative and the canonical NF-kappaB activation pathways by NF-kappaB-inducing kinase.
The NF-kappaB-inducing kinase (NIK) induces proteolytic processing of NF-kappaB2/p100 and, hence, the generation of NF-kappaB dimers such as p52:RelB but was suggested not to signal for the processing of IkappaB. Here, we show that although the induction of IkappaB degradation in lymphocytes by TNF is independent of NIK, its induction by CD70, CD40 ligand, and BLyS/BAFF, which all also induce NF-kappaB2/p100 processing, does depend on NIK function. Both CD70 and TNF induce recruitment of the IKK kinase complex to their receptors. In the case of CD70, but not TNF, this process is associated with NIK recruitment and is followed by prolonged receptor association of just IKK1 and NIK. Recruitment of the IKK complex to CD27, but not that of NIK, depends on NIK kinase function. Our findings indicate that NIK participates in a unique set of proximal signaling events initiated by specific inducers, which activate both canonical and noncanonical NF-kappaB dimers.


Plasma amino acids and excretion of protein end products by mice fed 10 or 40% soybean protein diets with or without dietary benzo[a]pyrene or 1,2-dimethylhydrazine.
The effects of two carcinogens benzo[a]pyrene (BP) and symmetrical 1,2-dimethylhydrazine dihydrochloride (DMH), on plasma amino acid concentrations and on excretion of lipids and nitrogenous metabolites were studied in 7- to 8-wk-old male and female B6C3F1 mice. BP and DMH were fed at concentrations of 0.3125 and 0.0225 g/kg, respectively, in purified diets containing 10 or 40% soybean protein. Nutritional balances were measured over a 7-d period after 7 d of acclimatization. Females excreted less urea and more NH3 than males. Urinary urea-nitrogen, NH3, allantoin, uric acid and total urinary nitrogen were consistently higher in mice fed 40% protein than in those fed 10% protein. The increases in total and NH3 nitrogen paralleled the increase in nitrogen intake. Nitrogen of urea rose more, while that of allantoin and uric acid rose less, than nitrogen intake. Fecal lipid excretion, as a percentage of intake, was consistently higher in mice fed the 40% protein diets than in mice fed 10% protein. Plasma glycine and branched-chain amino acids were higher, but citrulline was lower, when the 40% protein diet was fed. Body weight gain was higher when the 10% protein diet was fed with BP than without it, but BP made no apparent difference in weight gain when the 40% protein diet was fed. BP interacted with dietary protein to influence the excretion of nitrogenous metabolites. In addition, BP feeding produced numerous BP X sex and BP X protein interactions for plasma amino acid concentrations. Compared to controls, feed intake and weight gain were, respectively, 8 and 61% lower in DMH-fed animals during wk 1, but no differences in intake or weight gain were found during wk 2. In contrast to BP, DMH had no significant effects on urinary or fecal nitrogen metabolites, except that urinary uric acid (relative to nitrogen intake) was 9% higher in DMH-fed mice than in controls. DMH-fed mice had 43% higher serum glutamate and 6% lower glutamine than controls.


Modulatory role of kolaviron in phenytoin-induced hepatic and testicular dysfunctions in Wistar rats.
Phenytoin, an anticonvulsant agent used for the treatment of epilepsy has been reported to exhibit toxic side effects on the liver and testes. The present study investigated the protective effects of kolaviron (KV, a bioflavonoid from Garcinia kola seeds) against hepatic and testicular damage in rats exposed to phenytoin. The study consisted of four groups of six rats per group. Group I rats received 2 mL/kg of corn alone while group II received 75 mg/kg of phenytoin (PHT) alone. Groups III and IV were co-treated with kolaviron (200 mg/kg KV) and vitamin E (500 mg/kg VTE), respectively, for 14 days. The antioxidant status, hepatic and reproductive functional parameters were subsequently determined. PHT treatment significantly (p < 0.05) increased superoxide dismutase (SOD) and catalase (CAT) activities, elevated lipid peroxidation (LPO) and hydrogen peroxide (H2O2) levels along with significant reduction in the hepatic and testicular levels of glutathione (GSH). Moreover, PHT exposure elicited significant increases in alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels. The significant reduction in seminal epithelium thickness and the diameter of seminiferous tubules was accompanied with marked decrease in sperm motility, sperm count, and viability in PHT-treated rats. However, antioxidant status and the functional indices of liver and testes were restored to near control levels in rats co-treated with KV and VTE. In conclusion, KV and VTE protect the liver and testes against functional impairment due to PHT treatment.


Effects of aging on the electroretinogram during ischemia-reperfusion in rats.
The effects of aging on the electroretinogram (ERG) during ischemia-reperfusion were investigated in rats. Flash-elicited ERG (a-wave, b-wave, and oscillatory potentials (OPs)) was recorded in young (4 months old) and aged rats (over 18 months old) before, during, and after exposure to 30- or 120-min ischemia induced by increasing intraocular pressure to 80 mmHg. The choroidal blood flow, measured by means of laser Doppler flowmetry, decreased to 40 to 60% of the baseline value during ischemia. Young rats showed no significant difference in the amplitude of each ERG component during ischemia between 30- and 120-min ischemia groups; 78.0 +/- 4.9 vs. 76.1 +/- 3.6% for a-wave, 63.4 +/- 3.1 vs. 60.6 +/- 3.0% for b-wave, and 59.6 +/- 5.9 vs. 57.5 +/- 6.7% for SigmaOP. In aged rats, however, 120-min ischemia caused a greater decrease, to 56.7 +/- 3.1% of the baseline value, in the a-wave amplitude than 30-min ischemia did, to 70.8 +/- 3.2%. The reduction of each ERG component in both 30- and 120-min ischemia experiments was greater in aged rats than in young rats. The recovery time for the amplitude of each ERG component during reperfusion was longer in aged rats than in young rats. The latency of b-wave and the second component of OPs prolonged during ischemia, and recovery time for the latency was longer in aged rats than in young rats. These results suggest that the electrophysiological function of the retina is less tolerable against ischemia-reperfusion in aged rats than in young rats.


ß1 integrin binding phosphorylates ezrin at T567 to activate a lipid raft signalsome driving invadopodia activity and invasion.
Extracellular matrix (ECM) degradation is a critical process in tumor cell invasion and requires matrix degrading protrusions called invadopodia. The Na(+)/H(+) exchanger (NHE1) has recently been shown to be fundamental in the regulation of invadopodia actin cytoskeleton dynamics and activity. However, the structural link between the invadopodia cytoskeleton and NHE1 is still unknown. A candidate could be ezrin, a linker between the NHE1 and the actin cytoskeleton known to play a pivotal role in invasion and metastasis. However, the mechanistic basis for its role remains unknown. Here, we demonstrate that ezrin phosphorylated at T567 is highly overexpressed in the membrane of human breast tumors and positively associated with invasive growth and HER2 overexpression. Further, in the metastatic cell line, MDA-MB-231, p-ezrin was almost exclusively expressed in invadopodia lipid rafts where it co-localized in a functional complex with NHE1, EGFR, ß1-integrin and phosphorylated-NHERF1. Manipulation by mutation of ezrins T567 phosphorylation state and/or PIP2 binding capacity or of NHE1s binding to ezrin or PIP2 demonstrated that p-ezrin expression and binding to PIP2 are required for invadopodia-mediated ECM degradation and invasion and identified NHE1 as the membrane protein that p-ezrin regulates to induce invadopodia formation and activity.


A decade of decline: Grant funding for researchers with disabilities 2008 to 2018.
Recent data highlights an imbalance in research grant success among groups underrepresented within the biomedical workforce, including racial/ethnic minorities and women. However, there is no data on grant success for researchers with disabilities. For these analyses, aggregate data on self-reported disability status for National Institute on Health (NIH) research grant applicants and awardees was obtained from 2008 to 2018, including disability category: mobility/orthopedic, hearing, visual disabilities, and other disabilities. The percentage of applications and awards, as well as grant success rates (% of applicants receiving awards), by Principal Investigators (PIs) disability status were calculated. Data was desegregated, and logistic models determined trend of applicants reporting disability over time. The percentage of NIH grant applicants with PIs reporting a disability significantly declined from 1.9% in 2008, to 1.2% in 2018 (p<0.001). Data on grant awardees was similar, 1.9% of awards in 2008, declining to 1.2% in 2018 (p<0.001) had PIs reporting a disability. Across all years, the percentage of applications and awards with PIs reporting visual disabilities was lower than the percentage reporting mobility/orthopedic, or hearing disabilities (16.5%, 34.2%, and 37.8% in 2008, respectively). Overall grant success rates differed by disability status (27.2% for those reporting disability vs 29.7% in those reporting no disability, p<0.001). The lowest overall grant success rate was among PIs reporting unknown disability status or who withheld this status (18.6%). These results underscore the underrepresentation of researchers with disabilities among grant applicants and awardees, and indicate lower grant success rates among PIs reporting disabilities.


Interviews with Global Pharmacists and Healthcare Professionals in Great Britain to Establish Personal Experiences around Professional Development Activity.
Professional development activity is needed to ensure practitioners are up to date and providing optimal patient care. This includes, but is not restricted to, mandatory continuing professional development (CPD) or continuing education (CE) requirements, which differ by professions globally and within countries. This study aimed to investigate perceptions, participation, and individual practice for healthcare professionals in Great Britain (GB) and pharmacists globally to identify similarities and differences after the introduction of revalidation for pharmacists in GB. Qualitative data was received through interviews, which was analysed using content analysis. In total, 24 interviews were completed with pharmacists registered globally, and healthcare professionals registered in GB. A culture of CPD was seen for healthcare professionals in GB and globally for pharmacists; there was no consistent model. Face-to-face activity was common, with an increase in online provision, especially where large geographies were seen. Most learning was completed in the professional's own time. Multiple providers were seen, with the evaluation of events using questionnaires being commonplace. Different formats of learning were useful for different topics, with skills learning being better when face-to-face. Although varied requirements were in place, regulation should support patient-based practice outcomes. This study showed that commitment to learning was similar in different professions in GB and by pharmacists globally, with similar benefits and challenges.


Epitope-specific immune responses to rotavirus vaccination.
Rotavirus gastroenteritis is a leading cause of infant mortality in developing countries and an important cause of morbidity in children under 2 yr of age in the United States. Vaccine programs have evaluated animal rotavirus strains that are attenuated in humans but antigenically similar to some human strains. Whether a single vaccine strain can elicit protective immunity in humans to rotaviruses of the same or different serotypes is an important question in determining vaccine efficacy. We used characterized serotype-specific monoclonal antibodies directed at VP7 in a competitive solid-phase immunoassay to measure epitope-specific immune responses to serotypes 1, 2, and 3 in sera of children who received a candidate serotype-3 rotavirus vaccine. Antibodies to serotype 3 were detected in 72% of sera samples, and to serotype 1 and 2 in only 11% each. Also, a VP3-specific monoclonal antibody which neutralizes three serotypically distinct strains of rotavirus was used to detect the presence of similar antibodies in 56% of the test sera. This finding suggests a mechanism of heterotypic immunity.


Impact of the COVID-19 pandemic on referral to and delivery of gynecologic oncology care.
To evaluate the impact of the COVID-19 pandemic on referral to and delivery of gynecologic oncology care at a National Cancer Institute-designated Comprehensive Cancer Center. We conducted a retrospective cohort study of patients referred for evaluation by a gynecologic oncologist at Washington University in St. Louis from October 2019 - February 2020 (pre-COVID-19), and April - August 2020 (COVID-19). The primary outcome, time from referral to evaluation by a gynecologic oncologist, was compared between the two time periods. Secondary outcomes included time from initial evaluation to treatment and delays/interruptions in care due to the pandemic. Sub-group analyses were performed on patients with a cancer diagnosis to evaluate the impact of COVID-19 on treatment decision making. 884 patients were referred during the study period. Total referrals fell by 32% (526 to 358 patients, p < 0.001) and referrals for cancer fell by 18% (228 to 188 patients, p = 0.049). The pandemic did not impact time from referral to initial gynecologic oncology appointment overall (pre-COVID-19: 19.1 vs. COVID-19: 17.4 days, p = 0.315) or among patients with cancer (14.4 vs. 13.9 days, p = 0.662). Time from initial appointment to cancer treatment decreased by 9 days (34 days to 25 days, p = 0.001). Referrals to gynecologic oncology decreased significantly during the early months of COVID-19. Though time from referral to evaluation was not impacted by the pandemic, time to treatment initiation decreased despite institutional changes related to COVID-19.


The next step in learning from sentinel events in healthcare.
The aim of this study was to evaluate the current status of handling and learning from sentinel events (SEs) in Dutch academic hospitals and to develop a basis for the first steps in a joint and transparent approach to improve learning from SEs. Survey by the Netherlands Federation of University Medical Centres (NFU) as part of the project 'Quality-based Governance'. All eight Dutch University Medical Centres (UMCs). Three methods are used to identify the root cause of SEs: the Systematic Incident Reconstruction and Evaluation, Prevention and Recovery Information System for Monitoring and Analysis or TRIPOD method. Experts with different backgrounds are involved in the analysis of SEs. UMCs have different policies regarding the selection of recommendations for implementation. Some UMCs implement all recommendations formulated by the analysis team and in some UMCs the head of the involved department selects recommendations for implementation. No predetermined criteria have been established for this selection. Most UMCs confirm that similar SEs reoccur, which might be due to the quality of the analysis of the SEs or the quality of the recommendations. There is a large variety in handling SEs in Dutch academic hospitals and standards for the selection of recommendations are lacking. A next step to decrease the number of (similar) SEs lies in a joint and transparent approach to objectively assess recommendations and further define strategies for successful implementation. Selecting high-quality recommendations for implementation has the potential to lead to a decrease in the number of (similar) SEs and increase in the quality and safety of Dutch healthcare.


Tularemia: review of eight cases of tick-borne infection and the epidemiology of the disease in Georgia.
In the period 1960 to 1979, 177 cases of tularemia occurred in residents of Georgia. A tick bite was the implicated source of exposure in eight cases (4.5%), whereas 91 cases (51.4%) were associated with direct contact with infected rabbits. In Georgia and other southeastern states, the epidemiology of human tularemia infection primarily involves rabbits. However, a diagnosis of tularemia should still be considered in this region in a febrile patient with or without a primary lesion or reported exposure to rabbits. A history of having been bitten by a tick may be the major clue in determining the diagnosis. A primary ulcerative lesion on the legs or in concealed body areas such as the axillary or intergluteal regions, is commonly the presenting sign in the patient with tick-borne tularemia.


SIZ1 negatively regulates aluminum resistance by mediating the STOP1-ALMT1 pathway in Arabidopsis.
Sensitive to proton rhizotoxicity 1 (STOP1) functions as a crucial regulator of root growth during aluminum (Al) stress. However, how this transcription factor is regulated by Al stress to affect downstream genes expression is not well understood. To explore the underlying mechanisms of the function and regulation of STOP1, we employed a yeast two hybrid screen to identify STOP1-interacting proteins. The SUMO E3 ligase SIZ1, was found to interact with STOP1 and mainly facilitate its SUMO modification at K40 and K212 residues. Simultaneous introduction of K40R and K212R substitutions in STOP1 enhances its transactivation activity to upregulate the expression of aluminum-activated malate transporter 1 (ALMT1) via increasing the association with mediator 16 (MED16) transcriptional co-activator. Loss of function of SIZ1 causes highly increased expression of ALMT1, thus enhancing Al-induced malate exudation and Al tolerance. Also, we found that the protein level of SIZ1 is reduced in response to Al stress. Genetic evidence demonstrates that STOP1/ALMT1 is epistatic to SIZ1 in regulating root growth response to Al stress. This study suggests a mechanism about how the SIZ1-STOP1-ALMT1 signaling module is involved in root growth response to Al stress.


Social Buffering of Stress in Development: A Career Perspective.
This review provides a broad overview of my research group's work on social buffering in human development in the context of the field. Much of the focus is on social buffering of the hypothalamic-pituitary-adrenocortical (HPA) system, one of the two major arms of the mammalian stress system. This focus reflects the centrality of the HPA system in research on social buffering in the fields of developmental psychobiology and developmental science. However, buffering of the cardiovascular and autonomic nervous system is also discussed. The central developmental question in this area derives from attachment theory, which argues that the infant's experience of stress and arousal regulation in the context of her early attachment relationships is not an immature form of social buffering experienced in adulthood but rather the foundation out of which individual differences in the capacity to gain stress relief from social partners emerges. The emergence of social buffering in infancy, changes in social buffering throughout childhood and adolescence, the influence of early experience on later individual differences in social buffering, and critical gaps in our knowledge are described.


CT Features of Coronavirus Disease 2019 (COVID-19) Pneumonia in 62 Patients in Wuhan, China.
OBJECTIVE. The purpose of this study was to investigate 62 subjects in Wuhan, China, with laboratory-confirmed coronavirus disease (COVID-19) pneumonia and describe the CT features of this epidemic disease. MATERIALS AND METHODS. A retrospective study of 62 consecutive patients with laboratory-confirmed COVID-19 pneumonia was performed. CT images and clinical data were reviewed. Two thoracic radiologists evaluated the distribution and CT signs of the lesions and also scored the extent of involvement of the CT signs. The Mann-Whitney U test was used to compare lesion distribution and CT scores. The chi-square test was used to compare the CT signs of early-phase versus advanced-phase COVID-19 pneumonia. RESULTS. A total of 62 patients (39 men and 23 women; mean [± SD] age, 52.8 ± 12.2 years; range, 30-77 years) with COVID-19 pneumonia were evaluated. Twenty-four of 30 patients who underwent routine blood tests (80.0%) had a decreased lymphocyte count. Of 27 patients who had their erythrocyte sedimentation rate and high-sensitivity C-reactive protein level assessed, 18 (66.7%) had an increased erythrocyte sedimentation rate, and all 27 (100.0%) had an elevated high-sensitivity C-reactive protein level. Multiple lesions were seen on the initial CT scan of 52 of 62 patients (83.9%). Forty-eight of 62 patients (77.4%) had predominantly peripheral distribution of lesions. The mean CT score for the upper zone (3.0 ± 3.4) was significantly lower than that for the middle (4.5 ± 3.8) and lower (4.5 ± 3.7) zones (p = 0.022 and p = 0.020, respectively), and there was no significant difference in the mean CT score of the middle and lower zones (p = 1.00). The mean CT score for the anterior area (4.4 ± 4.1) was significantly lower than that for the posterior area (7.7 ± 6.3) (p = 0.003). CT findings for the patients were as follows: 25 patients (40.3%) had ground-glass opacities (GGO), 21 (33.9%), consolidation; 39 (62.9%), GGO plus a reticular pattern; 34 (54.8%), vacuolar sign; 28 (45.2%), microvascular dilation sign; 35 (56.5%), fibrotic streaks; 21 (33.9%), a subpleural line; and 33 (53.2%), a subpleural transparent line. With regard to bronchial changes seen on CT, 45 patients (72.6%) had air bronchogram, and 11 (17.7%) had bronchus distortion. In terms of pleural changes, CT showed that 30 patients (48.4%) had pleural thickening, 35 (56.5%) had pleural retraction sign, and six (9.7%) had pleural effusion. Compared with early-phase disease (≤ 7 days after the onset of symptoms), advanced-phase disease (8-14 days after the onset of symptoms) was characterized by significantly increased frequencies of GGO plus a reticular pattern, vacuolar sign, fibrotic streaks, a subpleural line, a subpleural transparent line, air bronchogram, bronchus distortion, and pleural effusion; however, GGO significantly decreased in advanced-phase disease. CONCLUSION. CT examination of patients with COVID-19 pneumonia showed a mixed and diverse pattern with both lung parenchyma and the interstitium involved. Identification of GGO and a single lesion on the initial CT scan suggested early-phase disease. CT signs of aggravation and repair coexisted in advanced-phase disease. Lesions presented with a characteristic multifocal distribution in the middle and lower lung regions and in the posterior lung area. A decreased lymphocyte count and an increased high-sensitivity C-reactive protein level were the most common laboratory findings.


Acceptability and Demand of Therapy Dog Support Among Oral Health Care Providers and Caregivers of Pediatric Patients.
Purpose: This cross-sectional study evaluated the acceptability and demand for therapy dog support in pediatric dentistry (TDSPD). Methods: Caregiver surveys measured acceptability and demand for TDSPD using a five-point Likert scale (one equals "not at all", five equals "very much"). Provider surveys measured acceptability for TDSPD using a five-point Likert scale. Scores of four or five were regarded as positive. Surveys were administered in the pediatric dental clinic at Case Western Reserve University, Cleveland, Ohio. Results: The mean±SD of acceptability and demand from the caregiver survey was 4.67±0.96 and 3.86±1.61, respectively. Ninety percent (n equals 174) of caregivers indicated acceptability for TDSPD to support their child. Sixty-eight percent (n equals 130) of caregivers indicated demand for TDSPD. The mean±SD of acceptability from the provider survey was 3.63±1.50. Sixty-two percent (n equals 47) of provider survey respondents accepted the overall integration of therapy dogs to support patients. Thematic analysis of the qualitative provider responses yielded concerns for risk of accident (36 percent), infection control (50 percent), and clinic efficiency (33 percent). Caregiver survey qualitative responses were positive (68 percent), with respondents also sharing concerns for efficiency and zoonosis. Conclusions: Responses support the acceptability of and demand for therapy dog support in pediatric dentistry.


Diagnostic and Predictive Applications of Functional Near-Infrared Spectroscopy for Major Depressive Disorder: A Systematic Review.
Major depressive disorder (MDD) is a global psychiatric disorder with no established biomarker. There is growing evidence that functional near-infrared spectroscopy (fNIRS) has the ability to aid in the diagnosis and prediction of the treatment response of MDD. The aim of this review was to systematically review, and gather the evidence from existing studies that used fNIRS signals in the diagnosis of MDD, correlations with depression symptomatology, and the monitoring of treatment response. PubMed, EMBASE, ScienceDirect, and Cochrane Library databases were searched for published English articles from 1980 to June 2019 that focused on the application of fNIRS for (i) differentiating depressed versus nondepressed individuals, (ii) correlating with depression symptomatology, and in turn (iii) monitoring treatment responses in depression. Studies were included if they utilized fNIRS to evaluate cerebral hemodynamic variations in patients with MDD of any age group. The quality of the evidence was assessed using the Newcastle-Ottawa quality assessment scale. A total of 64 studies were included in this review, with 12 studies being longitudinal, while the rest were cross-sectional. More than two-thirds of the studies (n = 49) had acceptable quality. fNIRS consistently demonstrated attenuated cerebral hemodynamic changes in depressed compared to healthy individuals. fNIRS signals have also shown promise in correlating with individual symptoms of depression and monitoring various treatment responses. This review provides comprehensive updated evidence of the diagnostic and predictive applications of fNIRS in patients with MDD. Future studies involving larger sample sizes, standardized methodology, examination of more brain regions in an integrative approach, and longitudinal follow-ups are needed.


Multiplexed Luminex xMAP assay for detection and identification of five adenovirus serotypes associated with epidemics of respiratory disease in adults.
Several serotypes of human adenovirus (HAdV) cause acute respiratory disease (ARD) among healthy adults, sometimes generating broad outbreaks with high attack rates and occasional fatalities. Timely serotype identification provides valuable epidemiological information and significantly contributes to prevention (vaccination) strategies. The prevalence of specific serotypes causing ARD varies geographically. HAdV-3, HAdV-4, HAdV-7, HAdV-14, and HAdV-21 are the serotypes most commonly found in adult populations in the Western Hemisphere. Unfortunately, conventional serotype identification is a tedious process which can take a week or longer. For this reason, new molecular methods for serotype identification are needed. Commercially available rapid antigen and PCR assays for the detection of HAdV are universal but do not distinguish between the different serotypes. We describe the development of a sensitive and specific multiplex assay capable of identifying serotypes 3, 4, 7, 14, and 21. Two sets of primers were used for nonspecific (universal) PCR amplification, and serotype-specific probes coupled to Luminex tags were used for target-specific extension (TSE). PCR and TSE primers were designed using known hexon gene sequences of HAdV. The TSE products of HAdV-3, HAdV-4, HAdV-7, HAdV-14, and HAdV-21 were correctly identified using the Luminex xMAP fluid microsphere-based array system. No cross-reactivity with other respiratory pathogens or other HAdV serotypes was observed. This multiplexed assay can be expanded to include more serotypes and will allow broad and rapid detection and identification of adenoviral serotypes in a high-throughput environment.


The use of three-dimensional nanostructures to instruct cells to produce extracellular matrix for regenerative medicine strategies.
Synthetic polymers or naturally-derived extracellular matrix (ECM) proteins have been used to create tissue engineering scaffolds; however, the need for surface modification in order to achieve polymer biocompatibility and the lack of biomechanical strength of constructs built using proteins alone remain major limitations. To overcome these obstacles, we developed novel hybrid constructs composed of both strong biosynthetic materials and natural human ECM proteins. Taking advantage of the ability of cells to produce their own ECM, human foreskin fibroblasts were grown on silicon-based nanostructures exhibiting various surface topographies that significantly enhanced ECM protein production. After 4 weeks, cell-derived sheets were harvested and histology, immunochemistry, biochemistry and multiphoton imaging revealed the presence of collagens, tropoelastin, fibronectin and glycosaminoglycans. Following decellularization, purified sheet-derived ECM proteins were mixed with poly(epsilon-caprolactone) to create fibrous scaffolds using electrospinning. These hybrid scaffolds exhibited excellent biomechanical properties with fiber and pore sizes that allowed attachment and migration of adipose tissue-derived stem cells. Our study represents an innovative approach to generate strong, non-cytotoxic scaffolds that could have broad applications in tissue regeneration strategies.


Performance of Glow Fixation GoCheck Kids and 2WIN Photoscreeners and Retinomax to Uncover Hyperopia.
A low-detail, glowing fixation device was added to GoCheck Kids (GCK) photoscreener in the hope of unmasking hyperopia and amblyopia risk factors (ARF). Pediatric eye patients were screened by GCK and 2WIN photoscreeners, and Retinomax autorefractor before being compared to AAPOS ARFs. Screening was attempted by 131 children who then had school bus accommodation-relaxing skiascopy (SBA-RS) before cycloplegic examination. By 2013 AAPOS uniform guidelines, sensitivity/specificity for GCK was 87%/68%, for 2WIN 87%/71% and for Retinomax 79%/68%. Detection of amblyopia had sensitivity/specificity by GCK of 78%/63%, for 2WIN 79%/65% and for Retinomax 77%/68%. Inconclusive screens were seven for GCK, six for 2WIN and 13 for Retinomax. Mean hyperopia for GCK (+2.49±0.74 D) was similar to cycloplegic refraction (+2.93±0.72 D) and SBA-RS (+2.80±0.82 D) while GCK was slightly more than Retinomax (+1.59±0.93 D, p=0.13) but significantly more than 2WIN (+1.02±0.49 D, p<0.01). GCK, 2WIN and Retinomax had similar validity detecting uniform amblyopia risk factors and amblyopia itself. The nondetailed glow fixation device allowed GCK to uncover substantial hyperopia while the detailed flashing fixation devices on 2WIN and Retinomax seemed to stimulate accommodation in some hyperopic children. NCT04297969. Data Access: http://www.abcd-vision.org/references/GCK%20glow%202WIN%20deidentify.pdf. A glow fixation device on a smart phone photoscreener allowed robust detection of hyperopia.


Thinking in circuits: toward neurobiological explanation in cognitive neuroscience.
Cognitive theory has decomposed human mental abilities into cognitive (sub) systems, and cognitive neuroscience succeeded in disclosing a host of relationships between cognitive systems and specific structures of the human brain. However, an explanation of why specific functions are located in specific brain loci had still been missing, along with a neurobiological model that makes concrete the neuronal circuits that carry thoughts and meaning. Brain theory, in particular the Hebb-inspired neurocybernetic proposals by Braitenberg, now offers an avenue toward explaining brain-mind relationships and to spell out cognition in terms of neuron circuits in a neuromechanistic sense. Central to this endeavor is the theoretical construct of an elementary functional neuronal unit above the level of individual neurons and below that of whole brain areas and systems: the distributed neuronal assembly (DNA) or thought circuit (TC). It is shown that DNA/TC theory of cognition offers an integrated explanatory perspective on brain mechanisms of perception, action, language, attention, memory, decision and conceptual thought. We argue that DNAs carry all of these functions and that their inner structure (e.g., core and halo subcomponents), and their functional activation dynamics (e.g., ignition and reverberation processes) answer crucial localist questions, such as why memory and decisions draw on prefrontal areas although memory formation is normally driven by information in the senses and in the motor system. We suggest that the ability of building DNAs/TCs spread out over different cortical areas is the key mechanism for a range of specifically human sensorimotor, linguistic and conceptual capacities and that the cell assembly mechanism of overlap reduction is crucial for differentiating a vocabulary of actions, symbols and concepts.


Enhanced Gasdermin-E-mediated Pyroptosis in Alzheimer's Disease.
Amyloid β protein (Aβ) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Aβ induces apoptosis, and gasdermin-E (GSDME) expression can switch apoptosis to pyroptosis. In this study, we demonstrated that GSDME was highly expressed in the hippocampus of APP23/PS45 mouse models compared to that in age-matched wild-type mice. Aβ treatment induced pyroptosis by active caspase-3/GSDME in SH-SY5Y cells. Furthermore, the knockdown of GSDME improved the cognitive impairments of APP23/PS45 mice by alleviating inflammatory response. Our findings reveal that GSDME, as a modulator of Aβ and pyroptosis, plays a potential role in Alzheimer's disease pathogenesis and shows that GSDME is a therapeutic target for AD.


Changes in bowel habits and patient-scored symptoms after Roux-en-Y gastric bypass and biliopancreatic diversion with duodenal switch.
Bariatric procedures are increasingly being used, but data on bowel habits are scarce. To assess changes in gastrointestinal function and patient-scored symptoms after Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion with duodenal switch (BPD/DS). University hospital in Sweden. We recruited 268 adult patients (mean age of 42.5 yr, body mass index 44.8, 67.9% female) listed for RYGB and BPD/DS. Patients answered validated questionnaires prospectively concerning bowel function, the Fecal Incontinence Quality of Life Scale, and the 36-Item Short Form Health Survey before and after their operation. Postoperatively, 208 patients (78.2% of 266 eligible patients) answered the questionnaires. RYGB patients had fewer bowel motions per week (8 versus 10) and more abdominal pain postoperatively (P<.001). Postoperatively, the 35 BPD/DS patients (69% versus 23%) needed to empty their bowel twice or more than twice daily, reported more flatus and urgency, and increased need for keeping a diet (P<.001). Concerning Fecal Incontinence Quality of Life Scale, coping and behavior was slightly reduced while depression and self-perception scores were improved after RYGB. Lifestyle, coping and behavior, and embarrassment were reduced after BPD/DS (P<.05). In the 36-Item Short Form Health Survey, physical scores were markedly improved, while mental scores were largely unaffected. RYGB resulted in a reduced number of bowel movements but increased problems with abdominal pain. In contrast, BPD/DS-patients reported higher frequency of bowel movements, more troubles with flatus and urgency, and increased need for keeping a diet. These symptoms affected quality of life negatively, however, general quality of life was markedly improved after both procedures. These results will be of great value for preoperative counseling.


A model of organisational dysfunction in the NHS.
This paper explores the reasons for the sometimes seemingly irrational and dysfunctional organisational behaviour within the NHS. It seeks to provide possible answers to the persistent historical problem of intimidating and negative behaviour between staff, and the sometimes inadequate organisational responses. The aim is to develop a model to explain and increase understanding of such behaviour in the NHS. This paper is conceptual in nature based upon a systematic literature review. The concepts of organisational silence, normalised organisational corruption, and protection of image, provide some possible answers for these dysfunctional responses, as does the theory of selective moral disengagement. The NHS exhibits too high a level of collective ego defences and protection of its image and self-esteem, which distorts its ability to address problems and to learn. Organisations and the individuals within them can hide and retreat from reality and exhibit denial; there is a resistance to voice and to "knowing". The persistence and tolerance of negative behaviour is a corruption and is not healthy or desirable. Organisations need to embrace the identity of a listening and learning organisation; a "wise" organisation. The "Elephant in the room" of persistent negative behaviour has to be acknowledged; the silence must be broken. There is a need for cultures of "respect", exhibiting "intelligent kindness". A model has been developed to increase understanding of dysfunctional organisational behaviour in the NHS primarily for leaders/managers of health services, health service regulators and health researchers/academics. Research, with ethical approval, is currently being undertaken to test and develop the conceptual model to further reflect the complexities of the NHS culture.


[False low oximetry reading caused by patent blue vital dye during breast surgery].
Patent blue vital (patent blue V; Laboratoire Guerbet, France) is used to identify the sentinel node during surgery for invasive breast cancer. Detecting the sentinel node that first drains the primary tumor reduces the need for total breast and wide axillary node removal, with the problems that such radical surgery involves. Like other dyes, patent blue V can interfere with accurate pulse oximeter reading, leading to underestimation of real values. We report the case of a 31-year-old woman who underwent lumpectomy and removal of the sentinel node. After intradermal injection of patent blue V dye into the left breast (100 mg administered because the sentinel node was difficult to locate) a drop in peripheral oxyhemoglobin saturation from 99% to 93% was detected by the pulse oximeter. When arterial blood gas analysis showed normal values and other causes were ruled out, the diagnosis was false low oximetry reading due to patent blue V dye.


Cost-effectiveness of adding a non-invasive acoustic rule-out test in the evaluation of patients with symptoms suggestive of coronary artery disease: rationale and design of the prospective, randomised, controlled, parallel-group multicenter FILTER-SCAD trial.
Most patients with symptoms suggestive of chronic coronary syndrome (CCS) have no obstructive coronary artery disease (CAD) and better selection of patients to be referred for diagnostic tests is needed. The CAD-score is a non-invasive acoustic measure that, when added to pretest probability of CAD, has shown good rule-out capabilities. We aimed to test whether implementation of CAD-score in clinical practice reduces the use of diagnostic tests without increasing major adverse cardiac events (MACE) rates in patients with suspected CCS. FILTER-SCAD is a randomised, controlled, multicenter trial aiming to include 2000 subjects aged ≥30 years without known CAD referred for outpatient assessment for symptoms suggestive of CCS. Subjects are randomised 1:1 to either the control group: standard diagnostic examination (SDE) according to the current guidelines, or the intervention group: SDE plus a CAD-score. The subjects are followed for 12 months for the primary endpoint of cumulative number of diagnostic tests and a safety endpoint (MACE). Angina symptoms, quality of life and risk factor modification will be assessed with questionnaires at baseline, 3 months and 12 months after randomisation. The study is powered to detect superiority in terms of a reduction of ≥15% in the primary endpoint between the two groups with a power of 80%, and non-inferiority on the secondary endpoint with a power of 90%. The significance level is 0.05. The non-inferiority margin is set to 1.5%. Randomisation began on October 2019. Follow-up is planned to be completed by December 2022. This study has been approved by the Danish Medical Agency (2019024326), Danish National Committee on Health Research Ethics (H-19012579) and Swedish Ethical Review Authority (Dnr 2019-04252). All patients participating in the study will sign an informed consent. All study results will be attempted to be published as soon as possible. NCT04121949; Pre-results.