The influence of charge clustering on the anti-HIV-1 activity and in vivo distribution of negatively charged albumins.
The substitution of human serum albumin with negatively charged molecules, such as succinic acid (Suc-HSA) or aconitic acid (Aco-HSA), resulted in proteins with potent anti-HIV activities, by binding to viral gp120 (V3 loop). The aim of the present study was to investigate whether the distribution of negative charges on the albumin backbone influences the anti-HIV activity. Therefore, we prepared albumins with clusters of negatively charged groups by coupling of heparin. The effects of this substitution on anti-HIV activity, in vivo distribution and the protein structure as compared to random succinylation were assessed. In vitro studies indicated that HSA-modified with heparin 6 or 13 kD displayed anti-HIV activity (IC50=660 and 37 nM, respectively) and exhibited affinity for gp120-V3 loop, although the activity was lower than that of Suc-HSA. Combined derivatization of HSA with heparin 13 kD and aconitic acid groups resulted in significantly increased inhibitory actions (IC50=2.8 nM). Structural analysis showed that modification of HSA with heparin did not lead to extensive unfolding of the protein, meaning that these modified proteins were still globular in structure. In contrast, succinylation of HSA resulted in a highly randomly coiled conformation. Dynamic light scattering experiments revealed that, at neutral pH, the heparin fragments attached to the protein were wrapped around the molecule rather than sticking out into the solution. In conclusion, coupling of sufficient clustered negative charges, by coupling of Hep-fragments, on HSA resulted in a clear anti-HIV activity of the protein. Yet, random distribution of anionic groups in the albumin seemed more optimal for in vitro anti-HIV activity. The higher plasma and lymphatic concentrations of Hep-HSA compared to Suc-HSA seemed more favorable for an anti-HIV activity in vivo.


Validation of a testosterone and dihydrotestosterone liquid chromatography tandem mass spectrometry assay: Interference and comparison with established methods.
Testosterone (T) and its metabolite dihydrotestosterone (DHT) are androgens with different biologic profiles. T and DHT measurements are required for assessment of patients with ambiguous genitalia, hirsutism, during 5 alpha reductase treatment of prostate disorders, and new androgen formulations. Our laboratory has developed and validated a method to simultaneously measure serum T and DHT with liquid chromatography tandem mass spectrometry (LC-MS/MS) for use in a clinical chemistry laboratory. Analysis of sera from blood collected in tubes containing clot activator gave results of T that were fourfold higher than blood collected in plain tubes. Changing the ion pair selected for monitoring eliminated this interference by clot activators. Blood collected in fluoride-coated tubes gave serum T and DHT levels that were 20 and 15% lower, respectively than levels measured in blood collected in plain tubes (no additives). Addition of T enanthate to blood collected in plain tubes caused a dose related increase serum T levels due to the action of non-specific esterases in the red cells. This esterase activity could be avoided by using fluoride tubes for blood collection. Serum DHT levels were consistently lower when measured by LC-MS/MS versus radioimmunoassay. The differences were concentration dependent and the variance for the difference was large when serum DHT concentration was low. Celite chromatograph prior to radioimmunoassay reduced the differences between the two methods, thus confirming that higher levels of DHT obtained by immunoassays were probably due to interfering substances which were partially removed by Celite chromatography.


A Comparative Analysis on the Environmental Impact of Selected Methods for Determining the Profile of Fatty Acids in Cheese.
The fatty acid profile of cheese influences its sensory parameters, such as color, texture, or flavor. Examining the fatty acid profile also helps to assess the nutritional value of the cheese that is being tested. However, the determination of fatty acids in cheese samples is a multi-stage and time-consuming task. In addition, large amounts of toxic organic solvents are used to prepare samples for analysis purposes. This paper presents the results of a study to determine the fatty acid profile of yellow cheese samples. Six different methods of sample preparation were compared for analysis purposes. The profile of fatty acids was determined using gas chromatography with flame ionization detection (GC-FID). The study showed significant differences (p > 0.05) in the resulting fatty acid profile between the methods used. It was found that the most reliable fatty acid profile results were obtained using methods derived from the Folch method. In addition, tools such as the Analytical Eco-Scale tool and the Analytical Greenness Metric for Sample Preparation (AGREEprep) tool were used to assess the greenness of the methods used. In the case of the Analytical Eco-Scale tool, all six methods scored 'acceptable green analysis' with scores ranging from 61 to 73. However, an evaluation of methods using the AGREEprep metric showed that the results of the methods (0.13-0.27) did not show the "greenness" of the analytical methods.


Influence of polymorphic variations of IFNL, HLA, and IL-6 genes in severe cases of COVID-19.
The administration of vaccination doses to the global population has led to a decrease in the incidence of COVID-19. However, the clinical picture developed by infected individuals remains extremely concerning due to the great variability in the severity of cases even in vaccinated individuals. The clinical progression of the pathology is characterized by various influential factors such as sex, age group, comorbidities, and the genetics of the individual. The immune response to viral infections can be strongly influenced by the genetics of individuals; nucleotide variations called single-nucleotide polymorphisms (SNPs) in structures involved in the innate and adaptive immune response such as interferon (IFN)-λ, human leukocyte antigen (HLA), and interleukin (IL)-6 are frequently associated with pathological progression. In this study, we conducted a review of the main SNPs of these structures that are associated with severity in COVID-19. Searches were conducted on some platforms of the National Center for Biotechnology and Information (NCBI), and 102 studies were selected for full reading according to the inclusion criteria. IFNs showed a strong association with antiviral function, specifically, IFN-λ3 (IL-28B) demonstrated genetic variants commonly related to clinical progression in various pathologies. For COVID-19, rs12979860 and rs1298275 presented frequently described unfavorable genotypes for pathological conditions of hepatitis C and hepatocellular carcinoma. The high genetic variability of HLA was reported in the studies as a crucial factor relevant to the late immune response, mainly due to its ability to recognize antigens, with the HLA-B*46:01 SNP being associated with susceptibility to COVID-19. For IL-6, rs1554606 showed a strong relationship with the clinical progression of COVID-19. In addition, rs2069837 was identified with possible host protection relationships when linked to this infection.


Right coronary artery fistula misdiagnosed as right atrial cardiac myxoma: A case report.
The current study describes a case of right coronary artery fistula (CAF) misdiagnosed as right atrial myxoma (RAM). A 33-year-old man presented with a 13-year history of intermittent chest pain, and aggravation for 3 days. Echocardiography revealed an occupying lesion in the right atrium producing a partial dynamic tricuspid obstruction. The initial diagnosis was RAM, which causes partial right ventricular inflow tract obstruction. During cardiopulmonary bypass surgery, a giant mass was detected in the anterior wall of the right ventricle and an abnormal vascular fistula was observed at the bottom of the mass. Successful excision of the mass and closure of the fistula completely relieved the patient's presenting symptoms. The disease was subsequently diagnosed as right CAF draining to the myocardial void. The surgical management and misdiagnosis of the case are discussed herein.


Aminoterminal propeptide of type III procollagen in cord blood and amniotic fluid of appropriate-for-gestational-age infants: a predictor of age-related fetal growth rate.
Procollagen propeptide serum levels reflect the rate of collagen production. Because the prenatal period is unrivaled in terms of relative amounts of collagen synthesized per unit of time, this life episode must be the most sensitive period for the study of these biochemical markers of growth variability. N-terminal propeptide of type III procollagen (PIIINP) concentration was measured by two different methods (Fab'-fragment and whole antibody-based RIA assay) on paired samples of cord serum and amniotic fluid from a study cohort of 602 perinates with gestational age ranging from 20 to 41 wk. The aim of this study is to assess the clinical usefulness of the PIIINP assay for the evaluation of fetal somatic growth variation during the second half of normal pregnancies. It was demonstrated that the PIIINP level in cord serum, as well as in amniotic fluid, reflects age-related growth activity in "healthy" fetuses (n = 504) with normal intrauterine growth. This reflection was independent of the cumulative body mass or length already attained at the time of investigation. The PIIINP concentration closely mirrors the shape of the fetal somatic growth velocity curve, expressed as weight-specific gain (g/kg/d) during the second half of pregnancy. It can be concluded that PIIINP level in cord blood or amniotic fluid of fetuses with normal intrauterine growth is an interesting parameter for the assessment of maturity-related fetal growth potential.


Crystallization and preliminary crystallographic analysis of the ferredoxin component of carbazole 1,9a-dioxygenase from Nocardioides aromaticivorans IC177.
Carbazole 1,9a-dioxygenase (CARDO) catalyzes the dihydroxylation of carbazole by angular position (C9a) carbon bonding to the imino nitrogen and its adjacent C1 carbon. CARDO consists of a terminal oxygenase component and two electron-transfer components: ferredoxin and ferredoxin reductase. The ferredoxin component of carbazole 1,9a-dioxygenase from Nocardioides aromaticivorans IC177 was crystallized at 293 K using the hanging-drop vapour-diffusion method with ammonium sulfate as the precipitant. The crystals, which were improved by macroseeding, diffract to 2.0 A resolution and belong to space group P4(1)2(1)2.


[Study on Steady State Visual Evoked Potential Target Detection Based on Two-dimensional Ensemble Empirical Mode Decomposition].
Brain computer interface is a control system between brain and outside devices by transforming electroencephalogram (EEG) signal. The brain computer interface system does not depend on the normal output pathways, such as peripheral nerve and muscle tissue, so it can provide a new way of the communication control for paralysis or nerve muscle damaged disabled persons. Steady state visual evoked potential (SSVEP) is one of non-invasive EEG signals, and it has been widely used in research in recent years. SSVEP is a kind of rhythmic brain activity simulated by continuous visual stimuli. SSVEP frequency is composed of a fixed visual stimulation frequency and its harmonic frequencies. The two-dimensional ensemble empirical mode decomposition (2D-EEMD) is an improved algorithm of the classical empirical mode decomposition (EMD) algorithm which extended the decomposition to two-dimensional direction. 2D-EEMD has been widely used in ocean hurricane, nuclear magnetic resonance imaging (MRI), Lena image and other related image processing fields. The present study shown in this paper initiatively applies 2D-EEMD to SSVEP. The decomposition, the 2-D picture of intrinsic mode function (IMF), can show the SSVEP frequency clearly. The SSVEP IMFs which had filtered noise and artifacts were mapped into the head picture to reflect the time changing trend of brain responding visual stimuli, and to reflect responding intension based on different brain regions. The results showed that the occipital region had the strongest response. Finally, this study used short-time Fourier transform (STFT) to detect SSVEP frequency of the 2D-EEMD reconstructed signal, and the accuracy rate increased by 16%.


Antibacterial and in vitro anticancer activities of the antimicrobial peptide NRC-07 encapsulated in chitosan nanoparticles.
Antimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics and chemotherapy in the treatment of multidrug-resistant pathogens and drug-resistant cancers. Clinical application of AMPs is limited due to low stability and inefficient transport. Encapsulation in nanocarriers may improve their therapeutic potential. Chitosan nanoparticles (CS-NPs) are efficient carriers for proteins and peptides, improving the treatment of microbial infections and targeted drug delivery. We examined toxicity against cancer cell lines and antibacterial activities of the pleurocidin-like AMP NRC-07 upon encapsulation in CS-NPs by ionotropic gelation. The biological activities of various formulations of free and encapsulated NRC-07 and free nanoparticles were evaluated against Pseudomonas aeruginosa and breast cancer cells, using assays for cell viability and lactate dehydrogenase cytolysis with non-cancer cell lines as controls. NRC-07-containing nanoparticles decreased the bacterial and cancer cell viability in a concentration-dependent manner. Activities of encapsulated peptide were >2-fold higher than those of free NRC-07 peptide. Unloaded CS-NPs and free peptide were not cytotoxic against control cells. Encapsulation of NRC-07 into CS-NPs enhanced the antibacterial and selective cytotoxicity of the peptide, possibly enhancing anticancer activities. Encapsulation presents a promising tool for the development of efficient drug delivery systems.


Prevention of galactosamine-induced hepatotoxicity in rats with fructose-1,6-diphosphate.
Galactosamine (GalN) administration produces hepatitis-like liver injury in animals. The hepatotoxicity of GalN is attenuated by several interventions, including activation of the reticuloendothelial system (RES). Fructose-1,6-diphosphate (FDP) administration significantly increases the phagocytic activity of the RES in animals. Thus, investigations were designed to determine whether FDP affords protection against GalN toxicity. Rats were injected with GalN (375 mg/kg) and treated with 0.9% NaCl (n = 8) or FDP (n = 9). Eight rats were sham-operated. Serum glutamic oxaloacetic transaminase was 40 times higher in the saline group as compared to the FDP-treated rats (p less than 0.0001). Glutamic pyruvic transaminase, gamma-glutamyltranspeptidase and bilirubin were similarly elevated (saline vs. FDP, p less than 0.005, p less than 0.01 and p less than 0.05, respectively). These values were not different between FDP-treated and sham-operated rats. Extensive hepatic necrosis was observed in all saline-treated rats, whereas in the FDP group only isolated foci of hepatocellular necrosis were noted. The hepatoprotective effect of FDP in this model is attributed to its ability to enhance the phagocytic activity of RES and to suppress release of oxyradicals by the leukocytes during the inflammatory phase.


Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors.
Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.


Growth factor delivery to re-engineer periodontal tissues.
Repair of tooth-supporting structures destroyed by the chronic inflammatory disease periodontitis is a major goal of oral therapy. The field of tissue engineering combines materials science and biology to repair tissues and organs. Periodontal tissue engineering has been achieved with limited success by the utilization of guiding tissue (cell occlusive) membranes and bone grafting techniques. Over the past decade investigators have begun to utilize signaling molecules such as growth factors to restore lost tooth support due to periodontitis, the most common bone disease affecting humans. This review will provide information on the status of growth factor therapies being applied in periodontology to treat advanced alveolar bone loss.


The use of formaldehyde-treated 131-I-albumin in the study of digestive vacuoles and some properties of these particles from mouse liver.
The trichloroacetic acid-soluble radioactivity released during incubation of mouse liver particles containing intravenously injected formaldehyde-treated (131)I-albumin consisted almost entirely of (131)I-iodotyrosine. The material was shown to be excreted into the medium and was not due to disruption of the particles by acid. Triton X-100 or the absence of sucrose in the medium inhibited hydrolysis of the particle-associated labeled protein. This inhibition was due to disruption of the digestive vacuoles and dilution of the protein and cathepsins in the suspending medium. These results and other experimental evidence strongly suggest that the (131)I-albumin-containing liver particles are digestive vacuoles. The results also establish that (131)I-albumin may be used to study these vacuoles. High concentrations of sucrose (1 M) inhibited degradation of intraparticulate protein. However, 1 M salts inhibited only the rate of the digestion. Sucrose had an inhibitory effect on a crude cathepsin preparation, and salts stimulated the activity when (131)I-albumin was used as substrate. The effect of high sucrose concentrations as an inhibitor of protein hydrolysis within digestive vacuoles was, therefore, most likely due principally to an inhibition of cathepsin activity within the vacuoles. The effect of salt was probably caused by a stimulation of both intra- and extra-particulate cathepsin activities, although 0.5-1.0 M KCl appeared to protect the particles.


Differences in psychosocial responses to pain between sufficiently and insufficiently active adults with arthritis.
Adults with arthritis struggle to meet the physical activity recommendation for disease self-management. Identifying psychosocial factors that differentiate adults who meet (sufficiently active) or do not meet (insufficiently active) the recommendation is needed. This study sought to examine differences in psychosocial responses to arthritis pain among adults who were sufficiently or insufficiently active. This prospective study included adults with medically diagnosed arthritis (N = 136, Mage = 49.75 ± 13.88 years) who completed two online surveys: (1) baseline: pain and psychosocial responses to pain and (2) two weeks later: physical activity. Psychosocial responses examined in this study were psychological flexibility in response to pain, pain anxiety and maladaptive responses to pain anxiety. A between-groups MANCOVA comparing sufficiently active (n = 87) to insufficiently active (n = 49) participants on psychosocial responses, after controlling for pain intensity, was significant (p = .005). Follow-up ANOVA's revealed that sufficiently active participants reported significantly higher psychological flexibility and used maladaptive responses less often compared to insufficiently active participants (p's < .05). These findings provide preliminary insight into the psychosocial profile of adults at risk for nonadherence due to their responses to arthritis pain.


Injectable dexamethasone administration enhances cortical GABAergic neuronal differentiation in a novel model of postnatal steroid therapy in mice.
Injectable dexamethasone (DXM) is widely used during the postnatal period in premature infants. However, this treatment has been associated with an increased incidence of neuromotor disorders. Few studies have directly addressed the impact of DXM therapy on neuronal differentiation. We used a murine model of postnatal steroid therapy in which mouse pups aged 3 and 4 postnatal days (P) received intraperitoneal injections of 1 mg . kg(-1) . 12 h(-1) of an injectable preparation that contained DXM and sulfites (DXM), pure DXM, or sulfites. The animals were weighed before they were killed on P5, P10, or P21, and their brains were investigated by immunohistochemistry with markers for neuronal differentiation. DXM administration was associated with a 20-30% reduction in body and brain weight gains and in cortical thickness on P5 and P10. gamma-Amino-butyric acid+ (GABA+) interneuron density was significantly increased (+50%) in the cerebral cortex of the animals given injectable DXM on P5 to P21 compared with controls (p < 0.01). In parallel, the density of cortical neurons expressing two interneuron markers (calbindin 28-kD and calretinin) increased significantly. These alterations occurred with injectable DXM but not with pure DXM or sulfites alone. In contrast, none of the study treatments modified the expression of other markers for neuronal transmission or axon myelination. In the animals that were given injectable DXM, cleaved caspase 3 antibody showed increased neuronal cell death, but calbindin antibody did not. In conclusion, in a murine model of postnatal steroid therapy, injectable DXM induced a selective increase in GABAergic neurons in the cerebral cortex.


[Pompe disease is a differential diagnosis in case of reduced physical capacity and abnormal muscular fatigue].
Late-onset Pompe disease is an inherited metabolic myopathy with low activity of alpha glucosidase and variable clinical symptoms. In this case report we describe a woman with long standing muscular fatigue and malaise with the diagnosis initially established by pathologic findings in the muscle biopsy. Enzyme replacement therapy is now a treatment option, and a prompt diagnosis is therefore relevant. This disease should be considered in patients with unexplained fatigue and reduced physical capacity, especially in case of concurrent elevated levels of creatine kinase and liver enzymes.


Selection bias and subject refusal in a cluster-randomized controlled trial.
Selection bias and non-participation bias are major methodological concerns which impact external validity. Cluster-randomized controlled trials are especially prone to selection bias as it is impractical to blind clusters to their allocation into intervention or control. This study assessed the impact of selection bias in a large cluster-randomized controlled trial. The Improved Cardiovascular Risk Reduction to Enhance Rural Primary Care (ICARE) study examined the impact of a remote pharmacist-led intervention in twelve medical offices. To assess eligibility, a standardized form containing patient demographics and medical information was completed for each screened patient. Eligible patients were approached by the study coordinator for recruitment. Both the study coordinator and the patient were aware of the site's allocation prior to consent. Patients who consented or declined to participate were compared across control and intervention arms for differing characteristics. Statistical significance was determined using a two-tailed, equal variance t-test and a chi-square test with adjusted Bonferroni p-values. Results were adjusted for random cluster variation. There were 2749 completed screening forms returned to research staff with 461 subjects who had either consented or declined participation. Patients with poorly controlled diabetes were found to be significantly more likely to decline participation in intervention sites compared to those in control sites. A higher mean diastolic blood pressure was seen in patients with uncontrolled hypertension who declined in the control sites compared to those who declined in the intervention sites. However, these findings were no longer significant after adjustment for random variation among the sites. After this adjustment, females were now found to be significantly more likely to consent than males (odds ratio = 1.41; 95% confidence interval = 1.03, 1.92). Though there appeared to be a higher consent rate for females than for males, the overall impact of potential selection bias and refusal to participate was minimal. Without rigorous methodology, selection bias may be a threat to external validity in cluster-randomized trials. NCT01983813 . Date of registration: Oct. 28, 2013.


Symbolic dynamics of music from Europe and Japan.
After a brief introduction to the theory underlying block-entropy and its relation to the dynamics of complex systems as well as certain information theory aspects, we study musical texts coming from two distinct musical traditions, Japanese and Western European, encoded via symbolic dynamics. We quantify their information content, also known as the degree of "non-randomness" which essentially defines the complexity of the text. We analyze the departure of "total randomness" to the constraints underlying the dynamics of the symbol generating process. Following Shannon on his attribution of these constraints as the key factors of the emergence of complexity, we observe that it can be accurately assessed by the texts' block-entropy vs block-length scaling laws.


Compatible volumetric 3-D TV systems: a proposal.
Three types of 3-D TV system compatible with existing 2-D TV systems are proposed. These systems are not based on stereoscopic image techniques and do not impose any constraints on the viewer for 3-D perception. The first system makes use of the existing conventional color TV system for development of a 3-D TV system. The second system is based on the present monochromatic TV system. The third system depends on a light-emitting diode tank for 3-D display. To prove the validity of these systems a simulated experiment is demonstrated for the reproduction of a 3-D image using still photographs. All these systems are compared for their relative merits and demerits.


[Finite element analysis of the maxillary central incisor with traditional and modified crown lengthening surgery and post-core restoration in management of crown-root fracture].
To construct three-dimensional finite element models with modified crown lengthening surgery and post-core restoration in management of various crown-root fracture types, to investigate the intensity and distribution of stressin models mentioned above, and to compare and analyze the indications of traditional and modified crown lengthening surgeries from the mechanic point of view. Nine three-dimensional finite element models with modified crown lengthening surgery and post-core restoration were established and analyzed by micro-CT scanning technique, dental impression scanner, Mimics 10.0, Geomagic studio 9.0 and ANSYS 14.0 software. The von Mises stress of dentin, periodontal ligament, alveolar bone, post and core, as well as the periodontal ligament area and threshold limit value were calculated and compared with the findings of traditional crown lengthening models which had been published earlierby our research group. The von Mises stress intensity of modified crown lengthening models were: dentin>post>core>alveolar bone>periodontal ligament. The maximum von Mises stress of dentin(44.37-80.58 MPa)distributed in lingual central shoulder. The periodontal ligament area of the modified crown lengthening surgery was reduced by 6% to 28%, under the same crown-root fracture conditions, the periodontal ligament area of modified crown lengthening models was larger than that of the traditional crown lengthening models. In modified crown lengthening surgery models, the von Mises stress of periodontal ligament of B3L1m, B3L2m, B3L3m models exceeded their limit values, however, the von Mises stress of periodontal ligament of the B2L2c, B2L3c, B3L1c, B3L2c, B3L3c models exceeded their limit values in traditional crown lengthening surgery models. The modified crown lengthening surgery conserves more periodontal supporting tissues, which facilitates the long-term survival of teeth. The indication of modified crown lengthening surgery is wider than traditional method. The maxillary central incisors with labial fracture at gingival margin level and with palatal fracture at or below the alveolar crest level are not the indication of the crown lengthening surgery.


[Delayed facial palsy after vestibular schwannoma resection: the role of viral reactivation. Our experience in 8 cases].
To study the role of herpes virus reactivation in the onset of more than three days-delayed facial paralysis (FP) following vestibular schwannoma (VS) surgery and advocate a specific medical management. Retrospective study on 8 cases from a series of 348 patients operated on of a VS between 1996 and 2002. Seven of the eight patients were given intravenously acyclovir (30 mg x kg(-1) x d(-1) for 5 days) and methyl-prednisolone (2 mg x kg(-1) x d(-1) for 7 days). A serologic testing looking for specific anti-herpes simplex viruses type 1 and 2 (HSV-2) and varicella-zoster virus (VZV) antibodies at the onset of the FP and 2 weeks later could be done in only 3 cases. Mean delay of FP onset was 8.75 days. Mean time for recovery with intravenous treatment was 90 days. All treated patients had a House and Brackmann grade 1 recovery. The last one had only a grade 3 after 400 days of evolution: he could not be treated because of postoperative transient psychiatric problems. Serologic testing revealed in those patients in whom it could be done either a high level of anti-HSV or -VZV antibodies at the time of onset or a dramatic increase in anti-HSV or anti-VZV antibodies between the two samples, strongly suggesting a HSV or VZV reactivation. HSV or VZV reactivation can be evocated in most cases of delayed FPs arising in the postoperative course of VSs, suggesting usefulness of emergency-given steroid and acyclovir intravenous regimen to block virus replication and fight secondary oedema and inflammation causative of nerve lesions. Evoked reactivation mechanism is comparable to that already suspected in delayed FP arising with the same delay in middle ear surgical procedures.


Generation of the induced pluripotent stem cell(iPSC) line (AHQUi001-A) from a patient with familial hypertriglyceridemia (FHTG) carrying a heterozygous p.C310R (c.928 T > C) mutation in LPL gene.
Familial hypertriglyceridemia (FHTG) is an autosomal dominant disorder of lipoprotein metabolism, partly caused by mutations in the LPL gene, which encodes for the lipoprotein lipase. LPL deficiency can impair triglyceride hydrolysis which causes elevated plasma triglyceride levels. An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) of a 53 years-old male patient with FHTG who had a heterozygous p.C310R (c.928 T > C) mutation in the LPL gene based on the sendai virus delivery system. The cellular model will offer a powerful tool to investigate pathogenic mechanisms in FHTG and to develop a treatment for FHTG.


Respiratory sensations in asthma: physiological and clinical implications.
Dyspnea is a cardinal symptom of asthma and may arise from several pathophysiological mechanisms, including pulmonary hyperinflation, stimulation of vagal receptors, and, rarely, chemoreceptor stimulation. The language that patients use to describe their breathlessness may provide important clues about the physiology underlying symptoms in a particular patient. Several physiological derangements may contribute to dyspnea in a given individual. The variability in the severity of breathlessness for any given degree of airflow obstruction may relate to differences in the relative importance of these physiological changes and/or to a range of perceptual abilities in asthmatic patients. One hypothesis that is under current investigation is that defective perception of asthma symptoms may lead to undertreatment and the potential for greater morbidity and mortality from asthma.


Nested Stromal-Epithelial Tumor of the Liver: A Review.
Nested stromal-epithelial tumor (NSET) is a rare liver tumor, which is most commonly seen in the pediatric age group. To the best of our knowledge, there has been no published review on this rare tumor in the English literature so far. In this review, we will discuss all the reported details of the published cases, including demography, clinical presentation, molecular histogenesis, imaging, gross pathology and histopathology, immunohistochemical findings, treatment modalities, and outcome of NSET of the liver. Thirty-eight cases of NSET have been reported in the last 20 years in the English literature. This tumor produces a very large and calcified mass in the liver and characteristically can present as Cushing syndrome. NSET is a nonbiliary and nonhepatocytic tumor with biphasic differentiation into 2 components of epithelial and stromal cells. The epithelial cells are arranged as nests of mildly atypical epithelial cells with a few mitotic figures. The stromal component is composed of myofibroblasts and desmoplastic stroma which often shows ossification and calcification. Immunohistochemically, this tumor is positive for both epithelial and mesenchymal markers. The majority of the reported cases in the literature had benign behavior with an indolent course.


Increased brain signal variability accompanies lower behavioral variability in development.
As the brain matures, its responses become optimized. Behavioral measures show this through improved accuracy and decreased trial-to-trial variability. The question remains whether the supporting brain dynamics show a similar decrease in variability. We examined the relation between variability in single trial evoked electrical activity of the brain (measured with EEG) and performance of a face memory task in children (8-15 y) and young adults (20-33 y). Behaviorally, children showed slower, more variable response times (RT), and less accurate recognition than adults. However, brain signal variability increased with age, and showed strong negative correlations with intrasubject RT variability and positive correlations with accuracy. Thus, maturation appears to lead to a brain with greater functional variability, which is indicative of enhanced neural complexity. This variability may reflect a broader repertoire of metastable brain states and more fluid transitions among them that enable optimum responses. Our results suggest that the moment-to-moment variability in brain activity may be a critical index of the cognitive capacity of the brain.


Roles of Mitogen-Activating Protein Kinase Kinase Kinase Kinase-3 (MAP4K3) in Preterm Skeletal Muscle Satellite Cell Myogenesis and Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation Regulation.
BACKGROUND Preterm skeletal muscle genesis is a paradigm for myogenesis. The role of mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3) in preterm skeletal muscle satellite cells myogenesis or its relationship to mammalian target of rapamycin complex 1 (mTORC1) activity have not been previously elaborated. MATERIAL AND METHODS Small interfering RNA (siRNA) interference technology was used to inhibit MAP4K3 expression. Leucine stimulation experiments were performed following MAP4K3-siRNA interference. The differentiation of primary preterm skeletal muscle satellite cells was observed after siRNA-MAP4K3 interference. Western blot analysis was used to determine the expression of MAP4K3, MyHC, MyoD, myogenin, p-mTOR, and p-S6K1. The immunofluorescence fusion index of MyHC and myogenin were detected. MAP4K3 effects on preterm rat satellite cells differentiation and its relationship to mTORC1 activity are reported. RESULTS MAP4K3 siRNA knockdown inhibited myotube formation and both MyoD and myogenin expression in primary preterm rat skeletal muscle satellite cells, but MAP4K3 siRNA had no effect on the activity of mTORC1. In primary preterm rat skeletal muscle satellite cells, MAP4K3 knockdown resulted in significantly weaker, but not entirely blunted, leucine-induced mTORC1 signaling. CONCLUSIONS MAP4K3 positively regulates preterm skeletal muscle satellite cell myogenesis, but may not regulate mTORC1 activity. MAP4K3 may play a role in mTORC1 full activation in response to leucine.


Recurrent Lymphocytic Pleural Effusion as a Complication of Ventriculopleural Shunt Meningitis Caused by Cutibacterium Acnes.
Cutibacterium acnes (C. acnes) is part of the normal flora and has been linked to many invasive and pleural infections. Though it is usually considered a contaminant bacterium, full antimicrobial therapy might result in the resolution of foreign body-related infections. In this report, we describe an infection that started as ventriculopleural shunt meningitis but was complicated by a recurrent lymphocytic pleural infection. Ultimately, there was a resolution of pleural effusions after treatment of C. acnes.


Game theory in biology: 50 years and onwards.
Game theory in biology gained prominence 50 years ago, when Maynard Smith & Price formulated the concept of an evolutionarily stable strategy (ESS). Their aim was to explain why conflicts between animals of the same species usually are of a 'limited war' type, not causing serious injury. They emphasized that game theory is an alternative to previous ideas about group selection, which were used by ethologists to explain limited aggression. Subsequently, the ESS concept was applied to many phenomena with frequency dependence in the evolutionary success of strategies, including sex allocation, alternative mating types, contest behaviour and signalling, cooperation, and parental care. Both the analyses of signalling and cooperation were inspired by similar problems in economics and attracted much attention in biology. Here we give a perspective on which of the ambitions in the field have been achieved, with a focus on contest behaviour and cooperation. We evaluate whether the game-theoretical study of the evolution of cooperation has measured up to expectations in explaining the behaviour of non-human animals. We also point to potentially fruitful directions for the field, and emphasize the importance of incorporating realistic behavioural mechanisms into models. This article is part of the theme issue 'Half a century of evolutionary games: a synthesis of theory, application and future directions'.


Tuberous sclerosis complex: a review of neurological aspects.
Tuberous sclerosis complex is characterized by hamartomatous lesions involving skin, brain, kidneys, eyes and heart. Pathologically, tuberous sclerosis is a disorder of cell migration, proliferation and differentiation. Cell lineage and cell migration disorders in the developing cortex of tuberous sclerosis complex patients might produce very different neurological phenotypes including epilepsy, cognitive impairment and autism. Cortical tubers constitute the hallmark of the disease and are pathognomonic of cerebral tuberous sclerosis. Epilepsy is the most common neurological feature, occurring in 96% of patients. Seizures often begin in the first months of life and are frequently severe and intractable. The treatment of seizures has recently benefited from the advent of the new anti-epileptic drugs. Selected drug-resistant patients with tuberous sclerosis complex could be considered for surgical treatment. Clear localization of the most active epileptogenic focus and the zone of the cortical abnormality may lead to tuberectomy and improved seizure control in selective drug-resistant patients. The finding of multiple areas of cerebral involvement should not automatically preclude epilepsy surgery in a child with intractable seizures and a well defined seizure origin.


Clinicopathological features and survival in EBV-positive diffuse large B-cell lymphoma not otherwise specified.
In this retrospective study, we report 70 cases of Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS) among 1696 DLBCL-NOS cases diagnosed between 2006 and 2019 (prevalence of 4.1%). At diagnosis, median age was 68.5 years; 79% of the cases presented with an advanced-stage disease (III-IV), 48% with extranodal lesions, and 14% with an hemophagocytic lymphohistiocytosis (HLH) (8 at diagnosis and 1 on therapy). A total of 46 cases presented a polymorphic pattern, and 21 were monomorphic. All had a non-germinal center B phenotype, with the majority of tumor cells expressing CD30 and programmed death ligand 1 (98% and 95%, respectively). Type II and III EBV latency was seen in 88% and 12% of the cases, respectively. Patients were treated with immunochemotherapy (59%) or chemotherapy (22%), and 19% received palliative care due to advanced age and altered performance status. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival (OS) at 5 years were 52.7% and 54.8%, respectively. Older age (>50 years) and HLH were associated with shorter PFS and OS in multivariate analysis (PFS: hazard ratio [HR], 14.01; 95% confidence interval [CI], 2.34-83.97; and HR, 5.78; 95% CI, 2.35-14.23; OS: HR, 12.41; 95% CI, 1.65-93.53; and HR, 6.09; 95% CI, 2.42-15.30, respectively). Finally, using a control cohort of 425 EBV- DLBCL-NOS, EBV positivity was associated with a shorter OS outcome within patients >50 years (5-year OS, 53% [95% CI, 38.2-74] vs 60.8% [95% CI, 55.4-69.3], P = .038), but not in younger patients.


DNA-Assisted Solubilization of Carbon Nanotubes and Construction of DNA-MWCNT Cross-Linked Hybrid Hydrogels.
A simple method for preparation of DNA-carbon nanotubes hybrid hydrogel based on a two-step procedure including: (i) solubilization of multi-walled carbon nanotubes (MWCNT) in aqueous solution of DNA, and (ii) chemical cross-linking between solubilized MWCNT via adsorbed DNA and free DNA by ethylene glycol diglycidyl ether is reported. We show that there exists a critical concentration of MWCNT below which a homogeneous dispersion of MWCNT in hybrid hydrogel can be achieved, while at higher concentrations of MWCNT the aggregation of MWCNT inside hydrogel occurs. The strengthening effect of carbon nanotube in the process of hydrogel shrinking in solutions with high salt concentration was demonstrated and significant passivation of MWCNT adsorption properties towards low-molecular-weight aromatic binders due to DNA adsorption on MWCNT surface was revealed.


Computational Model Development of Drug-Target Interaction Prediction: A Review.
In the medical field, drug-target interactions are very important for the diagnosis and treatment of diseases, they also can help researchers predict the link between biomolecules in the biological field, such as drug-protein and protein-target correlations. Therefore, the drug-target research is a very popular study in both the biological and medical fields. However, due to the limitations of manual experiments in the laboratory, computational prediction methods for drug-target relationships are increasingly favored by researchers. In this review, we summarize several computational prediction models of the drug-target connections during the past two years, and briefly introduce their advantages and shortcomings. Finally, several further interesting research directions of drug-target interactions are listed.


Rebooting the genome: The role of negative feedback in horizontal gene transfer.
Horizontal Gene Transfer (HGT) is one of the key mechanisms driving bacterial evolution. Conjugative plasmids are fundamental vehicles for HGT in bacteria, playing an essential role in the spread of antibiotic resistances. Although the classical view has stressed the instrumental role of these mobile genetic elements in the dissemination of antibiotic resistance genes, plasmids contain a rich physiology devoted to horizontal and vertical reproduction. This particular lifestyle imposes specific constrains and trade-offs on plasmid physiology, and plasmids have evolved dedicated circuits to balance the opposing demands of vertical and horizontal reproduction. Recent studies on the transcriptional networks of IncW plasmids and other incompatibility groups have unveiled common architectures in the regulatory networks of different plasmid groups. Comparative studies show that negative feedback loops (NFLs) with strong gains are preferred, opening the question of a possible convergent evolution dictated by certain adaptive properties of this particular network motif. System analysis of NFLs with strong feedback gains indicate that this architecture exhibits transient overshooting after horizontal gene transfer. Since plasmid burden is dependent on the expression of plasmid functions, transcriptional overshooting results in a transient increase of the burden immediately after conjugation. We discuss the possible implications of this phenomenon on plasmid propagation, and the regulatory networks that plasmids have evolved to counteract the detrimental side effects of transient overshooting.


How to remove a chest drain.
RATIONALE AND KEY POINTS: This article aims to help nurses to undertake the removal of a chest drain in a safe, effective and patient-centred manner. This procedure requires two practitioners. The chest drain will have been inserted aseptically to remove air, blood, fluid or pus from the pleural cavity. ▶ Chest drains may be small or wide bore depending on the underlying condition and clinical setting. They may be secured with a mattress suture and/or an anchor suture. ▶ Chest drains are usually removed under medical instructions when the patient's lung has inflated, the underlying condition has resolved, there is no evidence of respiratory compromise or failure, and their anticoagulation status has been assessed as satisfactory. ▶ Chest drains secured with a mattress suture should be removed by two practitioners. One practitioner is required to remove the tube and the other to tie the mattress suture (if present) and secure the site. REFLECTIVE ACTIVITY: Clinical skills articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: 1. How reading this article will change your practice. 2. How this article could be used to educate patients with chest drains. Subscribers can upload their reflective accounts at: rcni.com/portfolio .


Electrical crosstalk suppression for a compact optical segmented modulator.
Advanced coding formats can improve the spectral efficiency in optical transmission systems, while the generation can be expensive and power hungry when electrical digital-to-analog converts (DACs) are utilized. Optical segmented modulators can supersede electrical DACs with the merits of low cost and power efficiency. However, due to their compact size, the leakage current between the adjacent segments results in considerable electrical crosstalk, which impairs the linearity of the modulators and distorts the modulated signal. Here, we propose and demonstrate an electrical crosstalk suppression scheme for optical segmented modulators by introducing a complementary doped region as an insulator. Two depletion regions with high impedances are formed, resulting in the decrease in leakage current and crosstalk. Qualitative and quantitative analysis are performed, and experimentally, in a ring based segmented modulator, more than 5 dB crosstalk improvement is successfully achieved within the 30 GHz range.


Spatial heterogeneity of soil carbon exchanges and their drivers in a boreal forest.
Boreal forests have a large impact on the global greenhouse gas balance and their soils constitute an important carbon (C) reservoir. Mature boreal forests are typically a net CO2 sink, but there are also examples of boreal forests that are persistent CO2 sources. The reasons remain often unknown, presumably due to a lack of understanding of how biotic and abiotic drivers interact to determine the microbial respiration of soil organic matter (SOM). This study aimed at identifying the main drivers of microbial SOM respiration and CO2 and CH4 soil chamber-fluxes within dry and wet sampling areas at the mature boreal forest of Norunda, Sweden, a persistent net CO2 source. The spatial heterogeneity of the drivers was assessed with a geostatistical approach combined with stepwise multiple regression. We found that heterotrophic soil respiration increased with SOM content and nitrogen (N) availability, while the SOM reactivity, i.e., SOM specific respiration, was determined by soil moisture and N availability. The latter suggests that microbial activity was N rather than C limited and that microbial N mining might be driving old-SOM decomposition, which was observed through a positive correlation between soil respiration and its δ13C values. SOM specific heterotrophic respiration was lower in wet than in dry areas, while no such dependencies were found for chamber-based soil CO2 fluxes, implying that oxygen depletion resulted in lower SOM reactivity. The chamber-based soil CH4 flux differed significantly between the wet and dry areas. In the wet area, we observed net CH4 emission that was positively related to soil moisture and NH4+-N content. Taken together, our findings suggest that N availability has a strong regulatory effect on soil CO2 and CH4 emissions at Norunda, and that microbial decomposition of old-SOM to release bioavailable N might be partly responsible for the net CO2 emission at the site.


Effects of in ovo injection of sulfur-containing amino acids on heat shock protein 70, corticosterone hormone, antioxidant indices, and lipid profile of newly hatched broiler chicks exposed to heat stress during incubation.
This study hypothesizes that in ovo sulfur amino acids (SAA) injection can alleviate the heat or oxidative stress of hatched chicks. Thus, the study aimed to assess the impact of in ovo injection of SAA with heat stress during the incubation on heat shock protein 70 (HSP70), corticosterone hormone, antioxidant indices, and lipid profile of newly hatched broiler chicks. Eggs were incubated under optimal incubation temperature (37.8°C) from days 1 to 10 then under high temperature (39.6°C for 6 h daily) between 10 and 18 D of the incubation. At day 17.5 of incubation, 150 eggs were randomly divided into 3 groups of 50 replicate eggs. The first group served as control (non-injected group, NIG), the second group was only injected with saline solution (saline-injected group, SIG), and the third group was injected with a mixture of 5.90 mg L-methionine plus 3.40 mg L-cysteine (sulfur amino acids-injected group, SAAIG). The results exhibited that serum HSP70 and corticosterone concentrations were significantly reduced (P < 0.001) in the SAAIG compared with the NIG and SIG. In ovo SAA injection significantly augmented the antioxidant indices in the serum and tissues compared with the NIG and SIG. HSP70 mRNA relative expression was decreased but glutathione peroxidase (GSH-Px) mRNA relative expression was augmented in the tested tissues (P < 0.001) in the SAAIG compared with the NIG. The SAAIG had significantly (P < 0.05) lower levels in serum lipid profile compared to those of the control and SIG. In conclusion, in ovo SAA injection (methionine plus cysteine) in the embryonated eggs exposed to heat stress increased GSH-Px gene expression and antioxidant indices, and reduced HSP70 gene expression, corticosterone concentrations, and lipid profile of newly hatched broiler chicks.


Fluoroquinolone treatment failure in gonorrhea. Emergence of a Neisseria gonorrhoeae strain with enhanced resistance to fluoroquinolones.
Although emergence of clinical isolates of Neisseria gonorrhoeae with decreased susceptibilities to fluoroquinolones and treatment failures in gonorrhea have been reported, there have been no clinical reports that fluoroquinolone treatments actually select quinolone-resistant strains, nor have isolates that exhibited clinically significant resistance been analyzed for resistance mechanisms. To report a case of fluoroquinolone treatment failure in gonorrhea and emergence of a posttreatment isolate with enhanced resistance to fluoroquinolones; and to study mechanisms of quinolone resistance in the isolates from this patient. A patient with gonococcal urethritis treated with ofloxacin, 200 mg, three times daily for 5 days is described. Pretreatment and posttreatment isolates were tested for minimum inhibitory concentrations (MICs) of antimicrobial agents and analyzed for alterations in DNA gyrase and topoisomerase IV. They were also examined for ofloxacin uptake. Treatment failure with multiple doses of ofloxacin was observed in this case of gonorrhea. The pretreatment isolate showed decreased susceptibilities to fluoroquinolones (MIC of ofloxacin, 1.0 mg/l; MIC of ciprofloxacin, 0.25 mg/l), and had amino acid changes of Ser-91-->Phe in GyrA and Ser-87-->Ile in ParC. The posttreatment isolate exhibited an increase in resistance to fluoroquinolones (MIC of ofloxacin, 8.0 mg/l; MIC of ciprofloxacin, 1.0 mg/l). This isolate had identical alterations in GyrA and ParC, but exhibited significantly reduced uptake of ofloxacin. This isolate also showed a small decrease in susceptibilities to cephalosporins. Alterations in DNA gyrase and topoisomerase IV confer clinically significant resistance to fluoroquinolones in N. gonorrhoeae strains. Treatment with multiple doses of fluoroquinolones is likely to bring about selection of more fluoroquinolone-resistant strains of N. gonorrhoeae and to influence susceptibilities to cephalosporins.


Systeme International in the ICU in the United States.
This article provides a brief review of the Système International (SI) and demonstrates how its routine use for measurements in the ICU might improve education and patient safety in the United States. We apply standard information on SI to common ICU situations. We contrast the confusion and waste from obsolete and/or nonstandard systems of measurement still used in the United States to the clarity and consistency that would result from converting to SI. Examples are drawn from basic weights and measures, electrolyte and other chemical solutions, acid-base physiology, blood gas analysis, BPs, vascular resistances, trauma kinematics, indirect calorimetry, cardiac work, and work of breathing. In addition to simplifying physiologic measurements and relationships, SI provides a common language for international collaboration and communication. Because it would thus improve critical care practice, SI should be increasingly accepted in the United States and especially promoted in the ICU.


Immunosuppressant Responsive Neuropsychiatric Systemic Lupus Erythematosus Manifestations Initially Diagnosed As Schizophrenia and Bipolar Disorder.
Systemic lupus erythematosus (SLE) is a well-documented multi-system autoimmune disease with increased frequency noted in younger females and among minority populations. Disease-defining signs and symptoms can vary widely and involve multiple organ systems including the nervous system. Involvement of the nervous system, known as neuropsychiatric SLE (NPSLE) can present as manifestations consistent with central nervous system or peripheral nervous system pathologies, with the former including presentations of psychiatric illnesses. This case report reviews a 21-year-old Black female's presentation that was most notable for psychosis with other findings on examination and laboratory investigation resulting in a diagnosis of NPSLE. Our patient had a positive initial response to high-dose steroids with improvement of her psychosis and was planned for further treatment with the well-known chemotherapy and immunomodulatory agent, cyclophosphamide.


An HBV-tolerant immunocompetent model that effectively simulates chronic hepatitis B virus infection in mice.
Hepatitis B virus (HBV) is the leading cause of liver disease and hepatic carcinoma (HCC). Approximately 350 million people worldwide are infected with HBV and at risk of chronicity. An efficient HBV-tolerant murine model that mimics HBV infection in humans is desirable for HBV-related research. In this study, we investigated and established a murine model by hydrodynamic injection (HDI) of pAAV/HBV into the tail vein of AAVS1 site element-transgenic mice. In 80% of the injected mice, the serum level of HBsAg reached 103-4 IU/ml and persisted for more than half a year. Next, the model was used to evaluate RNA interference (RNAi)-based antiviral therapy. Data obtained using the model demonstrated that this model will facilitate the elucidation of the mechanisms underlying chronic HBV infection and will also be useful for evaluating new antiviral drugs.


Computerized cognitive training in children and adolescents with attention deficit/hyperactivity disorder as add-on treatment to stimulants: feasibility study and protocol description.
Cognitive training has received increasing attention as a non-pharmacological approach for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents. Few studies have assessed cognitive training as add-on treatment to medication in randomized placebo controlled trials. The purpose of this preliminary study was to explore the feasibility of implementing a computerized cognitive training program for ADHD in our environment, describe its main characteristics and potential efficacy in a small pilot study. Six ADHD patients aged 10-12-years old receiving stimulants and presenting residual symptoms were enrolled in a randomized clinical trial to either a standard cognitive training program or a controlled placebo condition for 12 weeks. The primary outcome was core ADHD symptoms measured using the Swanson, Nolan and Pelham Questionnaire (SNAP-IV scale). We faced higher resistance than expected to patient enrollment due to logistic issues to attend face-to-face sessions in the hospital and to fill the requirement of medication status and absence of some comorbidities. Both groups showed decrease in parent reported ADHD symptoms without statistical difference between them. In addition, improvements on neuropsychological tests were observed in both groups - mainly on trained tasks. This protocol revealed the need for new strategies to better assess the effectiveness of cognitive training such as the need to implement the intervention in a school environment to have an assessment with more external validity. Given the small sample size of this pilot study, definitive conclusions on the effects of cognitive training as add-on treatment to stimulants would be premature.


Impact of long-term chromosomal shuffling on the multispecies coalescent analysis of two anthropoid primate lineages.
Multispecies coalescent (MSC) theory assumes that gene trees inferred from individual loci are independent trials of the MSC process. As genes might be physically close in syntenic associations spanning along chromosome regions, these assumptions might be flawed in evolutionary lineages with substantial karyotypic shuffling. Neotropical primates (NP) represent an ideal case for assessing the performance of MSC methods in such scenarios because chromosome diploid number varies significantly in this lineage. To this end, we investigated the effect of sequence length on the theoretical expectations of MSC model, as well as the results of coalescent-based tree inference methods. This was carried out by comparing NP with hominids, a lineage in which chromosome macrostructure has been stable for at least 15 million years. We found that departure from the MSC model in Neotropical primates decreased with smaller sequence fragments, where sites sharing the same evolutionary history were more frequently found than in longer fragments. This scenario probably resulted from extensive karyotypic rearrangement occurring during the radiation of NP, contrary to the comparatively stable chromosome evolution in hominids.


A survey of population-based utility scores for cervical cancer prevention.
With human papillomavirus (HPV) vaccination introduced in a number of countries, there is considerable interest in evaluating the cost-effectiveness of HPV testing as the primary cervical screening test in these settings. However, the availability of utility scores for these newer interventions is limited. Our aim in this paper is to present utility scores for HPV vaccination, HPV testing and cytology based screening states among women targeted for cervical screening. We invited a random sample of women targeted for cervical screening (aged 20-69 years) living in Sydney, Australia, to participate in a face-to-face interview. Participants were asked to indicate preferences (rank and utility scores) for 10 hypothetical health states relating to HPV vaccination, cytology and primary HPV screening, cervical precursor disease and early stage cervical cancer. Preferences for hypothetical health states were measured through ranking then a two-stage standard gamble. Each participant's own health state was measured as a utility score using the EQ5D. Potential differences by age were assessed using the Wilcox Rank Sum test. A maximum of 276 women were contacted, of which 43 (mean age 49 years) agreed to be interviewed (15.6%). The overall health state of women as measured by the EQ5D was 0.86 (95% CI: 0.83-0.89). Of the 10 health states, the highest ranked were 'normal cytology' and 'HPV vaccination' (equal 1st). States involving an HPV positive result with a subsequent normal cytology or colposcopy were ranked below those for low grade cytological abnormalities with or without a subsequent colposcopic normal result (ranks 3-4 vs. 4-5). However, mean utility scores were broadly similar for all health states, except cervical cancer. No significant differences in scores were identified between age groups. Our survey suggests health states relating to HPV testing are ranked below 'low grade cytology' disease abnormalities. However, this difference was minimal on the utility scale, as most values for health states were largely clustered. These results provide a preliminary set of non-clinic population-based utilities that may be used with other values to explore the economic implications of introducing HPV testing as a primary screening tool in the context of HPV vaccination.


Early life stress inhibits expression of ribosomal RNA in the developing hippocampus.
Children that are exposed to abuse or neglect show abnormal hippocampal function. However, the developmental mechanisms by which early life stress (ELS) impairs normal hippocampal development have not been elucidated. Here we propose that exposure to ELS blunts normal hippocampal growth by inhibiting the availability of ribosomal RNA (rRNA). In support of this hypothesis, we show that the normal mouse hippocampus undergoes a growth-spurt during the second week of life, followed by a gradual decrease in DNA and RNA content that persists into adulthood. This developmental pattern is associated with accelerated ribosomal RNA (rRNA) synthesis during the second week of life, followed by a gradual decline in rRNA levels that continue into adulthood. Levels of DNA methylation at the ribosomal DNA (rDNA) promoter are lower during the second week of life compared to earlier development or adulthood. Exposure to brief daily separation (BDS), a mouse model of early life stress, increased DNA methylation at the ribosomal DNA promoter, decreased rRNA levels, and blunted hippocampal growth during the second week of life. Exposure to acute (3 hrs) maternal separation decreased rRNA and increased DNA methylation at the rDNA proximal promoter, suggesting that exposure to stress early in life can rapidly regulate the availability of rRNA levels in the developing hippocampus. Given the critical role that rRNA plays in supporting normal growth and development, these findings suggest a novel molecular mechanism to explain how stress early in life impairs hippocampus development in the mouse.


Adenoma characterization: adrenal protocol with dual-energy CT.
To determine the diagnostic performance of dual-energy computed tomography (CT) by using virtual unenhanced CT to characterize adrenal masses. This study is retrospective, HIPAA-compliant, and approved by the institutional review board. Between December 2009 and June 2010, 49 patients with 49 adrenal masses underwent 120-kVp unenhanced CT and 80-kVp and 140-kVp early and delayed contrast agent-enhanced dual-energy CT. Early virtual unenhanced (EVU) and delayed virtual unenhanced (DVU) CT images were composed of data sets of early and delayed contrast-enhanced CT, respectively. Adenomas were divided into lipid-rich adenoma and lipid-poor adenoma on the basis of lesion attenuation values measured according to unenhanced CT and percentage loss of enhancement. Absolute percentage loss of enhancement was calculated with the following equation: (CT(EE) - CT(DE)) × 100/(CT(EE) - CT(UE)), where CT(UE), CT(EE), and CT(DE) are adrenal mass attenuation values at unenhanced CT, early contrast-enhanced CT, and delayed contrast-enhanced CT, respectively. The sensitivity of adrenal protocol adenoma with delayed contrast-enhanced CT was obtained with a reference standard of unenhanced CT, pathologic examination, or size stability on follow-up examination findings. Lesion attenuation values measured on unenhanced CT, EVU CT, and DVU CT images were compared by using repeated measures analysis of variance with post hoc test. Of 49 masses, 33 were adenomas and 16 were nonadenomas. Adenoma group was 18 lipid-rich adenomas and 15 lipid-poor adenomas. Mean attenuation values of the lipid-rich adenomas on EVU CT images (11.7 HU ± 9.5) were significantly greater than those on unenhanced CT images (0.7 HU ± 7.2) (P = .001) and DVU CT images (6.6 HU ± 8.4) (P = .01). The sensitivities of EVU CT and DVU CT for lipid-rich adenoma were 39% (seven of 18) and 61% (11 of 18), respectively. The sensitivity for adenoma with percentage loss of enhancement values calculated from virtual unenhanced CT and early and delayed contrast-enhanced CT was 100% (33 of 33). Although adrenal protocol with dual-energy CT by using virtual unenhanced CT and washout rate can help diagnose all lipid-poor adenomas, it may miss lipid-rich adenomas that can be diagnosed on unenhanced CT images.


Pantomime of tool use: looking beyond apraxia.
Pantomime has a long tradition in clinical neuropsychology of apraxia. It has been much more used by researchers and clinicians to assess tool-use disorders than real tool use. Nevertheless, it remains incompletely understood and has given rise to controversies, such as the involvement of the left inferior parietal lobe or the nature of the underlying cognitive processes. The present article offers a comprehensive framework, with the aim of specifying the neural and cognitive bases of pantomime. To do so, we conducted a series of meta-analyses of brain-lesion, neuroimaging and behavioural studies about pantomime and other related tasks (i.e. real tool use, imitation of meaningless postures and semantic knowledge). The first key finding is that the area PF (Area PF complex) within the left inferior parietal lobe is crucially involved in both pantomime and real tool use as well as in the kinematics component of pantomime. The second key finding is the absence of a well-defined neural substrate for the posture component of pantomime (both grip errors and body-part-as-tool responses). The third key finding is the role played by the intraparietal sulcus in both pantomime and imitation of meaningless postures. The fourth key finding is that the left angular gyrus seems to be critical in the production of motor actions directed towards the body. The fifth key finding is that performance on pantomime is strongly correlated with the severity of semantic deficits. Taken together, these findings invite us to offer a neurocognitive model of pantomime, which provides an integrated alternative to the two hypotheses that dominate the field: The gesture-engram hypothesis and the communicative hypothesis. More specifically, this model assumes that technical reasoning (notably the left area PF), the motor-control system (notably the intraparietal sulcus), body structural description (notably the left angular gyrus), semantic knowledge (notably the polar temporal lobes) and potentially theory of mind (notably the middle prefrontal cortex) work in concert to produce pantomime. The original features of this model open new avenues for understanding the neurocognitive bases of pantomime, emphasizing that pantomime is a communicative task that nevertheless originates in specific tool-use (not motor-related) cognitive processes. <Please insert Graphical abstract here>.


Avances en tumores del estroma gastrointestinal: ¿hacia dónde vamos?
Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small intestine (30%). The advances in its knowledge and management succeeded in the last years have being spectacular. This review aims to summarize the most important of them for surgeons. We identified four areas of interest: molecular oncology, laparoscopic approach, management of GIST located at unusual locations, and management of advanced GIST. Advances in the field of molecular oncology lead to the discovery of new oncogenic mutations making the term Wil Type GIST obsolete. Moreover, these advances allow for the development of 2 new drugs: Avapritinib and Ripretinib, that added to the previous 3 commercially available drugs (imatinib, sunitinib and regorafenib) make possible the management of GIST with resistant mutations. The principles of the surgical management of primary GIST are well stablished which laparoscopic approach must accomplish. This approach is limited by 2 main factors: location and size. The diagnosis of GIST in unusual locations as esophagus, duodenum, rectum of out of the gastrointestinal tract (EGIST), implies an extraordinary therapeutic challenge, being imperative to manage them by surgeons and oncologist among others in the setting of a multidisciplinary team. The management of advanced/metastatic GIST has changed in a revolutionary fashion because surgery is now part of its treatment as adjuvant to tyrosine kinase inhibitors.


Benign Cutaneous and Subcutaneous Lesions on FDG-PET/CT.
18F-FDG, the most commonly used PET radiopharmaceutical in clinical practice, can also accumulate in inflammatory and infectious conditions. This may account for false-positive PET findings when staging or restaging a patient with malignancy. As clinical use of FDG-PET-CT is increasing, nuclear medicine physicians are encountering a myriad of cutaneous and subcutaneous lesions, many of which are incidental and benign. The most common cause for the FDG avidity of these lesions is inflammation. Although a specific diagnosis may not always be possible, background clinical history and morphologic features of the lesion on CT may help narrow the differential diagnosis. This article aims to familiarize nuclear medicine physicians and radiologists with various benign cutaneous and subcutaneous conditions encountered in routine clinical practice.


3β-Hydroxy-urs-12-en-28-oic acid confers protection against ZnONPs induced adversity in Caenorhabditis elegans.
Despite their well reported potent risk towards human health and environment Zinc oxide nanoparticles (ZnONPs) find an extensive commercial usage due to their antimicrobial properties. Here, we evaluated the efficacy of a natural triterpene ursolic acid (3β-hydroxy-urs-12-en-28-oic acid; UA) for overcoming the cytotoxic challenges of ZnONPs employing Ceanorhabditis elegans. The 24h LC50 of Zn-ONPs (<50nm TEM) was deduced as 4.75mgL-1. UA (25μM) was observed to defend against this toxicity by attenuating Reactive Oxygen Species (ROS) resulting into better survival at 2mgL-1 in a time dependent behavior. However, reproductive health remains compromised. Our study identifies UA as a natural inducer of metallothionein proteins along with antioxidant potential. We demonstrate that UA induces upregulation of predominantly antioxidant genes, including the superoxide dismutases (sod-1, sod-5 and sod-3), glutathione S-transferase 7 (gst-7), heat shock protein (hsp-16.2) along with the metal exposure responsive metallothionein (mtl-1 and mtl-2). Moreover, UA also restores elevated transcript levels of gst-4 during ZnONPs stress conditions to normal by directly scavenging ROS owing to its own antioxidant potential. Altogether, the toxic aspects of NPs that can be avoided compensated or postponed by supplementation of phytochemical(s) in biological system underscore their potential implications in near future.


Imaging of lipomatous soft tissue tumors.
The purpose is to give an overview of the imaging features of benign and malignant lipomatous tumors. Imaging characteristics which are helpful in the differential diagnosis between benign and malignant subtypes are highlighted.


Urinalysis by use of multi-test reagent strips: two dipsticks compared.
We compared Ames' "N-Multistix" with Boehringer's "Combur-8" ("Chemstrip-8") multi-test urine reagent strips by analysis of contrived urine specimens, testing accuracy, precision, specificity, and limits of detection of both products. Relative cost and ease of use were also examined. Each brand of urinary dipstick had specific advantages but it is unlikely that patient care would be adversely affected by preferential use of either product.


Characterization of the receptor for lymphotoxin; a spontaneous internalization without recycling and ligand-induced downregulation in HL-60 cells.
The receptor system for lymphotoxin (LT) was investigated by use of the human promyelocytic HL-60 cell line. Utilizing subcellular fractionation, internalization of cell surface bound recombinant LT (rLT) and transfer to lysosomes followed by degradation was demonstrated. Binding of rLT to its cell surface receptor induced a downregulation of the receptor which was persistent for at least 6 h. Downregulation of the receptors from the cell surface by activation of protein kinase C with the diacylglycerol OAG was completely reversible but the recovery of the binding capacity was dependent on protein synthesis as it was inhibited by cycloheximide. Treatment with cycloheximide alone resulted in a loss of binding capacity with a half life of approximately 2 h, suggesting a spontaneous consumption of receptors. Affinity cross-linking revealed three ligand-receptor complexes with Mr of 85, 105 and 125 kDa. Because of a strong tendency for ligand polymerization these results suggest oligomer binding of the ligand to a single receptor molecule with an apparent Mr of 70 kDa. N-linked glycosylation constituted 4 to 5 kDa of the total molecular weight. In conclusion, we demonstrated a spontaneous internalization of the receptor for LT without recycling, and that ligand binding resulted in an irreversible downregulation of the receptor.


Impact of Intraoperative Re-resection to Achieve R0 Status on Survival in Patients With Pancreatic Cancer: A Single-center Experience With 483 Patients.
The aim of this study was to test the hypothesis that intraoperative frozen section (FS) and re-resection results to achieve R0 status are associated with different long-term outcomes in pancreatic cancer patients. Recent data have challenged the survival benefit of additional resection in patients with pancreatic cancer in case of positive FS to achieve clear pathological section (PS). Patients who underwent surgery for exocrine pancreatic malignancy with curative intent were identified from a prospective database. Data were stratified by resection margin (group I: FS-R0 → PS-R0; group II: FS-R1 → PS-R0; group III: FS-R1 → PS-R1). Associations with survival were analyzed by univariate and multivariate analyses. A total of 483 patients met the inclusion criteria. Of these, 61 patients were excluded due to R2 or Rx status. Three hundred seventeen (75%) patients were allocated to margin group I, 32 (8%) to group II, and 73 (17%) to group III. Median overall survival in group I, II, and III was 29, 36, and 12 months (P < 0.001). There was no significant difference in survival between patients in Group I and II (P = 0.849), whereas patients in group III had significantly poorer outcome than group I (P < 0.001) and II (P = 0.039). The prognostic value of margin group status was confirmed on multivariate analysis (hazard ratio = 1.694, 95% confidence interval 1.175-2.442). FS analysis with intraoperative re-resection should be performed routinely in patients undergoing pancreatic cancer surgery with the aim to achieve a R0 resection.


Tissue-Specific Regulation of Gma-miR396 Family on Coordinating Development and Low Water Availability Responses.
Previously, it was reported that miR396s interact with growth-regulating factors (GRFs) to modulate plant growth, development, and stress resistance. In soybean, 11 gma-miR396 precursors (Pre-miR396a-k) were found, and 24 GmGRFs were predicted as targets of seven mature gma-miR396s (gma-miR396a/b/c/e/h/i/k). To explore the roles of the miR396-GRF module in low water availability response of soybean, we analyzed the expression of Pre-miR396a-k, and found that Pre-miR396a/i/bdgk/e/h were up-regulated in leaves and down-regulated in roots; on the contrary, GmGRF5/6/7/8/15/17/21 were down-regulated in leaves and GmGRF1/2/17/18/19/20/21/22/23/24 were up-regulated in roots of low water potential stressed soybean. Any one of gma-miR396a/b/c/e/h/i/k was able to interact with 20 GmGRFs (GmGRF1/2/6-11/13-24), confirming that this module represents a multi-to-multi network interaction. We generated Arabidopsis plants over-expressing each of the 11 gma-miR396 precursors (Pre-miR396a-k), and seven of them (miR396a/b/c/e/h/i/k-OE transgenic Arabidopsis) showed altered development. The low water availability of miR396a/b/c/e/h/i/k-OE was enhanced in leaves but reduced in seeds and roots. Contrary to previous reports, miR396a/b/c/i-OE seedlings showed lower survival rate than WT when recovering after rewatering under soil drying. In general, we believe our findings are valuable to understand the role of gma-miR396 family in coordinating development and low water availability responses, and can provide potential strategies and directions for soybean breeding programs to improve seed yield and plant drought tolerance.


Association of Estimated Long-term Exposure to Air Pollution and Traffic Proximity With a Marker for Coronary Atherosclerosis in a Nationwide Study in China.
Epidemiologic evidence of the mechanisms of the association between long-term exposure to air pollution and coronary heart disease (CHD) is limited and relies heavily on studies performed in Europe and the United States, where air pollution levels are relatively low. In particular, the association between air pollution and CHD in patients with underlying risks for CHD is understudied. To determine whether air pollution and proximity to traffic are associated with the coronary artery calcium (CAC) score, a key atherosclerotic marker. In this prospective, population-based cross-sectional study in a large-scale setting in China, 8867 consecutive patients aged 25 to 92 years with suspected CHD were recruited between November 17, 2015, and September 13, 2017. Participants were excluded if they had previous myocardial infarction, stenting, or coronary artery bypass grafting or incomplete risk factors and exposure data. Each participant underwent assessment of CAC and CHD risk factors at baseline. Data were analyzed from December 2017 to November 2018. Annual means of fine particulate matter with aerodynamic diameter less than 2.5 μm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) were estimated at the participants' residences using a validated geostatistical prediction model. Exposure to a nearby roadway was also estimated. Computed tomography measurement of CAC score. The mean (SD) age of the 8867 participants was 56.9 (10.4) years; 4378 (53.6%) were men. Annual mean (SD) PM2.5, NO2, and O3 measurements were 70.1 (20.0), 41.4 (14.7), and 93.9 (10.5) μg/m3, respectively. The mean (SD) CAC score was 91.4 (322.2) Agatston units. Exposure to PM2.5 and NO2, adjusting for CHD risk factors and multiple pollutants, were independently associated with increases in CAC scores of 27.2% (95% CI, 10.8% to 46.1%) per 30 μg/m3 PM2.5 and 24.5% (95% CI, 3.6% to 49.7%) per 20 μg/m3 NO2. For PM2.5, odds of both detectable CAC (Agatston score >0; odds ratio, 1.28; 95% CI, 1.13 to 1.45) and severe CAC (Agatston score >400; odds ratio, 1.59; 95% CI, 1.20 to 2.12) were increased. Associations of CAC with PM2.5 and NO2 were greater among male participants (PM2.5: 42.2%; 95% CI, 24.3% to 62.7%; NO2: 45.7%; 95% CI, 25.3% to 69.5%) and elderly participants (PM2.5: 50.1%; 95% CI, 28.8% to 75.0%; NO2: 55.5%; 95% CI, 31.8% to 83.6%) and those with diabetes (PM2.5: 62.2%; 95% CI, 30.9% to 101.0%; NO2: 31.2%; 95% CI, 13.9% to 51.0%). Independent association with CAC score was 9.0% (95% CI, -1.4% to 20.4%) for O3 per 15 μg/m3 and 2.4% (95% CI, -0.6% to 5.4%) for distance near roadway per 50% decrease. In this large Chinese study, long-term exposures to PM2.5 and NO2 were independently associated with severity of CAC. This finding may provide support for the pathophysiological role of coronary atherosclerosis through which air pollution exposure may be associated with CHD.


Atomic Structure and Dynamics of Single Platinum Atom Interactions with Monolayer MoS2.
We have studied atomic level interactions between single Pt atoms and the surface of monolayer MoS2 using aberration-corrected annular dark field scanning transmission electron microscopy at an accelerating voltage of 60 kV. Strong contrast from single Pt atoms on the atomically resolved monolayer MoS2 lattice enables their exact position to be determined with respect to the MoS2 lattice, revealing stable binding sites. In regions of MoS2 free from surface contamination, the Pt atoms are localized in S vacancy sites and exhibit dynamic hopping to nearby vacancy sites driven by the energy supplied by the electron beam. However, in areas of MoS2 contaminated with carbon surface layers, the Pt atoms appear at various positions with respect to the underlying MoS2 lattice, including on top of Mo and in off-axis positions. These variations are due to the Pt bonding with the surrounding amorphous carbon layer, which disrupts the intrinsic Pt-MoS2 interactions, leading to more varied positions. Density functional theory (DFT) calculations reveal that Pt atoms on the surface of MoS2 have a small barrier for migration and are stabilized when bound to either a single or double sulfur vacancies. DFT calculations have been used to understand how the catalytic activity of the MoS2 basal plane for hydrogen evolution reaction is influenced by Pt dopants by variation of the hydrogen adsorption free energy. This strong dependence of catalytic effect on interfacial configurations is shown to be common for a series of dopants, which may provide a means to create and optimize reaction centers.


Characterization and localization of receptors for epidermal growth factor in ovine skin.
Specific receptor sites for murine epidermal growth factor (EGF) have been characterized and their distribution determined in ovine skin. Binding of 125I-labelled EGF to skin membrane particles was temperature- and time-dependent, with equilibrium being reached within 1 h at 23 degrees C. Analysis of skin biopsies collected from ten castrated Merino sheep demonstrated the presence of a single class of saturable, high-affinity binding sites with a dissociation constant of 64 +/- 4 (S.E.M.) pmol/l and a binding capacity of 33.8 +/- 4.5 fmol/mg protein. Skin particle binding of 125I-labelled EGF was inhibited equipotently by mouse salivary gland EGF, EGF produced by recombinant DNA procedures and urogastrone. The EGF peptides 1-48, 6-53 and 7-53, derived from the native molecule by enzymatic cleavage, were much less potent. The relative binding potency of these molecules was correlated with their ability to induce precocious eyelid opening in mice and to inhibit wool follicle activity. Synthetic fragments representing the major structural domains of the EGF molecule (EGF(29-44), EGF(33-42) and EGF(3-31] were inactive in both the receptor and bioassays. Autoradiography of skin sections incubated with 125I-labelled EGF in vitro or of sections from skin which was perfused with 125I-labelled EGF in vivo demonstrated that EGF receptors were localized in undifferentiated cells of the epidermis and sebaceous glands, the inner and outer root sheath and bulb of wool follicles and in dermal arterioles. Differences in receptor concentration were observed between follicles following in-vivo perfusion of 125I-labelled EGF but not when the in-vitro labelling technique was used. The presence of receptors in these regions is consistent with the morphological changes in sheep skin in response to EGF administration which have been reported previously.


[Comparison of MDS-AC registration and conventional medical records in Iceland and other Nordic countries. A part of a Nordic study].
Complex functional decline and comorbid state is an important indicator of outcome for hospital care of older adults. In today acute care it is important to quickly be able to target those who might benefit from geriatric assessment. The MDS-AC is an evaluation system for geriatric acute care patients that records functional impairment and co-morbid states. The object of this study was to compare the MDS-AC registration with the traditional nurses and doctors records for chosen variables important to older patient care in Iceland and other Nordic countries. This was a randomised prospective Nordic study. The study took place in Reykjavík, Copenhagen, Umeå, Oslo and Helsinki. Participants in each country were chosen from 75 year old and older patients admitted to acute care medical wards, 160 patients from each country. The results presented here show data from selected variables collected with the MDS-AC instrument version 1,1 in the first 24 hours of admission, compared with hospital notes for the first 48 hours. For ADL and IADL impairments the medical record missed between 20 to 96% of items registered with the MDS-AC and between 33 to 100% when there is no impairment detected. This was true for all the participating Nordic countries but the Icelandic medical records were in comparison more often incomplete for the variables chosen. The MDS-AC documents better than traditional medical records several important variables relating to function among the elderly. It may be possible to improve documentation with a standardized instrument such as the MDS-AC.


MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity.
Development of retinal structure and function is controlled by cell type-specific transcription factors and widely expressed co-regulators. The latter includes the mixed-lineage leukemia (MLL) family of histone methyltransferases that catalyze histone H3 lysine 4 di- and tri-methylation associated with gene activation. One such member, MLL1, is widely expressed in the central nervous system including the retina. However, its role in retinal development is unknown. To address this question, we knocked out Mll1 in mouse retinal progenitors, and discovered that MLL1 plays multiple roles in retinal development by regulating progenitor cell proliferation, cell type composition and neuron-glia balance, maintenance of horizontal neurons, and formation of functional synapses between neuronal layers required for visual signal transmission and processing. Altogether, our results suggest that MLL1 is indispensable for retinal neurogenesis and function development, providing a new paradigm for cell type-specific roles of known histone modifying enzymes during CNS tissue development.


Enhancing Pain Relief in Temporomandibular Joint Arthrocentesis: Platelet-Rich Plasma and Hyaluronic Acid Synergy.
Temporomandibular joint (TMJ) disorders present complex challenges in pain management and functional restoration. This review delves into the innovative approach of using platelet-rich plasma (PRP) and hyaluronic acid (HA) combination therapy in TMJ arthrocentesis to address these issues. The potential benefits of this approach are highlighted through an exploration of mechanisms, clinical studies, safety considerations, and future directions. PRP's regenerative properties and HA's lubrication and anti-inflammatory effects offer a comprehensive solution to multifactorial TMJ pain and dysfunction. Clinical studies reveal significant pain reduction, improved mobility, and enhanced satisfaction in patients treated with PRP and HA. Although mild and transient adverse effects have been reported, the safety profile remains favorable. While the evidence is promising, more extensive randomized controlled trials are needed to establish sustained efficacy and safety. As research evolves, collaborative efforts among clinicians and researchers are crucial in realizing the potential of PRP and HA combination therapy, ultimately providing a novel pathway to alleviate TMJ-related pain and enhance patient well-being.


Facile Synthesis of N-Carboranyl Amines through an ortho-Carboryne Intermediate.
The efficient o-carboryne precursor 1-Li-2-OTf-o-C2 B10 H10 reacts with lithium amides at room temperature to give a series of N-carboranyl amines in moderate to high isolated yields. This reaction is compatible with a broad substrate scope from primary to secondary, alkyl to aryl amines. The reaction mechanism is also proposed on the basis of experimental results and DFT calculations. This represents the first general and efficient method for the synthesis of 1-NR(1) R(2) -o-carboranes.


Redox Status of Professional Soccer Players is Influenced by Training Load Throughout a Season.
The purpose of this study was to follow-up the variation of pro-/antioxidant status throughout a whole season in elite professional soccer players from the French league (n=19, 18.3±0.6 years) and to examine a possible link between these variations and training load. 5 time points (T1, T2, T3, T4, T5) were proposed to surround crucial periods of training during the whole season: the pre-season training/mid-season periods (T1-T2 and T3-T4), the championship or in-season periods (T2-T3 and T4-T5). At these times, blood samples were collected to measure pro-/antioxidant status (in erythrocytes: the ratio of reduced glutathione/oxidized glutathione, superoxide dismutase and glutathione peroxidase activities, in plasma: alpha-tocopherol, beta-carotene), and dietary intakes were also recorded. Training loads were quantified by the rating of perceived exertion method weekly throughout the season. Pro-/antioxidant-related measurements showed no modifications except for GSH/GSSG ratio, which evolved significantly between season periods: from 36.43±4.15 (T1) to 115.99±16.43 (T2) to 91.64±21.24 (T3) to 202.29±29.26 (T4) to 59.61±14.61 (T5). We observed a significant correlation (r(2)=0.84) between changes in GSH/GSSH ratio and cumulated mean training loads. In conclusion, these results suggest that the redox status of professional soccer players is altered according to training period (in-season periods) and that GSH/GSSH ratio variations are correlated with cumulated training loads.


Prevalence of fatigue after stroke: A systematic review and meta-analysis.
Post-stroke fatigue is a debilitating and long-lasting condition. However, there are uncertainties regarding its prevalence and variability between studies. This review aims to estimate the prevalence of fatigue and determine the factors responsible for its variation in the literature. A systematic review was conducted for all published studies (search to November 2020) using AMED, CINAHL, EMBASE, MEDLINE, PsycINFO, SCOPUS and Web of Science. Papers were included if they recruited participants with stroke, used a validated scale to measure fatigue and were in English. Two reviewers screened and assessed the relevant studies for eligibility (n = 96). The included papers were appraised using the Joanna Briggs Institute (JBI) tool for prevalence studies, and data were extracted by one reviewer. To understand the variation in PSF prevalence between papers, data were pooled and analysed based on relevant methodological (e.g. time of assessment) or clinical factors (e.g. depression) using Review Manager 5.4 software. While 48 studies were included and summarised (N = 9004), only 35 were appropriate for the meta-analysis (N = 6851). The most frequently used tool to measure fatigue was the Fatigue Severity Scale (FSS) (n = 31). The prevalence was calculated with a cut-off point of four or more using FSS and resulted in an estimate of 48% (95% CI 42-53%). Time of assessment (<6 vs ≥6 months), stroke type (ischaemic vs haemorrhagic/subarachnoid haemorrhage) and geographical location (East Asia vs Europe) could explain the prevalence variation between studies. Fatigue is prevalent among stroke survivors. This condition varies in terms of occurrence between studies; however, time of assessment, stroke type and geographical location might explain this variation. As this review estimates the overall burden of fatigue after stroke, it provides a useful indicator to inform policy, planning and healthcare professionals. Further efforts are required to investigate the mechanisms that lead to PSF, particularly in the groups that show high prevalence, in order to prevent or alleviate it.


Health related quality of life and mortality 10 years after a femoral neck fracture in patients younger than 70 years.
A femoral neck fracture (FNF) may have long term effects on the patient's health related quality of life (HRQoL) and mortality, especially in patients younger than 70 years. These long-term effects are unknown since most studies have a short follow-up. The aim of this study was to investigate self-assessed hip function, HRQoL and factors associated with 10-years mortality after a FNF. A prospective multicenter study with a 10-year follow-up of patients aged 20-69 years with a displaced and non-displaced FNF treated with closed reduction and internal fixation. The self-administered questionnaires EuroQol 5 Dimension (EQ-5D) and Hip Disability Outcome Score (HOOS) were used. Results of EQ-5D and HOOS was compared to sex and age matched general population data of Sweden. All patients that were deceased had their death date recorded. Factors associated with mortality were assessed by regression analysis of the baseline data including age, gender, harmful alcohol consumption according to AUDIT, co-morbidity measured by ASA-grade, body mass index, osteoporosis measured by dual energy x-ray absorptiometry (DXA) and smoking. Prevalence of co-morbidities and smoking was compared to general population data. From initial 182 included patients, 55 were deceased at 10-year follow-up, 4 were deregistered from public record and 35 declined participations. A total of 88 patients participated through self-administrated questionnaires. There were no significant differences in HOOS between gender and fracture type and the results were equivalent to general population data. The EQ-5D continued to improve compared to a 24-month follow-up (p = 0.006) but did not recover to pre-fracture level (p<0.001) though it was equivalent to general population data. Higher age, co-morbidity, osteoporosis and smoking were associated with increased mortality within 10 years after the fracture and the prevalence of co-morbidity and smoking was higher than the general population. Those patients who had survived 10 years after a FNF treated with CRIF had a HRQoL and hip function equivalent to age and sex matched general population of Sweden. However, a third of these relatively young patients had deceased 10 years after the hip fracture and they were more compromised than the general population.


Associations and Risk Factors of Diabetic Maculopathy.
Diabetic maculopathy is characterised by increased capillary leakage in the main retinal vessels and by alterations in the microcirculation of the macula. Maculopathy occurs frequently in type 1 and type 2 diabetic patients. Prevalence is higher in type 2 than in type 1 diabetic patients. Factors associated with the development of maculopathy are mostly unknown. As maculopathy is the main cause of vision deprivation in diabetic patients it is essential to know the associations and risk factors of diabetic maculopathy so that appropriate measures can be taken to prevent as well as treat diabetic maculopathy. We started the research work to find out the relation between diabetic maculopathy and various associated factors and risk factors for patients with diabetic retinopathy with maculopathy. This cross-sectional observational study done at the Department of Ophthalmology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka & National Institute of Ophthalmology & Hospital (NIO & H), Sher-e-Bangla Nagar, Dhaka, Bangladesh from January 2006 to June 2006. In this study out of 50 patients, diabetes was controlled in 20(40%) patients and uncontrolled in 30(60%). A significant percentage of patients (40%) had elevated blood pressure. Diabetic autonomic neuropathy was observed in 24% cases and polyneuropathy was observed in 36% cases. It is evident that diabetic maculopathy has association with dyslipidaemia, abnormal renal function due to nephropathy. This study lighted on the association of diabetic maculopathy with diabetic nephropathy, cardiac abnormalities and diabetic neuropathy.