Relationship between DMFT index and reproductive history- a cross-sectional study on enrollment phase of Azar cohort study.
Hormonal changes in women throughout life might affect the oral health. The aim of this study is to investigate the relationship between the Decayed, Missing, and Filled Teeth (DMFT) index and reproductive history. The present cross-sectional study was performed using data of Azar Cohort Study conducted in 2014, in Shabestar city, East Azerbaijan Province, Iran. In the present study, the data of all 8294 women from the enrollment phase of the Azar cohort were included. All available data related on the variables of reproductive history (including age at the onset of menstruation, age of onset of menopause, age of first pregnancy, and frequency of pregnancy), age at interview, educational level, socioeconomic status, frequency of tooth brushing, chronic diseases, body mass index and DMFT were extracted. Negative binomial regression with loglink was used to analyze the relationship between variables. Three regression models have been applied to adjust the effect of confounding variables. Model 1 adjusted for education, socio-economic status, age, chronic diseases, body mass index and frequency of tooth brushing. Model 2 adjusted for education, socioeconomic status, age, chronic diseases and body mass index. Model 3 adjusted for education, socio-economic status and age. The mean DMFT of 8294 women was 20.99 ± 8.95. In model 1, there was no significant relationship between DMFT and frequency of pregnancy. However, model 2 and 3 showed that in women who had four or more pregnancies, the DMFT rate was significantly higher than those who did not have a history of pregnancy (P = 0.02, P = 0.04). Age at the onset of menopause, age at the onset of menstruation and age of first pregnancy had no significant relationship with DMFT in the models. Brushing less than once a day and increasing age at interview had significant relationship with DMFT in the models (P < 0.001). Despite hormonal changes through the life, the history of reproductive showed no significant relationship with women's DMFT. Oral health education for women is an important step in promoting oral health and it is necessary to pay special attention to preventive programs in oral health policy for women specially with increasing the age.


A Systematic Review on the Current Trend in Nonsurgical Aesthetic Training for Knowledge, Skill, and Professional Identity Formation.
Non-surgical aesthetics is a rapidly growing healthcare domain and lacks pedagogically sound education and training programs. The trainee physicians often participate in short courses which are outside of the scope of an existing postgraduate training program to acquire the necessary knowledge and procedural skills. However, such training programs lack values and interests that shape critical thinking and holistic decision-making, often referred to as professional identity. This systematic review aims to analyze current trends in non-surgical aesthetic clinical education to form knowledge, skills, and professional identity. A detailed literature search was conducted in electronic databases-PubMed, Cochrane, Centre for Reviews and Dissemination, and Google Scholar-for relevant studies published between January 2010 and December 2020, with an update in September 2021. Fifty-five articles were identified through electronic searches, among which 40 were selected following a review of the abstracts. Sixteen articles were identified as the best evidence for the detailed and iterative review based on their relevance and fit to the inclusion criteria. Unfortunately, none of the included studies designed their questionnaire based on the Kirkpatrick Model, which is best known for analyzing and evaluating the results of training and educational programs. This systematic review provides valuable insight into graduate professional identity formation and graduates' readiness for independent clinical practice. Therefore, particular consideration should be given to incorporating these triggers when developing evidence-based postgraduate curricula for non-surgical aesthetics.


Role of low-molecular-weight substrates in functional binding of the tRNAPhe acceptor end by phenylalanyl-tRNA synthetase.
The functional roles of phenylalanine and ATP in productive binding of the tRNA(Phe) acceptor end have been studied by photoaffinity labeling (cross-linking) of T. thermophilus phenylalanyl-tRNA synthetase (PheRS) with tRNA(Phe) analogs containing the s(4)U residue in different positions of the 3'-terminal single-stranded sequence. Human and E. coli tRNA(Phe)s used as basic structures differ by efficiency of the binding and aminoacylation with the enzyme under study. Destabilization of the complex with human tRNA(Phe) caused by replacement of three recognition elements decreases selectivity of labeling of the alpha- and beta-subunits responsible for the binding of adjacent nucleotides of the CCA-end. Phenylalanine affects the positioning of the base and ribose moieties of the 76th nucleotide, and the recorded effects do not depend on structural differences between bacterial and eukaryotic tRNA(Phe)s. Both in the absence and presence of phenylalanine, ATP more effectively inhibits the PheRS labeling with the s(4)U76-substituted analog of human tRNA(Phe) (tRNA(Phe)-s(4)U76) than with E. coli tRNA(Phe)-s(4)U76: in the first case the labeling of the alpha-subunits is inhibited more effectively; the labeling of the beta-subunits is inhibited in the first case and increased in the second case. The findings analyzed with respect to available structural data on the enzyme complexes with individual substrates suggest that the binding of phenylalanine induces a local rearrangement in the active site and directly controls positioning of the tRNA(Phe) 3'-terminal nucleotide. The effect of ATP on the acceptor end positioning is caused by global structural changes in the complex, which modulate the conformation of the acceptor arm. The rearrangement of the acceptor end induced by small substrates results in reorientation of the 3'-OH-group of the terminal ribose from the catalytic subunit onto the noncatalytic one, and this may explain the unusual stereospecificity of aminoacylation in this system.


Agreement Between Upper Digestive Disease App and Provider Evaluation of Esophagectomy Symptoms in a Mobile App Tool.
The objective of this study was to assess the criterion validity of score thresholds for the Upper Digestive Disease (UDD) App. From December 15, 2017, to December 15, 2020, patients presenting after esophagectomy were offered the UDD App concurrent with a provider visit. This tool consists of 67 questions including 5 novel domains. Score thresholds were used to assign patients to a good, moderate, or poor category on the basis of domain scores. Providers were given performance descriptions for each domain and asked to assign patients to a category on the basis of their clinical evaluation. The weighted κ statistic was used to determine the magnitude of agreement between classifications based on the patients' UDD App scores and the providers' clinical evaluation. Fifty-nine patients in the study (76% male; median age, 63 years [interquartile range, 57-72 years]) reported outcomes using the UDD App. Providers reviewed between 1 and 10 patients at a median time of 296.5 days (interquartile range, 50-975 days) after esophagectomy. The magnitude of agreement between patients and providers was moderate for dysphagia (κ = 0.52; P < .001) and reflux (κ = 0.42; P < .001). Dumping-related hypoglycemia (κ = 0.03; P = .148), gastrointestinal complaints (κ = 0.02; P = .256), and pain (κ = 0.05; P < .184) showed minimal agreement, with providers underestimating the symptoms and problems reported by patients in these domains. Although there was agreement between UDD App assessment and provider evaluation of dysphagia and reflux after esophagectomy, there was discordance of scoring for dumping-related symptoms and pain. Future research is needed to determine whether thresholds for pain and dumping domains need to be revised or whether additional provider education on performance descriptions is needed.


The benefit of nonpharmacologic therapy to treat symptomatic osteoarthritis.
Osteoarthritis affects a large proportion of the population, especially the elderly, leading to pain and disability. To relieve pain, many patients are turning toward nonpharmacologic therapies. Conventional nonpharmacologic treatments such as weight loss and exercise are well accepted by the medical community, and some randomized controlled trials support the use of these treatments in patients with knee osteoarthritis. However, little information exists regarding the efficacy of these treatments for osteoarthritis at other sites. Less conventional treatments such as acupuncture and massage are emerging as promising options for osteoarthritis treatment, but the magnitude of benefit has varied between studies. More investigation is necessary to reach a conclusion regarding the efficacy of these treatments.


Simultaneous quantification of plant glyceroglycolipids including sulfoquinovosyldiacylglycerol by HPLC-ELSD with binary gradient elution.
Membrane lipids of photosynthetic organisms consist of glycerophospholipids and glyceroglycolipids. We investigated a method for the simultaneous quantitative analysis of neutral and acidic lipids using HPLC-ELSD, and quantified monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG) and sulfoquinovosyldiacylglycerol (SQDG). Ten complex lipid classes were separated with a binary gradient system consisting of chloroform and methanol-acetone-water-acetic acid (30:60:9:1, v/v/v/v) with 0.3% triethylamine (pH 4), and were eluted within 16 min. The contents of SQDG in ten edible plants ranged from 3 to 101 mg/100 g, and were positively correlated to the neutral glyceroglycolipids contents.


Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat model.
While genetic predisposition is a major factor, it is not known how development of attention-deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention, impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have previously shown that SHR have disturbances in the noradrenergic system and that the early life stress of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the present study we investigated the effect of maternal separation on approach behavior (response to a novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether maternal separation altered GABAA and NMDA receptor-mediated regulation of norepinephrine release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked release in SHR hippocampus but not in WKY. The results of the present study show that noradrenergic function is similarly altered by the early life stress of maternal separation in male and female SHR, while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI: Noradrenergic System.


A Tunable Dual-Band and Polarization-Insensitive Coherent Perfect Absorber Based on Double-Layers Graphene Hybrid Waveguide.
A suspended monolayer graphene has only about 2.3% absorption rate in visible and infrared band, which limits its optoelectronic applications. To significantly increase graphene's absorption efficiency, a tunable dual-band and polarization-insensitive coherent perfect absorber (CPA) is proposed in the mid-infrared regime, which contains the silicon array coupled in double-layers graphene waveguide. Based on the FDTD methods, dual-band perfect absorption peaks are achieved in 9611 nm and 9924 nm, respectively. Moreover, due to its center symmetric feature, the proposed absorber also demonstrates polarization-insensitive. Meanwhile, the coherent absorption peaks can be all-optically modulated by altering the relative phase between two reverse incident lights. Furthermore, by manipulating the Fermi energies of two graphene layers, two coherent absorption peaks can move over a wide spectrum range, and our designed CPA can also be changed from dual-band CPA to narrowband CPA. Thus, our results can find some potential applications in the field of developing nanophotonic devices with excellent performance working at the mid-infrared regime.


Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation.
Metazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate. PI3K-driven effector T cell determination silences TCF1 in one sibling cell, while its PI3K-attenuated sibling self-renews in tandem. Prior to bifurcations achieving irreversible plasma or effector cell fate determination, asymmetric signaling during initial divisions specifies a more proliferative, differentiation-prone lymphocyte in tandem with a more quiescent memory cell sibling. By triggering cell division but transmitting unequal intensity between sibling cells, nutrient-sensitive signaling may be a frequent arbiter of cell fate bifurcations during development and repair.


Mechanical design of the highly porous cuttlebone: A bioceramic hard buoyancy tank for cuttlefish.
Cuttlefish, a unique group of marine mollusks, produces an internal biomineralized shell, known as cuttlebone, which is an ultra-lightweight cellular structure (porosity, ∼93 vol%) used as the animal's hard buoyancy tank. Although cuttlebone is primarily composed of a brittle mineral, aragonite, the structure is highly damage tolerant and can withstand water pressure of about 20 atmospheres (atm) for the species Sepia officinalis Currently, our knowledge on the structural origins for cuttlebone's remarkable mechanical performance is limited. Combining quantitative three-dimensional (3D) structural characterization, four-dimensional (4D) mechanical analysis, digital image correlation, and parametric simulations, here we reveal that the characteristic chambered "wall-septa" microstructure of cuttlebone, drastically distinct from other natural or engineering cellular solids, allows for simultaneous high specific stiffness (8.4 MN⋅m/kg) and energy absorption (4.4 kJ/kg) upon loading. We demonstrate that the vertical walls in the chambered cuttlebone microstructure have evolved an optimal waviness gradient, which leads to compression-dominant deformation and asymmetric wall fracture, accomplishing both high stiffness and high energy absorption. Moreover, the distribution of walls is found to reduce stress concentrations within the horizontal septa, facilitating a larger chamber crushing stress and a more significant densification. The design strategies revealed here can provide important lessons for the development of low-density, stiff, and damage-tolerant cellular ceramics.


Experimental agents to improve fracture healing: utilizing the WNT signaling pathway.
The process of bone healing largely recapitulates bone development in the embryo and ideally achieves complete restoration of bone shape and structure. However, because successful fracture healing requires tight interactions of numerous cell types and signaling molecules, any disruption of this highly coordinated processes can result in delayed healing or even non-union formation. The rate of fracture healing complications in orthopedic patients is reported to be 5-20%. Therefore, there is a need for new therapeutic strategies to improve fracture healing in patients with healing complications. One treatment strategy would include the easy and safe application of a pharmacological agent inducing osteoanabolic effects during fracture healing. One potential promising molecular target is the osteoanabolic WNT signaling pathway. This pathway plays an important role during embryonic bone development, homeostasis, mechanotransduction, development of osteoporosis and bone regeneration. This review focuses on preclinical studies targeting WNT signaling molecules to accelerate fracture healing. The three main investigated antagonists of the WNT signaling pathway, which can be blocked experimentally by antibodies, are Sclerostin, Dickkopf-1 and Midkine. Treating animals with antibodies against these proteins enhanced bone formation in the fracture callus. This indicates a therapeutic potential for these antibodies to accelerate fracture healing in patients with orthopedic complications.


Hepatitis delta virus infection in a large cohort of chronic hepatitis B patients in Ethiopia.
Hepatitis D virus (HDV) infection is associated with a more severe outcome in patients with chronic hepatitis B (CHB); however, little is known about the presence of HDV in sub-Saharan Africa. We aimed to determine the prevalence of HDV infection, as well as its clinical, biological and virological characteristics, in a large CHB cohort in Ethiopia. In total, 1267 HIV-negative CHB patients at St. Paul's Hospital Millennium Medical College in Addis Ababa were screened for anti-HDV antibodies using ELISA assays. Confirmed positive samples were further tested for HDV RNA using a consensus commercial real-time RT-PCR assay. HDV genotypes were also determined for RNA-positive samples by nucleotide sequencing followed by phylogenetic analyses. Demographical, clinical and biological data from patients were recorded and compared based on HDV RNA results. Most patients (n = 748, 59.0%) were men, and the median age was 31 years (interquartile range 26-40). Anti-HDV antibodies were detected in 19 individuals (1.5%), 12 of whom were HDV RNA-positive with a viral load ranging from <2 to >8 log 10 IU/mL. All strains were genotype 1. HDV RNA-positive patients were more likely to have significant liver fibrosis (63.6% vs 24.7%, P = .007) and cirrhosis (45.5% vs 16.4%, P = .024). HDV infection is rare in Ethiopia but is associated with more advanced liver fibrosis.


Secondary chordoma of the mandible.
The first case of primary sacrococcygeal chordoma metastasising to the mandible and presenting with obstructed labour is described. The pathological features of this tumour, its clinical presentation and management are discussed.


Brown fat necrosis in the setting of congenital heart disease and prostaglandin E1 use: a case report.
We report a case of a child with D-transposition of the great arteries treated with prostaglandin E1 (PGE1) who subsequently developed extensive brown fat necrosis. To the best of our knowledge, no previous association among congenital heart disease, PGE1, and brown fat necrosis has been reported.


Developmental forms of human skeletal muscle AMP-deaminase.
Chromatography on phosphocellulose revealed the existence of two well-separable forms of skeletal muscle AMP-deaminase in the tissue extracts of 11- and 16-week-old human fetuses. One of these forms elutes from the column at the same salt concentration as the muscle isozyme found in the skeletal muscle extract from adult man, and seems to have similar kinetic properties. The second form, which was found only in vestigial amounts in adult human tissue extract, represents different kinetic properties and seems to be a form characteristic for the fetal period of ontogenesis.


Prognostic value of troponins in sepsis: a meta-analysis.
The role of biomarkers such as troponin in risk stratification of sepsis is still debated. The aim of this meta-analysis is to assess the relation between troponin elevation in sepsis and mortality. All observational studies from Embase, Medline and those manually searched up to September 2010 were included. Studies identified were those which reported on patients with a diagnosis of sepsis and if a 2 × 2 table could be constructed based on troponins and death. We pooled the relative risk (RR) and odds-ratio (OR) using the inverse variance method in studies that conducted univariate and multivariable (adjusted) analysis. Thirteen studies encompassing 1,227 patients were included. The prevalence of elevated troponin was 61 % ([95 %] CI 58-64 %). Elevated troponin was significantly associated with all-cause mortality (RR 1.91; CI 1.63-2.24), with homogeneity across studies. In adjusted analysis (four studies comprising 791 patients) according to prognostic scores, elevated troponin was associated with an increased risk of death (OR 1.92; CI 1.35-2.74). The area under the ROC curve was 0.68 (CI 0.63-0.71). Pooled sensitivity and specificity were 77 % (CI 61-88) and 47 % (CI 30-64) with heterogeneity across studies. It corresponded to positive and negative likelihood ratios of 1.50 (95 % CI: 1.20-1.90) and 0.49 (CI 0.38-0.64), respectively. Elevated troponin identifies a subset of patients with sepsis at higher risk of death. Further studies are needed to define the precise role of troponins and their optimal cut-offs.


Social support in schools and related outcomes for LGBTQ youth: a scoping review.
Recent research has increasingly focused on positive factors and supports for LGBTQ youth. This scoping review explores existing social support for LGBTQ youth in schools through the Ecological Systems Theory to respond to the following four objectives: (1) define social support systems in schools, (2) identify current research on outcomes for LGBTQ youth, (3) identify barriers to support LGBTQ youth in schools, and (4) identify areas for future research for LGBTQ youth and social support in schools. A systematic search (Arksey and O'Malley in Int J Soc Res Methodol 8(1):19-32, 2005) between 2007 through 2021 resulted in 94 articles. This review gave rise to an organizational framework to consolidate various systems of social support for LGBTQ youth in schools. Social support consisted of seven social support systems (family, curriculum, family, peers, school policies, GSAs and programs, and school climate) that are positively associated with the promotion of positive socioemotional, behavioural, and educational outcomes for LGBTQ youth. Though the literature has been clear surrounding the risks associated with LGBTQ youth, this scoping review provides a positive outlook on LGBTQ youth's school experiences and how these systems of social support allow for LGBTQ youth to act as active participants to foster a positive school climate and sense of safety. The online version contains supplementary material available at 10.1007/s44217-022-00016-9.


Idiotypic spreading promotes the production of pathogenic autoantibodies.
We propose that a major immunoregulatory abnormality in murine and human autoantibody-mediated disease is idiotypic spreading. By this mechanism, B cells with the genetic information to produce immunoglobulin (Ig) bearing certain public idiotypes (Ids) are selectively upregulated, probably by Id-recognizing helper T cells. The model in which we are testing the hypothesis is systemic lupus erythematosus (SLE) in humans and NZB/NZW F1 (BW) female mice. Recent experiments have shown that the number of public Ids expressed on the Ig of nephritic BW mice is quite restricted. IdX is the dominant Id on serum Ig; IdGN1 and IdGN2 are also common. All three Ids were initially derived from spontaneous antibodies to DNA. Together the three are present on 85% of the total Ig repertoire. Such restriction suggests idiotypic spreading. In glomerular Ig deposits from nephritic BW mice, IdGN1 and IdGN2 are found on 45% of the total Ig: IdX is present in minute amounts. Furthermore, suppression of IdGNs by administration of anti-IdGN1 to BW mice resulted in significant delay in the onset of nephritis, but the IdGNs escaped from control and eventually caused a fatal nephritis. Finally, studies of glomerular Ig deposits in renal biopsies of patients with SLE have shown that IdGN2 dominates such Ig, being present in 76% of renal biopsies from SLE patients and in 6% from patients with non-lupus immune nephritis. Therefore, we have concluded that IdGN1 and IdGN2 are markers of nephritogenic subsets of autoantibodies and are probably the products of idiotypic spreading most likely to cause disease. Finally, after a review of recent experiments suggesting the dominance of autoreactive, Mossman Type 2 T helper cells in nephritic BW mice, it is hypothesized that autoreactive, IdGN-recognizing helper T cells may be central to the sustained upregulation of pathogenic autoantibodies in murine and human SLE.


A review of thymic tumours.
Tumours of the thymus are uncommon and are generally regarded as being indolent. Whilst this is often true of thymomas; thymic adenocarcinoma and thymic neuroendocrine cancer can be aggressive and have a poor prognosis. Understanding the biology of these tumours is important for prognosis and management. The pathological features of these tumours are examined in detail. Imaging modalities for aiding in diagnosis and staging of these tumours are described; this includes CT and MRI, plus more recent advances including the use of FDG-PET and Indium-111 Octreotide scintigraphy. The treatment options available including curative surgery, debulking surgery, chemotherapy, somatostatin analogues and peptide receptor radionuclide therapy are discussed. The optimal chemotherapy regimens are still unclear, although promising results have been obtained with platinum-based chemotherapy. The role for adjuvant therapy in both thymic carcinoma and thymoma is unclear except, in patients with stage I thymomas. There is a high expression of somatostatin receptors in thymic tumours and anti-tumour benefit has been reported in patients treated with somatostatin analogues. A new development is the role of peptide receptor radionuclide therapy. This has become an established therapy in management of gastroenteropancreatic neuroendocrine tumours and its use has been recently described in case reports in both thymoma and thymic carcinoma.


GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice.
GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-D-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg.i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications.


Identification of candidate metabolite biomarkers for metabolic syndrome and its five components in population-based human cohorts.
Metabolic Syndrome (MetS) is characterized by risk factors such as abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), hypertension, and hyperglycemia, which contribute to the development of cardiovascular disease and type 2 diabetes. Here, we aim to identify candidate metabolite biomarkers of MetS and its associated risk factors to better understand the complex interplay of underlying signaling pathways. We quantified serum samples of the KORA F4 study participants (N = 2815) and analyzed 121 metabolites. Multiple regression models adjusted for clinical and lifestyle covariates were used to identify metabolites that were Bonferroni significantly associated with MetS. These findings were replicated in the SHIP-TREND-0 study (N = 988) and further analyzed for the association of replicated metabolites with the five components of MetS. Database-driven networks of the identified metabolites and their interacting enzymes were also constructed. We identified and replicated 56 MetS-specific metabolites: 13 were positively associated (e.g., Val, Leu/Ile, Phe, and Tyr), and 43 were negatively associated (e.g., Gly, Ser, and 40 lipids). Moreover, the majority (89%) and minority (23%) of MetS-specific metabolites were associated with low HDL-C and hypertension, respectively. One lipid, lysoPC a C18:2, was negatively associated with MetS and all of its five components, indicating that individuals with MetS and each of the risk factors had lower concentrations of lysoPC a C18:2 compared to corresponding controls. Our metabolic networks elucidated these observations by revealing impaired catabolism of branched-chain and aromatic amino acids, as well as accelerated Gly catabolism. Our identified candidate metabolite biomarkers are associated with the pathophysiology of MetS and its risk factors. They could facilitate the development of therapeutic strategies to prevent type 2 diabetes and cardiovascular disease. For instance, elevated levels of lysoPC a C18:2 may protect MetS and its five risk components. More in-depth studies are necessary to determine the mechanism of key metabolites in the MetS pathophysiology.


In electrospray ionization source hydrogen/deuterium exchange LC-MS and LC-MS/MS for characterization of metabolites.
A new method is described for performing hydrogen/deuterium (H/D) exchange in an electrospray ionization (ESI) source. The use of liquid chromatography (LC)-mass spectrometer equipped with an ESI source and deuterium oxide (D2O) as the sheath liquid allows H/D exchange experiments to be performed on-line. This directly provides information for determining the number and position of exchangeable hydrogens, aiding in the elucidation of the structures of drug metabolites. To demonstrate the utility of this method, LC-mass spectrometry (MS) and LC-MS/MS experiments were performed using either H2O or D2O as sheath liquid on a matrix metalloprotease (MMP) inhibitor (PD 0200126) and its metabolites. Examination of the mass shift of the deuteriated molecule from that of the protonated molecule allowed the number of exchangeable protons to be determined. Interpretation of the production-spectra helped to determine the location of the exchanged protons and assisted in the assignment of the site(s) of modification for each metabolite.


The many worlds hypothesis of dopamine prediction error: implications of a parallel circuit architecture in the basal ganglia.
Computational models of reinforcement learning (RL) strive to produce behavior that maximises reward, and thus allow software or robots to behave adaptively [1]. At the core of RL models is a learned mapping between 'states'-situations or contexts that an agent might encounter in the world-and actions. A wealth of physiological and anatomical data suggests that the basal ganglia (BG) is important for learning these mappings [2,3]. However, the computations performed by specific circuits are unclear. In this brief review, we highlight recent work concerning the anatomy and physiology of BG circuits that suggest refinements in our understanding of computations performed by the basal ganglia. We focus on one important component of basal ganglia circuitry, midbrain dopamine neurons, drawing attention to data that has been cast as supporting or departing from the RL framework that has inspired experiments in basal ganglia research over the past two decades. We suggest that the parallel circuit architecture of the BG might be expected to produce variability in the response properties of different dopamine neurons, and that variability in response profile may not reflect variable functions, but rather different arguments that serve as inputs to a common function: the computation of prediction error.


Transbilayer movement of fluorescent analogs of phosphatidylserine and phosphatidylethanolamine at the plasma membrane of cultured cells. Evidence for a protein-mediated and ATP-dependent process(es).
The internalization of fluorescent analogs of phosphatidylserine and phosphatidylethanolamine following their insertion into the plasma membrane of cultured Chinese hamster fibroblasts was examined. When liposomes containing the fluorescent lipid 1,2-(palmitoyl-N-4-nitrobenzo-2-oxa-1,3-diazole-amino-caproyl) phosphatidylserine [palmitoyl-C6-NBD)-PS), were incubated with monolayer cell cultures at 2 degrees C, spontaneous transfer of the fluorescent lipid from the liposomes to the cells occurred, resulting in prominent labeling of the plasma membrane. However, if the cells were washed and warmed to 7 degrees C for 30 min, the (palmitoyl-C6-NBD)-PS also labeled numerous intracellular membranes. Evidence is presented suggesting that this internalization was not due to endocytosis, but was the result of transmembrane movement of the (palmitoyl-C6-NBD)-PS at the plasma membrane followed by translocation of lipid monomers from the plasma membrane to internal membranes. This transmembrane movement was reversibly inhibited by depletion of cellular ATP levels and was blocked by treatment with structural analogs of the lipid or by pretreatment of cells with glutaraldehyde or N-ethyl-maleimide. A fluorescent analog of phosphatidylethanolamine [palmitoyl-C6-NBD)-PE), which also exhibits transmembrane movement at the plasma membrane at 7 degrees C (Sleight, R. G., and Pagano, R. E. (1985) J. Biol. Chem. 260, 1146-1154), was further studied. Its transmembrane movement was also inhibited by depletion of cellular ATP levels, or by pretreatment of cells with N-ethylmaleimide. The transmembrane movement of the fluorescent phosphatidylserine and phosphatidylethanolamine analogs was inhibited when the unnatural D-isomers of these lipids were used, further suggesting that this process was stereospecific and therefore likely to have been protein-mediated.


Enzyme immunoassay for flecainide.
In order to develop an enzyme immunoassay (ELISA) for measurement of plasma flecainide levels, we first synthesized flecainide-hemisuccinate-BSA as immunogen. A highly specific antiserum was then raised in rabbits. Enzyme-labelled flecainide was prepared by the mixed anhydride method using hemifumarate-flecainide and horse radish peroxidase. The limit of detection was 10 ng/ml, the method was linear up to 1,000 micrograms/l. The intra and inter-assay variation was 5.1-7.8%. Cross reactivity with various metabolites of flecainide or some chemically related drugs was less than 0.1%. By contrast the cross reaction with some structural analogues achieved 25%. The importance of parts of the aromatic ring structure in immunogenic properties of this drug is discussed.


Platinum (II) and (IV) spermidine complexes. Synthesis, characterization, and biological studies.
By reaction of K2PtCl4 with spermidine we have synthesized two tris-platinum covalent compounds of formula (PtI2)3(sper)2 and (PtCl2)3(sper)2, one ionic compound of formula (sperH3)2(PtCl4)3, and another one of a covalent nature of formula (PtCl2sperH)2 (PtCl4) having a partially protonated spermidine residue. Treatment of the tris-platinum compounds with hydrogen peroxide and hydrochloric acid led to the production of two compounds of formula cis-trans-cis-(PtIVCl2(OH)2)3(sper)2 and cis-(PtIVCl4)3(sper)2, respectively. All of them have been characterized by IR and 1H MNR spectroscopy and tested for their ability to interact with pUC8 plasmid DNA by the use of UV, CD, and electrophoretic techniques. The results suggest that all of these compounds modify the secondary structure of the double helix. We observed that the alteration in electrophoretic mobility of nicked and closed circular forms of DNA induced by the Pt(II) complexes is higher than that induced by the Pt(IV) complexes. The synthesized compounds were also assayed for antitumor activity in vitro against breast (MDA-MB468) and leukemia (HL-60) tumor cells. Only three of these complexes may be regarded as potential antitumor agents, since their ID50 values are lower than 10 micrograms/ml.


Molecular Mechanisms of Cytokinin Signaling.
Cytokinins regulate a myriad of plant growth and developmental processes. Recent molecular genetic studies in Arabidopsis have begun to unravel the molecular mechanisms underlying cytokinin perception and signal transduction. A family of cytokinin receptors has been identified, and these are homologous to bacterial two-component sensor kinases. Events immediately downstream of cytokinin binding are similar to the classic phosphorelay paradigm. The cytokinin signal appears to be transduced from the membrane-localized histidine kinase-like receptors into the nucleus via a transient translocation of the AHP proteins, which are Arabidopsis homologs of histidine phosphotransfer proteins. Once in the nucleus, the AHPs activate the type-B class of Arabidopsis response regulators (ARRs), which in turn activate the transcription of a second class of Arabidopsis response regulators, the type-A ARRs. A model of cytokinin signaling from perception at the plasma membrane to activation of gene expression in the nucleus is beginning to emerge.


Social inequalities in treatment receipt for childhood cancers in Ireland: A population-based analysis.
Treatment advances over the past five decades have resulted in significant improvements in survival from childhood cancer. Although survival rates are relatively high, social disparities in outcomes have been sometimes observed. In a population-based study, we investigated social inequalities by sex and deprivation in treatment receipt in childhood cancer in Ireland. Cancers incident in people aged 0 to 19 during 1994 to 2012 and treatments received were abstracted from the National Cancer Registry Ireland. Multivariable modified Poisson regression with robust error variance (adjusting for age, and year) was used to assess associations between sex and deprivation category of area of residence at diagnosis and receipt of cancer-directed surgery, chemotherapy or radiotherapy. Three thousand seven hundred and four childhood cancers were included. Girls were significantly less likely than boys to receive radiotherapy for leukemia overall (relative risk [RR] = 0.70; 95% confidence interval [CI] = 0.50-0.98), and acute lymphoblastic leukemia specifically (RR = 0.54; 95% CI = 0.36-0.79), and surgery for central nervous system (CNS) overall (RR = 0.83; 95% CI = 0.74-0.93) and other CNS (RR = 0.76; 95% CI = 0.60-0.96). Girls were slightly less likely to receive chemotherapy for non-Hodgkin lymphoma and surgery for Hodgkin lymphoma (HL), but these results were not statistically significant. Children residing in more deprived areas were significantly less likely to receive chemotherapy for acute myeloid leukemia or surgery for lymphoma overall and HL, but more likely to receive chemotherapy for medulloblastoma. These results may suggest social inequalities in treatment receipt for childhood cancers. Further research is warranted to explore whether similar patterns are evident in other childhood cancer populations and to better understand the reasons for the findings.


Is surgical intervention routinely required for congenital lobar overinflation? A case series from a tertiary hospital in Riyadh, Saudi Arabia.
Congenital lobar overinflation (CLO) is a congenital overinflation of a pulmonary lobe. The treatment choice depends on the severity of its symptoms. Surgical intervention is indicated for patients with significant symptomatology, while a conservative approach is used to treat incidental and mildly symptomatic lesions. However, the conservative approach for children with mild symptoms is not very common among pulmonologist. Therefore, we evaluated this approach to treating mildly symptomatic children. This retrospective study examined mildly symptomatic patients (n = 14) with a radiological diagnosis of CLO between June 2005 and August 2018 who were treated conservatively at KFSHRC in Riyadh. The participants' ages ranged between two days and four years, with follow-up period ranged from four months to 10 years. Fourteen patients with CLO-who were 2 days to four years old and comprised 10 boys (71.4%) and four girls (28.6%)-were treated conservatively. All patients were symptomatic upon presentation, and their main clinical findings were tachypnea (85.7%) and dyspnea (78.6%). A single lobe was affected for ten patients (71.4%). Congenital cardiac anomalies founded in six patients (42.9%). Radiological image showed overinflation of all patients' affected lobes. Significant mediastinal displacement was observed among two patients (14.3%). During their follow-up periods, nine patients (64.3%) became asymptomatic, three (21.4%) showed improvement, and two (14.3%) remained symptomatic and underwent lobectomy. The good outcomes for mildly symptomatic children with CLO in our series indicate that the conservative approach can be considered to treat these children at any age, along with close follow-up.


Pubescence, floral temperature and fecundity in species of Puya (Bromeliaceae) in the Ecuadorian Andes.
The effects of inflorescence pubescence on floral temperatures and fecundity were examined in four species of Puya in the Ecuadorian Andes. These species span an elevational range from 1,980-4,000 m and comparisons among these species showed that pubescence production increases significantly with elevation. Flower temperatures of glabrous or slightly pubescent species of Puya from lower elevations closely tracked air temperature, while those of the pubescent páramo species did not. Pubescence removal experiments on Puya hamata, a páramo species, demonstrated that pubescence is an effective insulator, maintaining elevated flower temperatures. In Puya clava-herculis (also a páramo species) elevated flower temperatures were associated with higher seed set. Thus, the greater production of inflorescence pubescence in páramo species of Puya may be an important factor contributing to reproductive success in these higher elevation species.


Role of air pollution tolerance index (APTI) method for green belt development: a review.
Air pollution has emerged as one of the most important aspects of environmental research, as the progress of human civilisation has significantly deteriorated the quality of air. Plants have a significant role in maintaining and monitoring ecological balance by actively participating in the cycling of gases such as oxygen and carbon dioxide and nutrients. Besides, they also provide a large leaf base for assimilation and deposition of airborne pollutants to reduce their concentration in the atmosphere. Plants, on the other hand, do not react to all types of pollutants. Hence, different plant species have different levels of potential to remediate a specific pollutant in the atmosphere. There are a variety of parameters on the basis of which plant species are selected for plantation. Before choosing any plant species for a plantation, each of these parameters should be thoroughly examined. Plants having greater air pollution tolerance index (APTI) values are more tolerant and act as a sink, whereas plants with lower APTI values are less tolerant and can be used to determine the air quality. With the help of the APTI method decisions regarding plant species, selection can be made while developing Green Belts around polluted or urban areas.


Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine.
We report that the expression of mutant G93A copper/zinc superoxide dismutase (SOD1), associated with familial amyotrophic lateral sclerosis, specifically causes a decrease in MTT reduction rate and ATP levels and an increase in both cytosolic and mitochondrial reactive oxygen species (ROS) production in human neuroblastoma SH-SY5Y cells compared to cells overexpressing wild-type SOD1 and untransfected cells. Exposure to N-acetylcysteine lowers ROS production and returns mitochondrial functional assays to control levels. No large aggregates of human SOD1 are detectable under basal growth conditions in any of the investigated cell lines. After proteasome activity inhibition, SOD1 aggregates can be detected exclusively in G93A-SOD1 cells, even though they do not per se enhance cell death compared to control cell lines. Our findings indicate that mitochondrial homeostasis is affected by mutant SOD1-generated ROS independently from the formation of aggregates and that this alteration is reversed by antioxidants.


Bioinspired butyrate-functionalized nanovehicles for targeted oral delivery of biomacromolecular drugs.
Ligand-functionalization can increase the affinity of nanoparticles (NPs) with targeted cells. However, one major defect of ligands still exists in oral administration: limited receptor recognition. The hindrance of mucus network and deactivation of enzymes severely challenge the targeting efficiency of macromolecular ligands. Inspired by "molecular exchange" between intestinal microbiota and host cells, we anchored microbiota metabolite butyrate on classical "mucus-inert" polyethylene glycol (PEG) NPs. Butyrate has unique advantages of low molecule weight, high hydrophilicity and chemical stability. Interestingly, in vitro mucus-permeability and in vivo mucus distribution of PEG NPs were not impaired by butyrate-functionalization. Enhanced cellular uptake was achieved via specific interaction between butyrate and the monocarboxylate transporter (MCT) on cell membranes, which subsequently ameliorated transepithelial transport and intestinal absorption in the ileum. In vitro safety assessment validated the non-toxicity of butyrate-modification. Finally, insulin-loaded Bu-PEG NPs generated a stronger hypoglycemic response on diabetic rats and 2.87-fold higher oral bioavailability compared with bare PEG NPs. This study demonstrated that butyrate-functionalization could improve the intestinal absorption of macromolecules by overcoming multiple obstacles in the gastrointestinal tract, providing a promising active targeting strategy for oral administration.


[Preparation and in vitro drug release study of long-circulating hydroxycamptothecin nanoparticles].
To prepare long-circulating hydroxycamptothecin nanoparticles and study its in vitro drug release characteristics. The HCPT-PEG-PCL-NPs were prepared by solvent-diffusion method using PEG-PCL block copolymer synthesized as a matrix and HCPT as an antitumor agent. Then the obtained NPs were evaluated and its in vitro drug release characteristics were investigated. When using PEG4000-PCL2000, PEG4000-PCL1250, PEG2000-PCL2000, PEG2000-PCL1250 as the carrier material to prepare NPs, the average particle size of NPs in turn were 116.1, 110.0, 119.9, 99.1 nm; the zeta potential were -22.4, - 16. 9, -33.5, - 28.8 mV; the entrapment efficiency were 88.29%, 83.10%, 80.67%, 77.46%; and the drug loading were 2.96%, 2.56%, 2.31%, 2.14%, respectively. HCPT-PEG-PCL-NPs all showed a certain degree of sustained-release characteristics and their release mechanisms were fitted to Weibull modle, which showed that the drug release process included passive diffusion and matrix-eroded procedure. The HCPT-PEG-PCL-NPs has high entrapment efficiency, drug loading, uniform particle size, and can retard drug release in vitro, so it provides an extensive prospect for clinical application of HCPT.


Characterization of human tumor necrosis factor produced by peripheral blood monocytes and its separation from lymphotoxin.
Cultures of human peripheral blood leukocytes (PBL) induced with phytohemagglutinin (PHA) and the phorbol ester 12-0-tetradecanoylphorbol 13-acetate (TPA) produced two types of cytotoxic proteins, indistinguishable in the in vitro assay employing murine L 929 cells as targets. One of these proteins had the antigenic and physicochemical properties of lymphotoxin (LT). We have identified the other cytotoxin as tumor necrosis factor (TNF), mainly on the basis of antigenic cross-reactivity demonstrated with antiserum to TNF, and also by its characteristic physicochemical properties and cell source. Unlike LT, PBL-derived TNF did not bind to Concanavalin A-Sepharose or to several other agglutinin-Sepharose columns specific for carbohydrate moieties common in glycoproteins. The molecular weight of native TNF determined by gel filtration was approximately 40,000 while SDS-PAGE revealed a single sharp peak of 16,500 +/- 500. When cultures of monocytes and lymphocytes separated by elutriation were stimulated with PHA and/or TPA, monocytes were the major source of TNF. In contrast, only lymphocytes produced LT. A mixture of antisera to TNF and LF neutralized all cytotoxicity of crude human lymphokine preparations for L 929 cells, suggesting that TNF and LT are either the only, or the major, cytotoxic proteins present in such crude lymphokine preparations demonstrable in this assay.


Bulk staining of sputum by the Ziehl-Neelsen method.
A trial of the Ziehl-Neelsen staining method employing bulk decolorization, rinsing and counter staining yielded reliable results. Of 110 patients who proved to be positive by direct microscopy, cross-contamination could not be proved in any. The advantage of the mass method is its economy.


Face recognition in patients with migraine.
Prosopagnosia is a rare dysfunction seen during the aura phase of migraine. We aimed to evaluate the face recognition, which has not previously been investigated in migraineurs during the interictal period, and its relationships with clinical features. Seventy-four migraineurs, with or without aura, diagnosed according to the International Headache Society criteria and 37 healthy control subjects were included. Benton face recognition test (BFRT) and judgment of line orientation test (LOT) for complex visual perception were applied to all participants. Migraineurs showed significantly lower performance in both of the BFRT and LOT scores (P = 0.027; P = 0.014, respectively), indicating impaired visuospatial perception. In the subgroup analysis, these impairments were more pronounced in the group with migraine without aura. Migraineurs had poorer performance in both face recognition and visuospatial perception. These findings could be based on functional differences in the migraineurs' brain or genetic changes.


Primary structure of Ac1-proteinase from the venom of Deinagkistrodon acutus (hundred-pace snake) from Taiwan.
The entire amino acid sequence of Ac1-Proteinase from Deinagkistrodon acutus venom was determined by using lysyl endopeptidase, metalloendopeptidase, trypsin and V8 protease. The hemorrhagic toxin had a typical zinc-chelating sequence His-Glu-X-X-His found in thermolysin.


Prognostic nomogram for patients with minor stroke and transient ischaemic attack.
Ischaemic stroke and transient ischaemic attack (TIA) share a common cause. We aim to develop and validate a concise prognostic nomogram for patients with minor stroke and TIA. A total of 994 patients with minor stroke and TIA were included. They were split into a derivation (n=746) and validation (n=248) cohort. The modified Rankin Scale (mRS) scores 3 months after onset were used to assess the prognosis as unfavourable outcome (mRS≥2) or favourable outcome (mRS<2). The final model included seven independent predictors: gender, age, baseline National Institute of Health Stroke Scale (NIHSS), hypertension, diabetes mellitus, white blood cell and serum uric acid. The Harrell's concordance index (C-index) of the nomogram for predicting the outcome was 0.775 (95% CI 0.735 to 0.814), which was confirmed by the validation cohort (C-index=0.787 (95% CI 0.722 to 0.853)). The calibration curve showed that the nomogram-based predictions were consistent with actual observation in both derivation cohort and validation cohort. The proposed nomogram showed favourable predictive accuracy for minor stroke and TIA. This has the potential to contribute to clinical decision-making.


Pharmacologic Management of Cancer-Related Pain in Pregnant Patients.
Despite being an essential part of whole-person care, patients with cancer often experience complex and under-treated pain. Managing cancer-related pain in patients who are also pregnant compounds the challenge for adequate pain management, as studies have largely excluded this population. Therapy for pain management should be guided by the cause and mechanism of pain. The objective of this review is to provide clinicians with an understanding of pain experienced by pregnant patients with cancer and medications that may be used to help manage cancer-related pain. Nociceptive pain results from damage to somatic or visceral tissues that may be directly caused by cancer. This type of pain can be managed in pregnant patients using acetaminophen and/or nonsteroidal antiinflammatory drugs as first-line agents. In nociceptive pain not managed by non-opioid analgesics, buprenorphine is recommended for those requiring chronic opioids to help manage their pain. Neuropathic pain that results from damage to the peripheral or central nervous system may also be directly caused by cancer, particularly chemotherapy. In pregnant patients, duloxetine and gabapentin should be considered first. Venlafaxine, pregabalin, tricyclic antidepressants, and sodium channel blockers should be avoided, if possible. Nociplastic pain is not directly caused by cancer but may be caused by ongoing peripheral nociceptive input or a condition that predates the cancer diagnosis. Duloxetine and gabapentin are reasonable agents to consider for treatment of nociceptive pain in pregnant patients. Cyclobenzaprine may also be helpful for nociplastic pain.


The accelerated hepatitis B virus vaccination schedule among hemodialysis patients, does it work? A randomized controlled trial.
Hemodialysis patients possess particular attributes which increase the susceptibility to hepatitis B virus (HBV) infections. HBV vaccination significantly decreased the number of new HBV-infected patients. However, the conventional vaccination schedule requires a 6-months duration. This study aimed to examine the efficacy the accelerated vaccination schedule among hemodialysis patients. In this study, 202 consecutive hemodialysis patients at New Jeddah hospital were enrolled. The inclusion criteria were: (1) age was above 18 years, (2) all patients had undetectable HBV surface antigen and antibody. Exclusion criteria included: (1) patient had a positive serum HBV surface antigen and antibody using enzyme-linked immunosorbent assay; (2) patient received a previous course of HBV vaccine, (3) patient who was pregnant. Patients were sequentially randomized to receive either Hepatitis B recombinant DNA vaccine (conventional schedule) or to receive combined hepatitis A and B vaccine injection (accelerated schedule). Testing for HBV surface antibodies was done one and three months after completion of the dosage schedule. The primary outcome was the proportion of seroprotection (defined by serum HBV surface antibodies ≥ 10 mIU/ml). Adverse reactions were evaluated regarding both fever and post-injection pain scale. Patients' age ranged from 18 to 71 years.After 1 and 3 months of completion of the vaccination schedule, there was no statistical difference in the proportion of seroprotected patients among both groups. Accelerated vaccination schedule using combined hepatitis A and B vaccine may be beneficial for HBV seroprotection among hemodialysis patients.


Failure of heterotopic osteogenesis by epithelial mesenchymal cell interactions in xenogeneic transplants in the kidney.
Transitional epithelium of the guinea pig and rabbit and an established WISH cell line, when grafted under the kidney capsule of cortisone treated mice, survived and proliferated, but never induced bone formation. On the contrary, when grafted intramuscularly into the same recipients, readily induced cartilage and/or bone.


Skull base tumours Part II. Central skull base tumours and intrinsic tumours of the bony skull base.
With the advances of cross-sectional imaging radiologists gained an increasing responsibility in the management of patients with skull base pathology. As this anatomic area is hidden to clinical exam, surgeons and radiation oncologists have to rely on imaging studies to plan the most adequate treatment. To fulfil these endeavour radiologists need to be knowledgeable about skull base anatomy, about the main treatment options available, their indications and contra-indications and needs to be aware of the wide gamut of pathologies seen in this anatomic region. This article will provide a radiologists' friendly approach to the central skull base and will review the most common central skull base tumours and tumours intrinsic to the bony skull base.


Surgical Considerations and Systemic Therapy of Melanoma.
Recent advances in effective medical therapies have markedly improved the prognosis for patients with advanced melanoma. This article aims to highlight the current era of integrated multidisciplinary care of patients with advanced melanoma by outlining current approved therapies, including immunotherapy, targeted therapy, radiation therapy, and other strategies used in both the adjuvant and the neoadjuvant setting as well as the evolving role of surgical intervention in the changing landscape of advanced melanoma.


Detection of 8-epi prostaglandin F2alpha in an extract of epidermal secretion of the catfish from the Arabian Gulf.
We provide herein mass spectrometric evidence for the existence of F2 isoprostanes in an epidermal secretion of the catfish from the Arabian Gulf. The compounds were extracted, purified by thin layer chromatography (TLC) and derivatized into the pentafluorobenzyl trimethylsilyl (PFB-TMSi) derivatives and quantified using SIM-negative ion gas chromatography-mass spectrometry based on the addition of tetradeuterated 8-epi PGF2alpha as internal standard prior to sample workup. Freshly collected secretions from the male catfish contained 5.63 and 4.17 ng/ml (two determinations) and from the female catfish 3.60 and 3.81 ng/ml (two determinations) of free 8-epi PGF2alpha. The level of these compounds increases approximately 8-fold upon storage of the extract at -20 degrees. In view of the potent reported actions of F2 isoprostanes on vasoconstriction and as thromboxane receptor antagonists, the presence of isoprostanes in the catfish secretions may contribute to the reported ulcer healing properties of these secretions.


Readability of characters on mobile phone liquid crystal displays.
Subject performance in reading characters on mobile phone liquid crystal displays was researched by using (a) English sentences with 3 or 4 different sizes of characters on 2 types of displays with different resolutions (n=23; age=31.6+/-6.0 years), (b) Japanese characters in 3 different sizes and 2 types of font (n=98; age=44.5+/-18.5 years), and (c) Japanese characters vertically enlarged 1-4 times (n=120; age=46.9+/-18.6 years). Subjective evaluation, reading speed, number of reading errors, and viewing distance were recorded. Readability was higher with higher resolution displays, and with Gothic than with Mincho font in Japanese. Young subjects shortened the viewing distance as characters became smaller, whereas elderly subjects increased the viewing distance irrespective of the size of characters. Characters of 3-5 mm are appropriate for the young but inadequate for the elderly. Readability of Japanese characters improved when they were vertically enlarged to approximately twice the width.


Age at menarche and prevalence of preterm birth: Results from the Healthy Baby Cohort study.
Little is known about the impact of age at menarche on preterm birth. The aim of this study was to examine the association between age at menarche and preterm birth. A total of 11,016 Chinese women who gave birth to live singleton infants were recruited from the Healthy Baby Cohort between 2012 and 2014 in the province of Hubei, China. Age at menarche was reported via face-to-face interviews and was categorized into five groups (≤11, 12, 13, 14 and ≥15 years). Gestational age was estimated using maternal last menstrual period. Preterm birth was defined as delivering a live singleton infant at <37 weeks' gestational age. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Earlier menarche (≤11 years) was associated with an increased prevalence of preterm birth (OR: 1.67, 95% CI: 1.18, 2.36) compared with menarche age at 13 years after controlling for the potential confounders. The findings of our study suggested that a history of earlier menarche might be useful for identifying women at higher risk of preterm birth.


Traumatic degloving lesion of male external genitalia.
Injury to the male external genitalia is relatively uncommon when compared with other parts of the human body. Trauma to external genitalia could result from accidents involving motor vehicles, power farm machinery, gun shot and stab injuries. We present a rare case of traumatic degloving injury of male external genitalia associated with partial penile amputation and loss of both testes sparing the internal abdominal and pelvic organs, resulting from run over by a heavy vehicle tyre.


Awake prone positioning for non-intubated patients with COVID-19-related acute hypoxic respiratory failure: a systematic review based on eight high-quality randomized controlled trials.
Awake prone positioning has been widely used in non-intubated patients with acute hypoxic respiratory failure (AHRF) due to COVID-19, but the evidence is mostly from observational studies and low-quality randomized controlled trials (RCTs), with conflicting results from published studies. A systematic review of published high-quality RCTs to resolve the controversy over the efficacy and safety of awake prone positioning in non-intubated patients with AHRF due to COVID-19. Candidate studies were identified through searches of PubMed, Web of Science, Cochrane, Embase, Scopus databases from December 1, 2019 to November 1, 2022. Literature screening, data extraction and risk of bias assessment were independently conducted by two researchers. Eight RCTs involving 2657 patients were included. Meta-analysis of fixed effects models showed that awake prone positioning did not increase mortality(OR = 0.88, 95%CI [0.72, 1.08]), length of stay in ICU (WMD = 1.14, 95%CI [-0.45, 2.72]), total length of stay (WMD = 0.11, 95%CI [-1.02, 1.23]), or incidence of adverse events (OR = 1.02, 95%CI [0.79, 1.31]) compared with usual care, but significantly reduced the intubation rate (OR = 0.72, 95%CI [0.60, 0.86]). Similar results were found in a subgroup analysis of patients who received only high flow nasal cannula (Mortality: OR = 0.86, 95%CI [0.70, 1.05]; Intubation rate: OR = 0.69, 95%CI [0.58, 0.83]). All eight RCTs had high quality of evidence, which ensured the reliability of the meta-analysis results. Awake prone positioning is safe and feasible in non-intubated patients with AHRF caused by COVID-19, and can significantly reduce the intubation rate. More studies are needed to explore standardized implementation strategies for the awake prone positioning. CRD42023394113.


[A subacute dementia: Inflammatory cerebral amyloid angiopathy].
We report a case of inflammatory cerebral amyloid angiopathy (CAA) that led to rapid cognitive decline, seizures, visual hallucinations, hyperproteinorrachia and right hemispheric leukopathy. Brain biopsy gave the diagnosis of CAA. Although no inflammatory infiltrate was found in the biopsy sample, corticosteroids led to a regression of the radiological lesions without significant clinical improvement. CAA is a rare disease, defined by lesions of classical cerebral amyloid angiopathy and perivascular infiltrates in contact with the affected vessels. In cases of rapidly progressive dementia associated with leukopathy, inflammatory amyloid angiopathy should be considered as cognitive disorders may improve after immunosuppressive therapy.


Laparoscopic resection of gastric schwannoma: A case report.
Gastric schwannomas are an extremely rare presentation of mesenchymal tumors originating from Schwann cells, accounting for 0.2% of all gastric tumors. Patients are usually asymptomatic, so these tumors are frequently detected incidentally. 68-year old male patient found to have a 5 cm mass in the lesser curvature of the stomach. After a careful preoperative evaluation, complete laparoscopic resection was performed. Pathology review confirmed a completely resected gastric Schwannoma. The patient's recovery was uneventful. At a one-year follow-up he remains asymptomatic and with no evidence of disease. We present the uncommon case of a gastric schwannoma that was appropriately treated with a laparoscopic approach and present a current literature review focusing on diagnostic and treatment methods of these rare tumors. Schwannomas should be included in the differential diagnosis of gastric tumors and can be appropriately treated with a laparoscopic approach.


Increased frequency of interleukin-1beta (-511) allele 2 in febrile seizures.
Febrile seizures can be the first sign of epilepsy. In a recent study, patients with temporal lobe epilepsy were reported to carry the interleukin-1beta allele 2 at position -511 more often than healthy control subjects. Because pro-inflammatory cytokines, such as interleukin-1, are well-known inducers of fever and therefore could play an important part in the pathogenesis of febrile seizures, we have, in this study, analyzed the cytokine gene polymorphism of interleukin-1beta at position -511 in children with febrile seizures and control subjects. We found a statistically significant increase in the frequency and the carriage of interleukin-1beta (-511) allele 2 in children with febrile seizures (n = 35) compared with healthy blood donors (n = 400) (P = 0.03 and P = 0.05, respectively). In previous studies, this allele has been connected to increased in vitro production of interleukin-1. Children with febrile seizures may therefore have an increased pro-inflammatory reaction during fever. This pro-inflammatory reaction may also predispose some children to the development of epilepsy.


Peritonitis caused by Mycobacterium abscesses in patients on continuous ambulatory peritoneal dialysis.
Nontuberculous mycobacteria are an uncommon cause of peritonitis in patients undergoing continuous ambulatory peritoneal dialysis. We report two cases of peritonitis caused by Mycobacterium abscesses from a single center, which were successfully treated. In endemic areas of tuberculosis, Zeil Neilsen staining should be part of the initial evaluation to allow early detection. Treatment requires removal of Tenckhoff catheter and second-line antibiotics until cultures become negative.


Influence of osmotic pressure changes on the opening of existing cracks in 2 intervertebral disc models.
An experimental hydrogel model and a numerical mixture model were used to investigate why the disc herniates while osmotic pressure is decreasing. To investigate the influence of decreasing osmotic pressure on the opening of cracks in the disc. In the degeneration process, the disc changes structure (i.e., cracks occur, and osmotic pressure decreases). Disc herniation typically develops when hydration declines, but, on the other hand, it is said that the anulus of a highly hydrated disc has a high risk of rupture. We hypothesized that disc herniation is preceded by the opening of cracks as a result of decreasing osmotic pressure. The osmotic pressure was changed in hydrogel samples with a crack, which was visualized with a confocal laser scanning microscope (Zeiss, Göttingen, Germany). A 2-dimensional finite element mixture model simulated a decrease in osmotic pressure around a crack in a swelling material. Experiments and simulations show that a decrease in osmotic pressure results in the opening of cracks. The simulations show high effective stress concentrations around the crack tip, while the overall stress level decreases, indicating an increased risk of crack growth. Decreasing osmotic pressure in a degenerating intervertebral disc enhances the opening of existing cracks, despite the concomitant decrease in anular stresses.


Postmenopausal sex hormones in relation to body fat distribution.
Being overweight or obese increases the risk of postmenopausal breast cancer. A potential reason may be the frequently observed positive association of BMI with endogenous sex hormones and its negative association with sex hormone-binding globulin (SHBG). The purpose of this study was to investigate whether a woman's body fat distribution shows a BMI-independent association with these breast cancer-related biomarkers. Performing cross-sectional analyses among 1,180 postmenopausal women, we assessed whether associations of surrogates for an abdominal (waist circumference; waist-to-hip ratio, WHR) and gluteofemoral (hip circumference) fat distribution with estrone, total and free estradiol, androstenedione, total and free testosterone, and SHBG changed after adjustment for, or stratification by, BMI. All anthropometric measures were positively associated with estrogens and free testosterone, and negatively with SHBG. After adjustment for BMI, associations of free estradiol, free testosterone, and SHBG with both waist circumference and WHR remained significant, but all initially significant associations with hip circumference were abolished. In stratified analyses, waist circumference and WHR correlated with free estradiol, free testosterone, and SHBG in women with a BMI < 30 kg/m(2) but not in women with a BMI ≥ 30 kg/m(2). The latter suggests that in obese women, a possibly unique effect of abdominal fat on these biomarkers may be masked by the already large amount of overall body fat. On the whole, our results indicate that waist circumference and WHR, but not hip circumference, are associated with SHBG and SHBG-related sex hormones (free estradiol and free testosterone) independently of BMI.


Performance of Acoustic Radiation Force Impulse Elastography for Staging Liver Fibrosis in Patients With Chronic Hepatitis C After Viral Eradication.
Data on noninvasive liver fibrosis staging after viral eradication are unclear. This histology-based study validated the performance of liver stiffness (LS) measurements after viral eradication. Consecutive participants with chronic hepatitis C (CHC) who received concomitant LS measurements through acoustic radiation force impulse (ARFI) elastography and percutaneous liver biopsy were prospectively screened and analyzed. Of the 644 patients, 521 (80.9%) underwent a biopsy at treatment baseline, and the remaining 123 (19.1%) underwent a biopsy at 3 years (median; interquartile range, 0.1) after the sustained virological response (SVR) to pegylated interferon-based and direct-acting antiviral treatments. The proportions of histological fibrosis stages did not differ significantly between the pretreatment and post-SVR groups (P = .0615). However, the LS values differed significantly (P < .0001). The median LS values (presented as shear wave velocities in meters per second) were 1.51 (0.92) for the pretreatment group and 1.22 (0.77) for the post-SVR group. The cutoffs (areas under the receiver operating characteristic curve, obtained using the bootstrap method) to dichotomize between METAVIR fibrosis stage F1 versus stages F2-F4, F1-F2 versus F3-F4, and F1-F3 versus F4 were 1.47 (0.8333, 95% confidence interval [CI] 0.7981-0.8663), 1.81 (0.8763, 95% CI 0.8376-0.9107), and 1.86 (0.8811, 95% CI 0.8378-0.9179) in the pretreatment group, respectively, and 1.22 (0.7872, 95% CI 0.7001-0.8624), 1.59 (0.8808, 95% CI 0.8034-0.9422), and 1.75 (0.9018, 95% CI 0.8201-0.9644) in the post-SVR group, respectively. The performance of LS measurements through ARFI elastography is promising to determine the liver fibrosis stage on necroinflammation-resolved histology in CHC after viral eradication.


Onchocerciasis and women's reproductive health: indigenous and biomedical concepts.
Women in a rural farming community in Etteh, Nigeria, have traditional beliefs about onchocerciasis which differ from the concepts of modern science. Recognizing these beliefs may allow health workers to gain the confidence and participation of the people and increase the effectiveness of control programmes.


LH levels in women with polycystic ovarian syndrome: have modern assays made them irrelevant?
To determine whether using newer monoclonal rather than polyclonal assays for measuring luteinising hormone (LH) alters the predictive value of LH and LH/follicle-stimulating hormone (FSH) ratios for polycystic ovarian syndrome. Prospective cohort study. Fertility and Reproductive Endocrinology Clinic within a New Zealand Teaching hospital. Seventy-eight women presenting with oligomenorrhoea or hirsutism and polycystic ovaries on pelvic ultrasound and 59 volunteer controls with ultrasonically normal ovaries and a regular menstrual cycle. Serum LH concentrations were measured using a polyclonal radio-immunoassay (Amerlex-M, Johnson & Johnson) and two monoclonal immunometric assays (Immulite, DPC; Cobas Core, Hoffman La Roche). The proportion of women with an elevated serum LH concentration in each group was calculated using both current local laboratory reference intervals and a new reference range derived from our control group. The LH/FSH ratios for women in both groups were also calculated using the three different LH assays. LH concentrations and LH:FSH ratios measured using polyclonal and monoclonal immunoassays. Using the local laboratory normal range, a significantly higher proportion of women had an elevated LH when measured with a polyclonal assay (23.1%) than when measured with a monoclonal assay (12.8% Core, 6.4% Immulite) (P < 0.05). LH/FSH ratios were significantly lower when monoclonal assay was used and receiver-operator characteristic curves suggest that LH/FSH ratios of 1 or lower provide the most reliable separation of women with polycystic ovarian syndrome from controls when these assays are used. Clinicians should be aware that the use of monoclonal LH assays will result in significantly lower measured LH levels and LH/FSH ratios in women with polycystic ovarian syndrome than previously used polyclonal assays. Account should be taken of the assay type used, when using endocrinological parameters in the diagnosis of polycystic ovarian syndrome, or the identification of women who have LH hypersecretion.


Variation in coronary angiography use in Out-of-Hospital cardiac arrest.
Multiple studies have examined the association of early coronary angiography (CAG) among out-of-hospital cardiac arrest (OHCA) patients with conflicting results. However, patterns of use of CAG among OHCA patients in real-world settings are not well-described. Utilizing data from the Resuscitation Outcomes Consortium's Continuous Chest Compressions trial for our analysis, we stratified patients based on initial arrest rhythm and ST-elevation on initial post-resuscitation electrocardiogram (ECG) and examined the rates of CAG in resuscitated patients. We also examined the rates of CAG across different trial clusters in the overall study population as well as in pre-specified patient subgroups RESULTS: Of 26,148 patients in the CCC trial, 5,608 survived to hospital admission and were enrolled in the study. Among them, 26 % underwent CAG. Patients with ST-elevation underwent CAG at a significantly higher rate than patients presenting without ST-elevation (70 % vs 31 %, p < 0.001). Similarly, patients presenting with shockable rhythms underwent CAG more frequently compared with patients with non-shockable rhythms (28 % vs 5 %, p < 0.001). There was marked variation in CAG frequency across different trial clusters with the proportion of patients within a trial cluster receiving CAG ranging from 4 % - 41 %. The proportion varied more among patients with ST-elevation (16 % - 82 %) or initial shockable rhythm (11 % - 75 %) compared with no ST-elevation (2 % - 28 %) or initial non-shockable rhythm (0 % - 19 %). Among a national cohort of OHCA patients, large variation in the use of CAG exists, highlighting the existing uncertainty regarding perceived benefit from early CAG in OHCA.


Role of surface N-acetylglucosamine residues on host cell infection by Trypanosoma cruzi.
We studied the role of surface GlcNAc residues on the surface of invasive (mouse-blood and insect-derived trypomastigotes) and non-invasive amastigote forms of Trypanosoma cruzi on parasite association with (i.e., surface binding plus internalization) macrophages and heart myoblasts. Removal of GlcNAc from the three forms of the parasite with beta-N-acetylglucosaminidase markedly increased the number of organisms per 100 cells and caused the organisms to associate with a greater percentage of host cells. N-Acetylglucosaminidase did not produce this effect after heat-inactivation and a substrate of the enzyme, N,N'-diacetylchitobiose, reduced it when it was present during the enzymatic treatment. The N-acetylglucosaminidase effect on T. cruzi was reversible after 2.5 h. When macrophages or myoblasts were treated with N-acetylglucosaminidase, their capacities to associate with blood or insect-derived trypomastigotes was reduced. Since removal of GlcNAc residues from the parasite surface increased their association with the host cells, GlcNAc would appear to interfere with the association process. On the other hand, GlcNAc residues on the host cell appear to favor the association.


Medaka (Oryzias latipes) as a sentinel species for aquatic animals: Medaka cells exhibit a similar genotoxic response as North Atlantic right whale cells.
Hexavalent chromium (Cr(VI)) is emerging as a major concern for aquatic environments, particularly marine environments. Medaka (Oryzias latipes) has been used as a model species for human and aquatic health, including the marine environment, though few studies have directly compared toxicological responses in medaka to humans or other aquatic species. We used a medaka fin cell line to compare the genotoxic response of medaka to Cr(VI) to the response observed in North Atlantic right whale cells to see if responses in medaka were similar to those of other aquatic species, particularly aquatic mammals. We used the production of chromosomal aberrations as a measure of genotoxicity. We found that in medaka cells, concentrations of 1, 5 and 10 microM sodium chromate damaged 17, 32 and 43% of metaphases, respectively and these same concentrations 1, 2.5, 5 and 10 microM sodium chromate damaged 14, 24 and 49% of metaphases, respectively, in North Atlantic right whale lung cells and 11, 32 and 41% of metaphases, respectively, in North Atlantic right whale testes cells. These data show that genotoxic responses in medaka are comparable to those seen in North Atlantic right whale cells, consistent with the hypothesis that medaka are a useful model for other aquatic species.


The effects of progress monitoring on subsequent readmission to psychiatric care: a six-month follow-up.
Monitoring patient progress and providing feedback to clinicians and patients about progress during therapy reduce depressive symptoms at treatment completion. However, the effects of feedback on patient outcomes following treatment completion are unknown. Accordingly, the current study aimed to examine the effect of feedback on readmission to psychiatric hospital following completion of a group psychotherapy program. This naturalistic historical follow-up study compared the risk of readmission to a psychiatric hospital for two patient cohorts examined by Newnham et al. (2010a,b); the first cohort received feedback (n=408) during a group psychotherapy program, whereas the second cohort did not receive feedback (n=439). The sample included inpatients and day patients, with primarily depressive and anxiety disorders who routinely completed the World Health Organization's Wellbeing Index. Feedback was associated with fewer readmissions over the six months following completion of the therapy program for patients who, at the point of feedback, were on track to make clinically meaningful improvement by treatment termination. The findings suggest feedback could result in cost saving and is associated with improved outcomes following treatment completion for patients deemed on track during therapy.


Complementary strand microRNAs mediate acquisition of metastatic potential in colonic adenocarcinoma.
Altered expression of specific microRNAs (miRNA) is known to occur during colorectal carcinogenesis. However, little is known about the genome-wide alterations in miRNA expression during the neoplastic progression of primary colorectal cancers. Using a miRNA array platform, we evaluated the expression of 668 miRNA in primary colonic adenocarcinomas. Biological functions of selected miRNA were evaluated with in vitro invasion assays. RNA was extracted for miRNA analysis from 65 primary colon cancers. We identified a seven-miRNA expression signature that differentiated stage I and stage IV primary colon cancers. We then demonstrated this signature was able to discriminate between stage II and III primary colon cancers. Six differentially expressed miRNA were downregulated in association with the development of metastases, and all 7 miRNA were complementary strand miRNA. We transfected HCT-116, a highly invasive colon cancer cell line, with corresponding downregulated miRNA and demonstrated that overexpression of three miRNA (miR200c*, miR143*, and miR424*) significantly abrogated invasive potential. We have identified a seven-miRNA signature that is associated with metastatic potential in the primary tumor. Forced overexpression of three downregulated miRNA resulted in attenuation of in vitro invasion, suggesting direct tumor suppressive function and further supporting the biological importance of complementary strand miRNA.


The sonographic appearances of breast implant rupture.
Implant rupture is a common late complication of breast implant procedures. Ruptures are often silent and difficult to diagnose clinically. This review demonstrates normal appearances and sonographic signs of implant rupture. Breast sonologists should be aware of these signs and pitfalls in interpretation when imaging breast implants.


Prevention and treatment of CMV infection after allogeneic bone marrow transplant.
CMV infection is the major infectious complication following bone marrow transplantation. It is most often related to reactivation of latent infection in patients who were CMV seropositive before BMT. The incidence and severity have recently been modified by the use of preventive and curative treatments. Prevention of CMV infection with the transfusion of seronegative blood products is useful only when donor and recipient are seronegative. High-dose acyclovir has been shown effective in one randomized study. A multicenter study is currently being performed in Europe to confirm this result. Intravenous gammaglobulins seemed to lower the number of patients who incur interstitial pneumonitis but not the incidence of viremia. They also decreased the incidence of gram-negative sepsis and severe GVH and improved survival. The treatment is based on the use of gancyclovir. Several studies show that gancyclovir is more effective in asymptomatic patients with viral isolation from blood or bronchoalveolar lavage. The addition to gancyclovir of high-dose gammaglobulin improves survival in symptomatic patients with interstitial pneumonitis. This progress in the prevention and treatment of CMV infection has improved the overall results of allogeneic bone marrow transplantation.


Quantification of betel quid hygroscopicity in context to saliva: A proof of concept for future studies.
The physical and chemical properties of various constitutional ingredients of betel quid (BQ) are well known in the literature. However, BQ as a whole has been rarely investigated for identifying its physical properties that can impact and modulate the disease progression of various pathologies, mainly oral submucous fibrosis (OSMF). It is quite conceivable that in the oral cavity environment, the amalgamated BQ might absorb saliva by virtue of its hygroscopic properties. As a proof of concept, we developed a methodology to quantify the hygroscopicity of the 'whole BQ' when it is mixed with saliva. To the best of our knowledge, this is the first study to report and quantify the hygroscopicity of BQ when mixed with saliva, and this forms a proof of concept for future implications in the pathogenesis of various pathologies.


Diabetes-related dysfunction of the small intestine and the colon: focus on motility.
In contrast to gastric dysfunction, diabetes-related functional impairments of the small and large intestine have been studied less intensively. The gastrointestinal tract accomplishes several functions, such as mixing and propulsion of luminal content, absorption and secretion of ions, water, and nutrients, defense against pathogens, and elimination of waste products. Diverse functions of the gut are regulated by complex interactions among its functional elements, including gut microbiota. The network-forming tissues, the enteric nervous system) and the interstitial cells of Cajal, are definitely impaired in diabetic patients, and their loss of function is closely related to the symptoms in diabetes, but changes of other elements could also play a role in the development of diabetes mellitus-related motility disorders. The development of our understanding over the recent years of the diabetes-induced dysfunctions in the small and large intestine are reviewed in this article.


Embryo donation: motivations, experiences, parenting, and child adjustment.
Embryo donation raises unique challenges for donors, recipients, and the resultant child, yet little is known about the outcomes for those involved. This review summarizes research on the motivations for donating and receiving embryos from others and the experiences that follow, including the outcomes for parenting and child adjustment. Research has shown that given the varied ways in which embryo donation is practiced, understanding the outcomes within different legislative and cultural contexts is vital. The lack of information on outcomes means that counselors and psychologists have little empirical evidence to guide them. Gaps in existing knowledge are identified as well as areas for future research.


Targeting bromodomain-containing proteins: research advances of drug discovery.
Bromodomain (BD) is an evolutionarily conserved protein module found in 46 different BD-containing proteins (BCPs). BD acts as a specific reader for acetylated lysine residues (KAc) and serves an essential role in transcriptional regulation, chromatin remodeling, DNA damage repair, and cell proliferation. On the other hand, BCPs have been shown to be involved in the pathogenesis of a variety of diseases, including cancers, inflammation, cardiovascular diseases, and viral infections. Over the past decade, researchers have brought new therapeutic strategies to relevant diseases by inhibiting the activity or downregulating the expression of BCPs to interfere with the transcription of pathogenic genes. An increasing number of potent inhibitors and degraders of BCPs have been developed, some of which are already in clinical trials. In this paper, we provide a comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on the development history, molecular structure, biological activity, interaction with BCPs and therapeutic potentials of these drugs. In addition, we discuss current challenges, issues to be addressed and future research directions for the development of BCPs inhibitors. Lessons learned from the successful or unsuccessful development experiences of these inhibitors or degraders will facilitate the further development of efficient, selective and less toxic inhibitors of BCPs and eventually achieve drug application in the clinic.


Rat thymocytes release a factor which inhibits muscarinic ligand binding.
Rat thymocytes incubated in RPMI medium for 120-300 min release a soluble factor of molecular weight below 10,000 Da which inhibits the binding of 3H-labeled muscarinic antagonists in an uncompetitive manner, i.e. it reduces maximal specific binding (Bmax) without changing the affinity of the ligand (KD). This factor inhibited muscarinic antagonist binding on thymocytes and rat cerebral cortex cellular membranes. Thymocytes from hydrocortisone-treated rats produced more factor per mg cell protein than thymocytes from untreated rats. The activity of the factor was unaffected by incubation with Cd2+ (1 mM) or Zn2+ (1 mM) or EDTA (1 mM), and its protein nature is supported by the following findings: it was trypsin sensitive, heat denaturated at 56 degrees C and precipitated by (NH4)2SO4 (40%, w/v). Inhibition by the factor was apparently irreversible after 1 h of incubation.


[Open versus arthroscopic shoulder stabilization. An analysis of the treatment costs].
In this study the total costs of clinical open and arthroscopic anterior shoulder stabilization were evaluated, analyzed and compared. From 1988 to 1998 147 patients underwent open (Bankart) or arthroscopic (ASK) anterior shoulder stabilization. We randomized two groups of 30 patients for each method (Bankart: 25 male, 5 female, 29 years of age; ASK: 25 male, 5 female, 26 years of age) and evaluated the costs of their clinical treatment. The total cost was significantly ( p<0.05, Mann-Whitney U-Test) higher for the open (5639 euro) than for the arthroscopic (4601 euro) therapy. There was a significant difference between the groups for the average cost of surgery (Bankart: 2741 euro; ASK: 2315 euro, p<0.05) and the average postoperative treatment cost (Bankart: 2202 euro; ASK: 1630 euro, p<0.05) whereas the average preoperative treatment cost was not significantly different (Bankart: 669 euro, ASK: 657 euro). The staff costs for the surgical procedure (Bankart: 1800 euro (32%), ASK: 1319 euro (29%)) and the postoperative staff costs of the nurses (Bankart: 1271 euro (23%), ASK: 997 euro (22%)) represented the greatest parts of the total costs. The average duration of the clinical treatment was 15.8 days for the open- and 12,4 days for the arthroscopic group.


Design of PEG-aptamer two piece macromolecules as convenient and integrated sensing platform: application to the label free detection of small size molecules.
A novel strategy for the fabrication of electrochemical label free aptasensor for small size molecules is purposed, and the strategy has been demonstrated by the development of an aptasensor for ochratoxin (A). A long spacer chain of polyethylene glycol (PEG) was immobilized on screen printed carbon electrode (SPCE) via electrochemical oxidation of its terminal amino-group. The amino-aptamer was covalently linked to carboxy end of immobilized PEG to form two piece macromolecules. The designed immobilized macromolecules resulted in the formation of long tunnels on SPCE surface, while aptamer acted as gate of the tunnels. The aptamer gates were closed due to change in conformation of aptamer upon target analyte binding, decreasing the electrochemical signal. The decrease in electrochemical signal was used for the detection of target molecule.


Nobel Lecture. The identification of the sodium pump.
The identification of the sodium potassium pump as a Na+, K+ -ATPase is described.


Potential disruption of thyroid hormones by perfluoroalkyl acids in an Arctic seabird during reproduction.
Arctic marine ecosystems are experiencing rapid change, such as ocean warming and enhanced pollutants. Perfluoroalkyl acids (PFAAs) arriving via long-range transport have been detected in Arctic wildlife, including seabirds which are considered sentinels of marine ecosystem health. There is evidence that PFAA exposure leads to the disruption of thyroid hormones (THs), such as thyroxine (T4) and triiodothyronine (T3), which play important roles in metabolism, incubation, and thermoregulation in seabirds. Here, we investigated relationships between PFAAs and THs [total T4 (TT4), free T4 (FT4), total T3 (TT3) and free T3 (FT3)] in blood plasma collected from 63 thick-billed murres (Uria lomvia) at a colony located in northern Hudson Bay (2016-2018). We then tested if PFAAs and TH levels were related to fitness-associated reproductive traits, such as body mass and hatch dates. PFUdA, PFOS, and PFTrDA were the dominant PFAAs in murre blood, accounting for approximately 77% of ∑PFAA. Females had higher PFAAs than males, possibly due to higher trophic feeding. While FT3 increased with PFOS, PFNA, PFDA, PFDoA, PFTeDA, ∑PFCA7, and ∑PFAA in murres, TT3 decreased with PFOS, PFDoA, and PFTeDA in males, but not females, suggesting thyroid disruption. TT3 increased with body mass, whereas several long-chain PFAAs were negatively correlated with body mass. Negative relationships between PFNA, PFDoA, PFTrDA, PFTeDA, and ∑PFAA with hatch dates may be the result of a disruption in incubation behaviour, resulting in earlier hatch dates. Consequently, TT3 concentrations were highest in males and females in 2018, a year in which PFAAs were lowest and hatch dates were delayed relative to 2017. As an Arctic seabird experiencing several indirect effects of climate change, the interaction of PFAAs on thyroid activity may cause additional stress to murres.


Experimental and theoretical investigation of ground state intramolecular proton transfer (GSIPT) in salicylideneaniline Schiff base derivatives in polar protic medium.
Ground state intramolecular proton transfer process has been comprehensively investigated in three salicylideneaniline Schiff base derivatives (SB1, SB2, and SB3) using experimental and theoretical methods. It has been confirmed that all the three Schiff base molecules in the ground electronic state exist in the enol form in non-polar and polar aprotic solvents. Keto form is being populated by the polar protic solvent through ground state intramolecular proton transfer (GSIPT) process. Ground state equilibrium between the enol and keto tautomers for SB1 and SB3 is mainly governed by the proton donating ability of the solvent. Ground state equilibria between the enol and keto tautomers of SB2 which is a positional isomer of SB3 is governed by the polarity and proton donating ability of the solvents. Excited state intramolecular proton transfer (ESIPT) process is also evidenced in all the three Schiff base molecules. Theoretical calculations at the B3LYP/cc-pVDZ level in the gas phase and in different solvents using polarisable continuum model (PCM) have failed to establish the GSIPT process. Microsolvation of individual enol and keto conformers has been investigated considering upto three solvent molecules. The energetics of the individual conformers together with the corresponding transition state have been calculated. It has been confirmed that the keto conformer is more stable compared to the enol conformer in microsolvated cluster of three methanol molecules. Lowering of activation energy for the enol to keto tautomerisation in the presence of methanol also supports the experimental observation for GSIPT process. TDDFT/B3LYP/cc-pVDZ single point calculations for microsolvated clusters of enol and keto form of the Schiff base molecules exhibit an excellent agreement with the experimentally obtained absorption spectra. Difference in spectral nature of the Schiff base molecules has been explained using natural bond orbital (NBO) analysis. Quantum theory of atoms in molecules (QTAIM) has also been utilised to understand the GSIPT process in detail.