Perceived psychosexual dimensions of cervical cancer survivors in India-An exploratory study.
Cervical cancer is the second most common cancer among women in India. Medical advancements have led to increased survival. However, sexuality and sexual concerns remain as major worries of patients after treatment. This study aims to understand the psychosexual experiences of cervical cancer survivors. Cervical cancer survivors (n = 30) aged 35-55 years were interviewed using a semi-structured interview schedule, after obtaining consent. The audio-recorded in-depth interviews were transcribed and analysed using thematic analysis. Three major themes in each group namely sexually active and sexually inactive evolved on analysis. Three themes were derived under sexually active group namely (i) Enablers of active sexual functioning (ii) Impediments of active sexual functioning (iii) Sexual health communication. The three themes under sexually inactive include (i) Attributes of sexual abstinence (ii) Impact of sexual abstinence (iii) Barriers of sexual health communication. Both sexually active and inactive survivors in India experience various psychosexual concerns post cancer treatment indicating a strong need for psychosocial care and focused clinical interventions.


Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone.
21-Hydroxylase deficiency presents with increased levels of cytochrome P450 21-hydroxylase substrates, progesterone and 17α-hydroxyprogesterone, which have been implicated in the production of androgens via the backdoor pathway. This study shows the biosynthesis of C11-oxy C21 steroids, 21-deoxycortisol and 21-deoxycortisone, and their metabolism by steroidogenic enzymes in the backdoor pathway yielding novel steroid metabolites: 5α-pregnan-11β,17α-diol-3,20-dione; 5α-pregnan-17α-ol-3,11,20-trione; 5α-pregnan-3α,11β,17α-triol-20-one and 5α-pregnan-3α,17α-diol-11,20-dione. The metabolism of 21-deoxycortisol was validated in LNCaP cells expressing the relevant steroidogenic enzymes showing for the first time that the steroid, produced at high levels in 21OHD, is metabolised via the C11-oxy derivatives of 5α-pregnan-17α-ol-3,20-dione and 5α-pregnan-3α,17α-diol-20-one to substrates for the lyase activity of CYP17A1, leading to the production of C11-oxy C19 steroids. 21-Deoxycortisol thus contributes to the pool of potent androgens in 21OHD, with novel steroid metabolites also presenting possible biomarkers in disease identification.


[Morphofunctional characteristics of the liver in arterial hepatography with maiodil].
During histological, quantitative histoenzymological studies of the preparations of the liver, lungs, spleen and gallbladder carried out in experiments on cats after maiodil arteriography of the liver no significant morphofunctional changes in these organs were revealed.


Energetics of outer membrane phospholipase A (OMPLA) dimerization.
Outer membrane phospholipase A (OMPLA) is a widely conserved transmembrane enzyme found in Gram-negative bacteria, and it is implicated in the virulence of a number of pathogenic organisms. The regulation of the protein's phospholipase activity is not well understood despite the existence of a number of high resolution structures. Previous biochemical studies have demonstrated that dimerization of OMPLA is a prerequisite for its phospholipase activity, and it has been shown in vitro that this dimerization is dependent on calcium and substrate binding. Therefore, to fully understand the regulation of OMPLA, it is necessary to understand the stability of the protein dimer and the extent to which it is influenced by its effector molecules. We have used sedimentation equilibrium analytical ultracentrifugation to dissect the energetics of Escherichia coli OMPLA dimerization in detergent micelles. We find that calcium contributes relatively little stability to the dimer, while interactions with the substrate acyl chain are the predominant force in stabilizing the dimeric conformation of the enzyme. The resulting thermodynamic cycle suggests that interactions between effector molecules are additive. These energetic measurements not only provide insight into the activation of OMPLA, but they also represent the first quantitative investigation of the association energetics of a transmembrane beta-barrel. This thermodynamic study allows us to begin to address the differences between protein-protein interfaces in transmembrane proteins with a helical fold to those of a beta-barrel fold and to more fully understand the forces involved in membrane protein interactions.


Successful intracytoplasmic sperm injection with testicular spermatozoa from a man with multiple morphological abnormalities of the sperm flagella: a case report.
The purpose of this study is to analyze the sperm morphology of a Chinese man affected with multiple morphological abnormalities of the sperm flagella (MMAF) and observe the intracytoplasmic sperm injection (ICSI) outcome. A Chinese man was diagnosed with multiple morphological abnormalities of the sperm flagella by semen analysis and electron microscopy. Testicular spermatozoa were injected intracytoplasmically, and the following ICSI results were observed. All the spermatozoa from his ejaculate were immotile and morphologically abnormal in the flagellum. In transmission electron microscopy assays, most spermatozoa showed disorganized fibrous sheath, accompanied by distortion of various cytoskeletal components, and missing of the central pair microtubules. Testicular sperm was injected to the oocytes in two ICSI cycles, with fertilization rates of 45.5 and 40.0%. Finally, a healthy female infant was delivered at the second ICSI cycle. Fertilization and pregnancy could be achieved by intracytoplasmic sperm injection, regardless of severe flagellar defects. ICSI is effective for MMAF-affected man, and testicular sperm is an alternative when no motile sperm is available.


DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance.
DNA is well-documented to stimulate immune response. However, the nature of the DNA to activate immune surveillance is less understood. Here, we show that the activation of cyclic GMP-AMP synthase (cGAS) depends on DNA mechanical flexibility, which is controlled by DNA-sequence, -damage and -length. Consistently, DNA-sequence was shown to control cGAS activation. Structural analyses revealed that a conserved cGAS residue (mouse R222 or human R236) contributed to the DNA-flexibility detection. And the residue substitution neutralised the flexibility-controlled DNA-potential to activate cGAS, and relaxed the DNA-length specificity of cGAS. Moreover, low dose radiation was shown to mount cGAS-mediated acute immune surveillance (AIS) via repairable (reusable) DNAs in hrs. Loss of cGAS-mediated AIS decreased the regression of local and abscopal tumours in the context of focal radiation and immune checkpoint blockade. Our results build a direct link between immunosurveillance and DNA mechanical feature.


Generation of Induced Pluripotent Stem Cells (iPSCs) from Adult Canine Fibroblasts.
Induced pluripotent stem cells hold great potential in regenerative medicine as it enables to generate pluripotent stem cells from any available cell types. Ectopic expression of four transcription factors (Oct4, Sox2, Klf4, and c-Myc) can reprogram fibroblasts directly to pluripotency as shown in multiple species. Here, we describe detailed protocols for generation of iPSCs from adult canine fibroblasts. Robust canine iPSCs will provide powerful tools not only to study human diseases, but also for the development of therapeutic approaches.


Release of neuropeptide Y and noradrenaline during afferent nerve stimulation.
The present study was carried out to investigate the possibility that noradrenaline (NA) and neuropeptide Y (NPY) are co-released after afferent vagal or saphenous stimulation (1, 5, 10 and 20 Hz) in chloralose-anaesthetized dogs. Electrical stimulation of the vagus elicited an increase in plasma NA levels for the 5, 10 and 20 (but not 1) Hz frequencies. Blood pressure only increased after a 20-Hz stimulation. In contrast, no change in plasma NPY levels was observed whatever the frequency of stimulation. Electrical stimulation of the saphenous nerve failed to change plasma NA and NPY levels. The present data suggest that (1) the release of NA varies according to the frequency of stimulation of nociceptive fibres, (2) NPY release does not seem to be involved in the pressor effect elicited by the stimulation of nociceptive-sensitive fibres, and (3) NPY and NA release are not necessarily linked.


Approach to improving sonographic visualization of elongated left lobe of the liver and its implications.
To determine whether visualization of the elongated left lobe of the liver can be improved by distending the stomach with water and the implications of this technique. Forty-three out of 87 patients with elongated left lobe of the liver found at abdominal CT were included in this study after obtaining informed consent. Their livers were examined using ultrasound before and after drinking water. The left lobe of the liver was scanned from the subxiphoid and left subcostal approaches, with the sound beam directed to the spleen and the left lobe of the liver neighboring or behind the stomach; the elongated left lobe of the liver overlying the spleen was detected by scanning from the 9th-11th intercostal approach of the left flank. The overall visualization of the elongated left lobe of the liver before and after filling the stomach with water was 4.7 % (2/43) and 100.0 % (43/43), respectively (P < 0.001); and the overall visualization of the spleen before and after filling the stomach with water was 4.7 % (2/43) and 100.0 % (43/43), respectively (P < 0.001). Distending the stomach with sufficient water can substantially improve visualization of elongated left lobe of the liver at ultrasound, potentially improving detection of tumors in the liver and preventing misdiagnosis.


Gold price and exchange rate in pre and during Covid-19 period in India: Modelling dependence using copulas.
This study examines the dynamic relationship between the gold price and the exchange rate in pre- and during Covid-19 pandemic in India. We consider the periods of about equal length for both the pre- and during Covid-19 by considering the data from January 1, 2019 till February 28, 2021. The descriptive analysis shows a significant increase in the dynamics of gold price and exchange rate after mid-March 2020. The results derived from the ARDL approach show a positive and significant relationship between the gold price and exchange rate both in the long and short run. We have selected the best fitted bivariate copula to study the joint distribution of the gold price and the exchange rate. Using the copula model, we examine the relationship between the gold price and exchange rate in a bivariate framework. We have studied the dependence between them including the tail dependencies using the fitted copula. Our findings reveal that the gold price and exchange rate are significantly correlated for the entire study period, and it also reveals that there is no tail dependence. However, the mutual association between the variables is not confirmed in the considered Covid-19 period.


Longitudinal 5-Year Evaluation of Bone Density and Microarchitecture After Roux-en-Y Gastric Bypass Surgery.
Bone health declines in the initial years after Roux-en-Y gastric bypass (RYGB), but long-term skeletal effects are unclear. To document longitudinal changes in bone mineral density (BMD) and microarchitecture 5 years after RYGB. Prospective 5-year observational study of 21 adults with severe obesity receiving RYGB at an academic medical center. Spine and hip areal BMD were measured by dual-energy X-ray absorptiometry, and trabecular volumetric BMD (vBMD) of the spine was assessed by quantitative CT (QCT). We measured vBMD and microarchitecture of the distal radius and tibia by high-resolution peripheral QCT in a subset of subjects. Serum type I collagen C-terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (P1NP) were also measured. Areal BMD declined by -7.8% ± 7.6% at the spine and -15.3% ± 6.3% at the total hip by 5 years after RYGB (P ≤ 0.001), although the rate of bone loss slowed in later years. Trabecular spine vBMD decreased by -12.1% ± 12.3% by 5 years (P ≤ 0.001). At peripheral sites, vBMD continued to decrease steadily throughout 5 years, with parallel declines in cortical and trabecular microarchitecture, leading to decreases in estimated failure load of -20% and -13% at the radius and tibia, respectively (P < 0.001). Five years after RYGB, CTX and P1NP were 150% and 34% above baseline (P < 0.001 and P = 0.017, respectively). Sustained high-turnover bone loss and bone microarchitectural deterioration occur in the 5 years after RYGB. Adults receiving RYGB warrant assessment of bone health.


CREG mediated adventitial fibroblast phenotype modulation: a possible therapeutic target for proliferative vascular disease.
Proliferative vascular diseases, of which neointimal formation is a key pathological feature, cause significant morbidity and mortality worldwide. Adventitia is the outermost connective tissue that surrounds an artery. In recent years, accumulating data indicate that adventitial fibroblasts participate in the formation of neointimal lesions. Our previous studies have demonstrated that cellular repressor of E1A-stimulated genes (CREG) plays critical roles in reducing neointimal hyperplasia by promoting vascular smooth muscle cell (VSMC) differentiation and grow arrest and inhibiting migration. Hence, it is plausible that genetical modification with CREG gene in adventitial fibroblasts might inhibit angiotensin II-induced transdifferentiation to myofibroblasts, proliferation and migration, as well as adventitial thickening, finally decreasing neointimal formation. Possible mechanisms may include CREG direct attenuation of reactive oxygen species derived from reduced cathepsin-dependent activation of NADPH oxidase and indirect suppression of the downstream of NADPH oxidase including ERK1/2, JNK and p38 MAPK pathways in adventitial fibroblasts. Therefore, CREG may be a potential therapeutic target for proliferative vascular diseases.


Transcriptomic analysis of brine shrimp Artemia franciscana across a wide range of salinities.
Brine shrimp Artemia franciscana, a commercially important species, can thrive in a wide range of salinities and is commonly found in hypersaline lakes and solar salterns. Transcriptome analysis can enhance the understanding of the adaptative mechanisms of brine shrimp in aquaculture. RNA sequencing (RNAseq) data was generated from A. franciscana adults that were salt-adapted for 2-4 weeks at five salinities: 35, 50, 100, 150, and 230 psu. Long-read isoform sequencing (IsoSeq) data was used to construct a high-quality transcriptome assembly. Also, the gene expression patterns in A. franciscana adults were examined. Notably, the transcriptional response of A. franciscana's acclimation to intermediate salinities (50-150 psu) displayed frequently and differentially U-shaped or inverted U-shaped expression patterns. In addition, the types of genes showing two nonmonotonic expression patterns were distinct from each other. The coordinated shifts in gene expression suggest different homeostatic strategies of A. franciscana at specific salinities; such strategies may enhance population fitness at extreme salinities. Our study should promote a scientific concept for the gene expression patterns of A. franciscana along a broad salinity gradient, and a variety of salinity and prey should be monitored for testing the gene expression pattern of this important aquaculture species.


Novel insecticidal 1,6-dihydro-6-iminopyridazine derivatives as competitive antagonists of insect RDL GABA receptors.
The ionotropic γ-aminobutyric acid (GABA) receptor (iGABAR) is an important target for insecticides and parasiticides. Our previous studies showed that competitive antagonists (CAs) of insect iGABARs have the potential to be used for developing novel insecticides and that the structural modification of gabazine (a representative CA of mammalian iGABARs) could lead to the identification of novel CAs of insect iGABARs. In the present study, a novel series of 1,3-di- and 1,3,5-trisubstituted 1,6-dihydro-6-iminopyridazines (DIPs) was designed using a versatile strategy and synthesized using facile methods. Electrophysiological studies showed that several target DIPs (30 μM) exhibited excellent antagonistic activities against common cutworm and housefly iGABARs consisting of RDL subunits. The IC50 values of 3-(4-methoxyphenyl), 3-(4-trifluoromethoxyphenyl), 3-(4-biphenylylphenyl), 3-(2-naphthyl), 3-(3,4-methylenedioxyphenyl), and 3,5-(4-methoxyphenyl) analogs ranged from 2.2 to 24.8 μM. Additionally, several 1,3-disubstituted DIPs, especially 3-(4-trifluoromethoxyphenyl) and 3-(3,4-methylenedioxyphenyl) analogs, exhibited moderate insecticidal activity against common cutworm larvae, with >60% mortality at a concentration of 100 mg kg-1 . Molecular docking studies showed that the oxygen atom on the three-substituted aromatic ring could form a hydrogen bond with Arg254, which may enhance the activity of these DIPs against housefly iGABARs. This systematic study indicated that the presence of a carboxyl side chain shorter by one methylene than that of gabazine at the 1-position of the pyridazine ring is effective for maintaining the stable binding of these DIPs in insect iGABARs. Our study provides important information for the design of novel insect iGABAR CAs. © 2022 Society of Chemical Industry.


Review of the in vitro spectrum of activity of imipenem.
Imipenem (N-formimidoyl thienamycin, MK0787), a new carbapenem was found to have the widest antimicrobial activity of currently available beta-lactam drugs. Enterobacteriaceae had minimal inhibitory concentrations of imipenem of 8.0 micrograms/ml or less for 99.8 percent of clinical isolates. Only rare strains of Enterobacter species and Proteus mirabilis have higher imipenem minimal inhibitory concentration results. Hemophilus and Neisseria species were inhibited, but minimal inhibitory concentrations of imipenem were higher than those reported for third-generation cephalosporins. Only Pseudomonas maltophilia and Pseudomonas cepacia strains were imipenem resistant (MIC50 greater than 32 micrograms/ml) among the commonly isolated non-enteric gram-negative bacilli. All anaerobes were found susceptible to imipenem with the exception of some strains of Clostridium difficile. Staphylococcus species and non-enterococcal streptococci were very susceptible to imipenem. Streptococcus faecalis had higher minimal inhibitory concentrations of imipenem (MIC90 3.1 micrograms/ml) and S. faecium strains were frankly resistant. Methicillin-resistant S. aureus isolates had a MIC90 of 27.2 micrograms imipenem/ml. Imipenem was generally bactericidal except for marked minimal inhibitory and minimal bactericidal concentration differences with enterococci, Listeria, methicillin-resistant staphylococci, and some P. aeruginosa strains. The minimal inhibitory and minimal bactericidal concentrations of imipenem were not significantly influenced by organism inoculum size, probably because of its beta-lactamase stability to nearly all commonly encountered bacterial enzymes. Imipenem was found to be an excellent inhibitor of beta-lactamases and a potent enzyme inducer. The induction characteristic seems responsible for the antagonistic interactions of imipenem with some enzyme-labile beta-lactams in combination. Imipenem had limited stability in some in vitro susceptibility test systems. The 10 micrograms disk test or dry-form broth micro-dilution systems were preferred, applying the interpretive criteria from the National Committee for Clinical Laboratory Standards (M2-A3). Imipenem-resistant strains were rarely found in clinical practice and bacteria resistant to newer beta-lactams and aminoglycosides were generally very susceptible to this new carbapenem.


Editorial Commentary: Restoring Native Meniscal Anatomy With Medial Meniscus Allograft Transplantation and Augmentation of the Meniscotibial Ligament May Decrease Meniscal Graft Extrusion.
While studies have shown significant clinical improvement after medial meniscus allograft transplantation (MMAT) with good long-term graft survivorship, progression to osteoarthritis still occurs, even in the presence of intact grafts. Several factors can potentially explain the lack of chondroprotection despite graft survivorship, including meniscal degeneration, tearing, and remodeling after the initial procedure. A major factor contributing to progression of osteoarthritis is meniscal extrusion, which is seen in up to 60% of patients and seems to be more of an issue in medial meniscus transplantation compared to lateral and is present even immediately postoperatively. Grafts without extrusion provide protective effects similar to the native meniscus, while greater than 3 mm of extrusion leads to nearly complete loss of the protective effects. A reconstruction of the meniscotibial ligament, in addition to standard MMAT, may significantly decrease meniscal extrusion. Optimization of graft size, quality, and meniscal root positioning is best to prevent extrusion and restore native biomechanics.


Preparation and characterization of a decentralized modular yellow water nutrient recovery system.
The peculiarity of human urine as a resource, in terms of ethical and cultural considerations, and human perception, demands the development of a highly decentralized modular system, to enable the feasibility of the emerging concept of nutrient recovery in this regard. Consequently, a modular reactor, with packed bed of granular Gastropod shell (GS) was constructed for nutrient recovery from yellow water and the operational parameters were derived in simulated and pilot studies. Prior to the design of the modular reactor, both the raw and calcined GS were screened in a batch reactor for nutrient fraction recovery (i.e. total phosphorus (TP) and total nitrogen (TN)). The TP recovery was more favorable than the TN, but the TN recovery was the rate determining step. Despite the low TN capture efficiency of the reactor, the hydrolysis of the urea fraction that promotes nitrogen loss from yellow water was greatly impeded. The system showed higher selectivity for the nutrient fraction than the other constituents of the human urine, as manifested in the high residual COD and creatinine values in the treated yellow water. The volume of yellow water treated and the nutrient recovery capacity of the modular reactor were HRT dependent. A diminution in the nutrient recovery efficiency was observed in the pilot study, when compared with the simulated studies of the same HRT.


Uptake of coronavirus disease 2019 (COVID-19) vaccination among general hospital staff in Israel.
Data from all general hospitals in Israel to April 2021 show that the mean hospital rate of staff vaccination was 84.4% for the first dose and 77.1% for the second dose, which are lower than general population rate, with mean 7% who did not complete their vaccinations. Healthcare workers have an important role in influencing the wider community.


Application of the cell-free turkey herpesvirus vaccine by the aerosol route for the prevention of Marek's disease in chickens.
In field trials approximately 300,000 birds were vaccinated against Marek's disease (MD) by aerosol spray with 1,000 to 5,000 PFU of cell-free HVT vaccine per chick. Chicks were sprayed in the trays of the hatchers which still contained dust and down after hatching. Prior to spraying, the incoming and outgoing air ducts were closed. The chicks were sprayed for 12--15 min. with HVT in 250 to 300 ml. of diluent, and after completion of spraying the chicks remained in contact with the aerosol for approximately 10 minutes. In birds vaccinated by aerosol spray the incidence of MD ranged from 0.0% to 24.4%; while the incidence of MD in birds vaccinated by subcutaneous inoculation varied from 0.02 to 23.9%. In trial 1 the incidence of MD in birds vaccinated by aerosol spray was essentially the same as those vaccinated by subcutaneous inoculation; whereas, the incidence of MD (Trial 2 and 3) was higher in birds vaccinated by aerosol as compared to chickens vaccinated by subcutaneous inoculation.


Measuring the association between fathers' involvement and risky behaviours in adolescence.
Understanding the drivers of adolescent risky behaviour is important given the costs that such behaviours impose on society and young people themselves. Evidence shows that early parent-child relations shape children's development and behaviour, however we know relatively little about the potential causal pathways that lead to risky behaviour and the differential impact of fathers' and mothers' childcare involvement. This study tests whether paternal involvement in childcare at age 11 is associated with adolescent risky behaviour at age 14. Accounting for likely mediators, we run a Structural Equation model on three sweeps (2008-2015) of the UK's Millennium Cohort Study. Results show significant associations between father's involvement and reduction in adolescent risky behaviour. Father's involvement and father-adolescent closeness are shown to be stronger predictors of risky behaviours relative to mother's involvement and mother-adolescent closeness. This has implications for delinquency prevention programs that should be (re)designed to encourage healthy father-child bonds in adolescence.


History, research and practice of forensic anthropology in Thailand.
Forensic anthropology is an increasingly developing discipline born about a century ago in the United States with the objective to contribute the knowledge of bone biology and physical anthropology to the emerging needs of the court of law. The development of research in biological and forensic anthropology has made rapid progress worldwide in the past few years, however, in most countries--with the exception of the United States--forensic anthropology work is still considered within the duties of the forensic pathologist. This paper attempts to summarise the history and development of forensic anthropology in Thailand by providing information on past and current research and practice that can help forensic practitioners to apply existing methods in forensic cases and mass disasters. It is hoped that the lessons learned from the tsunami catastrophe and the emerging need for positive identification in medicolegal settings will lead to rapid advances in education, training and professional engagement of anthropologists from the forensic departments and the law enforcement agencies in Thailand.


Simultaneous expression of cocaine-induced behavioral sensitization and conditioned place preference in individual rats.
Conditioned place preference and locomotor sensitization are rodent behavioral models commonly used to investigate the actions of drugs of abuse. However, few studies have examined both paradigms in the same group of animals. We were interested in developing a combined protocol which successfully induced both conditioned place preference and sensitization simultaneously in cocaine-treated Sprague-Dawley rats in order to test the hypothesis that the magnitude of these two phenomena would be positively correlated. We used an open-field with a removable place preference insert to assess these measures independently. Cocaine-conditioned animals demonstrated a significant shift in preference for the drug-paired compartment and a sensitized locomotor response which was not observed in saline-conditioned animals challenged with cocaine. There was no significant relationship between locomotor sensitization and conditioned place preference in individual animals. We further examined these results with respect to each rat's initial response to cocaine, response to a novel environment and central zone entries in an open-field. Locomotor sensitization demonstrated an inverse correlation with the initial cocaine response. In contrast, conditioned place preference demonstrated an inverse correlation with the centre response. These results demonstrate that the combination of the acute cocaine response and the centre response in a novel open-field environment can be used to indicate the propensity of a given rat to exhibit either behavioral sensitization or conditioned place preference; however, it seems that sensitization and place preference are not necessarily co-expressed to a similar extent in the same individual animal.


Regional rates of brain protein synthesis are unaltered in dexmedetomidine sedated young men with fragile X syndrome: A L-[1-11C]leucine PET study.
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein (FMRP), a putative translation suppressor, is absent or significantly reduced in FXS. One prevailing hypothesis is that rates of protein synthesis are increased by the absence of this regulatory protein. In accord with this hypothesis, we have previously reported increased rates of cerebral protein synthesis (rCPS) in the Fmr1 knockout mouse model of FXS and others have reported similar effects in hippocampal slices. To address the hypothesis in human subjects, we applied the L[1-11C]leucine PET method to measure rCPS in adults with FXS and healthy controls. All subjects were males between the ages of 18 and 24 years and free of psychotropic medication. As most fragile X participants were not able to undergo the PET study awake, we used dexmedetomidine for sedation during the imaging studies. We found no differences between rCPS measured during dexmedetomidine-sedation and the awake state in ten healthy controls. In the comparison of rCPS in dexmedetomidine-sedated fragile X participants (n = 9) and healthy controls (n = 14) we found no statistically significant differences. Our results from in vivo measurements in human brain do not support the hypothesis that rCPS are elevated due to the absence of FMRP. This hypothesis is based on findings in animal models and in vitro measurements in human peripheral cells. The absence of a translation suppressor may produce a more complex response in pathways regulating translation than previously thought. We may need to revise our working hypotheses regarding FXS and our thinking about potential therapeutics.


Incorporation of fatty acids into the outer and inner membranes of isolated rat liver mitochondria.
Acyl-CoA: phospholipid acyl-transferase activity as well as phospholipase A activity were detected in inner and outer membrane preparations from rat liver mitochondria. Both enzyme systems have an optimum pH around 8 and act preferentially on phosphatidylethanolamine. While phospholipase A activity is much lower in the inner membrane than in the outer membrane of mitochondria the reverse is true for the incorporation of (14C)-oleic acid into endogenous phosphatidylethanolamine. These results bring an indirect evidence that the inner membrane per se possesses a phospholipase A activity.


Effects of N-Glycosylation Deletions on Cypridina Luciferase Activity.
Cypridina luciferase (Cluc), a secreted luminescent protein identified from Cypridina noctiluca, has two N-glycosylation sites. In this study, we evaluated the effects of N-glycosylation on Cluc properties by creating site-directed mutagenic modifications at the consensus sequence for N-glycosylation (Asn-X-Ser/Thr). Eight variants consisting of four single- and double-residue mutants each were characterized. The producibility and relative specific activity were apparently reduced in mutant Cluc although the thermostability and secretion efficiency were not affected. These results suggested that N-glycosylation modifications and the proper amino acid sequence of the N-glycan binding sites of Cluc are required for the complete protein folding to form a stable catalytic center, for the proper conformation of substrate-protein interaction residues, or for both and that defects in the glycosylation modification are not related to secretion process and stability of the protein.


Distinct effects of orexin A on spontaneous and evoked synaptic currents in the rat nucleus tractus solitarius.
Orexins are produced in hypothalamic areas and orexin-containing neurons are distributed in widespread areas of the central nervous system. Orexins regulate several physiological functions such as arousal, food intake and autonomic control. The presence of orexin-containing neuron terminals and orexin receptors has been confirmed in the nucleus tractus solitarius (NTS), which receives primary afferent fibers from peripheral organs including baroreceptors. However, the neuronal effects of orexin-1 receptor (OX1R) activation were not examined. Here, we aimed to determine the effects of OX1R activation on excitatory synaptic transmission. OX1R activation increased the frequency of spontaneous excitatory synaptic currents (sEPSCs). This effect was blocked by the prior application of L-NAME. In contrast, the amplitude of evoked excitatory postsynaptic currents (eEPSCs) was suppressed by OX1R activation, and this effect was prevented by a cannabinoid receptor 1 blocker, AM251, but not by the pretreatment with L-NAME. Altogether, these results suggest that OX1R activation increases sEPSCs frequency by stimulating NO production, whereas it inhibits eEPSCs by releasing endocannabinoids in the NTS. Thus, OX1R activation had distinct effects on spontaneous and evoked excitatory synaptic transmissions in the NTS.


[Comparative studies of the detection of antibodies against BHV-5 using the enzyme-linked immunosorbent assay, serum neutralization test, cell assay and immunofluorescence test].
A comparison of the analyses of 490 serum samples from various flocks of sheep for the detection of BHV-5 antibodies using ELISA, serum neutralisation test, cell assay and immunofluorescence assay showed nearly identical results regarding the distinction between positive and negative serum samples. The percentage of serum samples with antibodies against BHV-5 antigen differed from test to test: ELISA 268 (54.7%), cell assay 323 (65.8%), immunofluorescence assay 222 (46.6%) and serum neutralisation test 221 (45.1%). With ELISA, cell assay and immunofluorescence assay the experiment can be carried out more simply and rapidly than with serum neutralisation test.


Correction of a severely rotated maxillary central incisor with the Whip device.
The following case report presents an appliance named Whip device used for the correction of severe rotations of anterior teeth in pre-adolescent patient. A 9-year-old boy with a severe 90 degrees rotation of upper left central incisor was treated with a Whip appliance. After 3 months of treatment, the position of the upper left central incisor was orthodontically corrected.


Changes in the size of pulse-labelled DNA fragments induced in human cells by inhibitors of uracil-DNA glycosylase and DNA methylation.
An inhibitor of uracil-DNA glycosylase, uracil, induces an increase in the size of pulse-labelled DNA fragments in human cells in vivo suggesting that dUMP incorporation into DNA and uracil-DNA glycosylase contribute to the small size of pulse-labelled DNA. It is also shown that inhibition of DNA methylation in vivo by ethionine and 5-azacytidine induces a decrease in the size of pulse-labelled DNA, and the effect is partially suppressed by uracil. In vitro experiments with purified uracil-DNA glycosylase from human placenta show that DNA hypermethylation inhibits the enzyme. The data make it possible to explain the antimutagenic effect of ethionine in mammalian cells [1] by stimulation of the repair of DNA containing incorporated uracil on the basis of the hypothesis that DNA-uracil repair stimulates mismatch correction leading to preferential excision of misincorporated nucleotides from daughter DNA strands.


The Ahmed shunt versus the Baerveldt shunt for refractory glaucoma: a meta-analysis.
The purpose of this study was to compare the efficacy and tolerability of the Ahmed glaucoma valve (AGV) implant and the Baerveldt implant for the treatment of refractory glaucoma. We comprehensively searched four databases, including PubMed, EMBASE, Web of Science, and the Cochrane Library databases, selecting the relevant studies. The continuous variables, namely, intraocular pressure reduction (IOPR) and a reduction in glaucoma medication, were pooled by the weighted mean differences (WMDs), and the dichotomous outcomes, including success rates and tolerability estimates, were pooled by the odds ratio (ORs). A total of 929 patients from six studies were included. The WMDs of the IOPR between the AGV implant and the Baerveldt implant were 1.58 [95 % confidence interval (CI): -2.99 to 6.15] at 6 months, -1.01 (95 % CI: -3.40 to 1.98) at 12 months, -0.54 (95 % CI: -4.89 to 3.82) at 24 months, and -0.47 (95 % CI: -3.29 to 2.35) at 36 months. No significant difference was detected between the two groups at any point in time. The pooled ORs comparing the AGV implant with the Baerveldt implant were 0.51 (95 % CI: 0.33 to 0.80) for the complete success rate and 0.67 (95 % CI: 0.50 to 0.91) for qualified success rate. The Baerveldt implant was associated with a reduction in glaucoma medication at -0.51 (95 % CI: -0.90 to -0.12). There were no significant differences between the AGV implant and the Baerveldt implant on the rates of adverse events. The Baerveldt implant is more effective in both its surgical success rate and reducing glaucoma medication, but it is comparable to the AGV implant in lowering IOP. Both implants may have comparable incidences of adverse events.


Effect of torso geometry on the magnetocardiogram.
Calculations of the effect of torso geometry on the extracorporeal magnetic field produced by a simple cardiac source have been carried out. Contrary to the results at present in the literature, it is found that the field solution is stable under perturbations of geometry in the sense that small relative changes in geometry produce comparably small changes in the magnetic field. Thus, simplified torso models may have a wider range of validity and usefulness than was previously thought.


Polyunsaturated fatty acids downregulate the low density lipoprotein receptor of human HepG2 cells.
The aim of the study was to investigate the effect of different fatty acids on the low density lipoprotein (LDL) receptor of cultured human liver HepG2 cells. Previous studies investigating the effect of fatty acids on LDL expression have reported conflicting findings and are limited to measurements of LDL receptor binding activity. Therefore, this study is unique in that the relative effects of different fatty acids on the LDL receptor were investigated at three different stages of expression: 1) functional cellular LDL binding activity, 2) amount of LDL receptor protein and 3) LDL receptor mRNA level. The HepG2 cells were incubated for 24 hr with either 100 &mgr;M palmitic, oleic, linoleic or eicosapentaenoic acid (EPA). The measurement of LDL receptor binding activity was with colloidal gold-LDL conjugates, cellular LDL receptor protein was by western blotting and LDL receptor mRNA by Southern blotting of reverse-transcribed, polymerase chain reaction-amplified cDNA. The LDL receptor binding activity, protein and mRNA levels decreased as the degree of unsaturation of the fatty acids increased (palmitic acid greater-than-or-equal oleic acid > linoleic acid > EPA) and the inverse relationship held whether or not cholesterol was included in the culture media. The relative differences were very similar for the three stages of expression indicating that modulation of the LDL receptor by the fatty acids occurred at the level of gene transcription. The increased susceptibility to oxidation of the polyunsaturated fatty acids was unlikely to be a factor in the effect because EPA and linoleic acid (250 &mgr;M) still downregulated the LDL receptor in the presence of the antioxidant vitamin E (50 &mgr;M). In conclusion, the polyunsaturates, linoleic acid and EPA, effectively downregulated the LDL receptor of HepG2 cells compared to palmitic acid. The effects of these fatty acids were observed at the level of LDL receptor binding activity, protein and mRNA, strongly suggesting that the fatty acid effects were at the level of gene transcription.


Implant-retained dentures for full-arch rehabilitation: a case report comparing fixed and removable restorations.
Dental implants as abutments for full-arch restorations are a well-documented treatment modality. This report presents a case in which the patient was treated initially with fixed restorations supported by either implants or natural teeth and subsequently treated with a removable implant/telescopic crown-supported overdenture. Advantages and disadvantages of each approach are described and discussed. While the fixed restoration resulted in a functionally satisfactory treatment outcome, the patient was displeased with the esthetic appearance. The main concern was the unnaturally long tooth shape necessary to compensate for the insufficient alveolar ridge height. Replacement of the existing restoration with an implant-supported removable overdenture led to a functionally and esthetically acceptable result. When deciding whether to use a fixed or removable implant-supported full-arch restoration, a multitude of factors must be considered. Due to the possible need for additional surgical steps to enhance the esthetic appearance surrounding fixed restorations, removable implant-supported partial dentures often are the better choice.


Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway.
Gadd45a, a p53-regulated and DNA damage-inducible gene, is implicated in protection against tumor malignancy, although the underlying mechanism remains to be defined further. Here we demonstrate that Gadd45a plays an important role in suppression of tumor angiogenesis. Gadd45a deletion significantly increases microvessel density in tumors and stimulates an angiogenic response in a chicken embryo chorioallantoic membrane assay. Disruption of endogenous Gadd45a promotes tube formation and migration of endothelial cells. We further show that Gadd45a deletion increases phosphorylation of STAT3 at Ser-727 and, in turn, elevates the STAT3 transcriptional activity. This process substantially induces both expression and secretion of VEGFa, a STAT3 responsive gene, and promotes tumor angiogenesis. Interestingly, Gadd45a is able to physically associate with mammalian target of rapamycin (mTOR), a kinase that mediates Ser-727 phosphorylation of STAT3. The interaction of Gadd45a with mTOR suppresses STAT3 phosphorylation at Ser-727 and leads to down-regulated expression of VEGFa. Further analysis reveals that Gadd45a overexpression attenuates the association between mTOR and STAT3, whereas Gadd45a disruption strengthens this interaction, indicating that Gadd45a suppression of STAT3 phosphorylation is mainly through the dissociation of mTOR with STAT3. Taken together, these findings provide the first evidence that Gadd45a inhibits tumor angiogenesis via blocking of the mTOR/STAT3 pathway.


Virilizing oncocytic adrenocortical carcinoma: clinical and immunohistochemical studies.
Oncocytic tumors of the adrenal cortex are rare, mostly nonfunctioning and benign. Report virilizing oncocytic adrenocortical carcinoma in a 50-year-old woman. She presented a recent and progressive virilization syndrome, associated with high blood pressure. Hormonal evaluation showed elevated serum testosterone and delta-4-androstenedione levels, normal urinary free cortisol level and incomplete suppression of cortisol at the 1 mg dexamethasone suppression test. CT scan of the abdomen revealed a 35 mm left adrenal mass. The patient underwent a left adrenalectomy, and the histological study showed a 3 cm oncocytic adrenocortical carcinoma with signs of malignancy. Immunohistochemical study revealed that tumor cells expressed the steroidogenic enzymes involved into androgen synthesis (3βHSD and P450c17α), P450 aromatase and luteinizing hormone (LH) receptors. Post-operatively, signs of virilization improved rapidly, serum testosterone and delta-4-androstenedione levels returned to normal, as did the dexamethasone suppression test. During follow-up CT-scan and 18-FDG PET/CT showed a right ovary mass, corresponding to a follicular cyst associated with hyperthecosis. The patient is alive with no recurrence 48 months after adrenal surgery. Oncocytic adrenocortical carcinomas, although extremely rare, should be considered in women with a virilization syndrome. In this woman immunohistochimical studies revealed the presence of steroidogenic enzymes involved into androgen synthesis and aromatization, and LH receptors could be implicated in this pathology.


Co-Inhibition of Androgen Receptor and PARP as a Novel Treatment Paradigm in Prostate Cancer-Where Are We Now?
Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)-enzalutamide and abiraterone-have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25-30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020-rucaparib and olaparib-has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2-10 years.


Resting-state EEG as a potential indicator to predict sleep quality in depressive patients.
To investigate the changes in sleep quality, heart rate variability (HRV) and resting-state electroencephalogram (rsEEG) in patients with major depressive disorder (MDD), and to explore whether HRV and rsEEG may be served as more convenient tools to assess sleep quality in MDD patients. We included a total of 91 subjects (46 healthy controls and 45 MDD patients) and compared their sleep quality, HRV and power spectra of rsEEG. Correlation analyses were conducted to discuss the relationship between HRV and seven factors of PSQI. Multiple linear regression model was used to examine whether absolute band power could predict sleep quality in MDD patients. We found higher PSQI scores and lower levels of HRV in depressive individuals compared with healthy controls. In MDD patients, sleep latency was negatively correlated with RMSSD and HF. Delta, theta, and alpha band power of rsEEG were higher in MDD patients. Regression analyses showed delta band power of TP8, as well as theta, alpha band power of AF3 predicts PSQI score of MDD patients. The findings of our study show that some aspects of sleep problems had negative correlations with parasympathetic activity and the regression model supports that the band power of rsEEG may be used as a potential indicator to evaluate the sleep quality in MDD patients. Cortical hyperarousal may be one of the reasons leading to poor sleep quality of MDD patients. And resting-state EEG can be used as a potential indicator for clinical assessment of MDD patients' sleep quality.


Relaxation Times of Ligand-Receptor Complex Formation Control T Cell Activation.
One of the most important functions of immune T cells is to recognize the presence of the pathogen-derived ligands and to quickly respond to them while at the same time not responding to its own ligands. This is known as absolute discrimination, and it is one of the most challenging phenomena to explain. The effectiveness of pathogen detection by T cell receptor is limited by chemical similarity of foreign and self-peptides and very low concentrations of foreign ligands. We propose a new mechanism of how absolute discrimination by T cells might function. It is suggested that the decision to activate or not to activate the immune response is controlled by the time to reach the stationary concentration of the T-cell-receptor-ligand-activated complex, which transfers the signal to downstream cellular biochemical networks. Our theoretical method models T cell receptor phosphorylation events as a sequence of stochastic transitions between discrete biochemical states, and this allows us to explicitly describe the dynamical properties of the system. It is found that the proposed criterion on the relaxation times is able to explain available experimental observations. In addition, we suggest that the level of stochastic noise might be an additional factor in the activation mechanisms. Furthermore, our theoretical approach explicitly analyzes the relationships between speed, sensitivity, and specificity of T cell functioning, which are the main characteristics of the process. Thus, it clarifies the molecular picture of T cell activation in immune response.


Reduced 123I-BMIPP uptake implies decreased myocardial flow reserve in patients with chronic stable angina.
Long-chain fatty acid (LCFA) is the main energy source for normal myocardium at rest, but in ischemic myocardium, the main energy substrate shifts from LCFA to glucose. 123I-BMIPP is a radiolabeled LCFA analog. In chronic stable angina without previous infarction, we suppose that reduced 123I-BMIPP uptake is related to the substrate shift in myocardium with decreased myocardial flow reserve (MFR). The purpose of this study was to relate 123I-BMIPP uptake to rest myocardial blood flow (MBF), hyperemic MBF, and MFR assessed with 15O-water positron emission tomography (PET). We enrolled 21 patients with chronic stable angina without previous infarction, all of whom underwent 123I-BMIPP single-photon emission computed tomography (SPECT) and 15O-water PET. The left ventricle was divided into 13 segments. In each segment, rest MBF and hyperemic MBF were measured by PET. 123I-BMIPP uptake was evaluated as follows: score 0=normal, 1=slightly decreased uptake, 2=moderately decreased uptake, 3=severely decreased uptake, and 4=complete defect. 123I-BMIPP uptake was compared with rest MBF, hyperemic MBF, and MFR. The numbers of segments with 123I-BMIPP scores 0, 1, 2, 3, and 4 were 178, 40, 25, 24, and 0, respectively. The rest MBFs for scores 0, 1, 2, and 3 were 0.93+/-0.25, 0.86+/-0.21, 0.97+/-0.30, and 0.99+/-0.37 ml/min/g, respectively. The hyperemic MBFs for scores 0, 1, 2, and 3 were 2.76+/-1.29, 1.84+/-0.74, 1.37+/-0.39, and 1.08+/-0.40 ml/min/g, respectively. The MFRs for scores 0, 1, 2, and 3 were 3.01+/-1.38, 2.20+/-0.95, 1.44+/-0.22, and 1.10+/-0.26, respectively. As 123I-BMIPP uptake declined, hyperemic MBF and MFR decreased. In chronic stable angina without previous infarction, reduced 123I-BMIPP uptake implies decreased MFR.


Preparation, cytotoxicity and interactions with nucleophiles of three isomeric transplatinum complexes containing methylpiperidine ligands.
Three isomeric complexes, trans-[PtCl2(NH3)(2-methylpiperidine)], trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)], were prepared and their cytotoxicities against six ovarian cancer cell lines, three sensitive and three resistant to cisplatin, were measured. There were no significant differences in the cytotoxicities of the three isomers against these cell lines. The interactions of the three complexes with reduced glutathione (GSH) and with ubiquitin (Ub), as a model protein, were studied. The trans-[PtCl2(NH3)(2-methylpiperidine)] reacted approximately twice as slowly with GSH as did the other two isomers. In the 1:1 interactions of the three complexes with ubiquitin (Mr = 8565 amu), trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)] attained 100% modification while trans-[PtCl2(NH3)(2-methylpiperidine)] reached only less than 50% modification. Trans-[PtCl2(NH3)(2-methylpiperidine)] reacts significantly less efficiently with GSH and proteins than the other two isomers yet this is not reflected in the cytotoxicity values. These results indicate that for these complexes, in these cell lines, cytosolic detoxification probably does not play a dominant role in determining the cytotoxicity of the complexes.


Multi-omics analysis of fecal samples in colorectal cancer Egyptians patients: a pilot study.
Colorectal cancer (CRC) is a public health concern and the second most common disease worldwide. This is due to genetic coding and is influenced by environmental aspects, in which the gut microbiota plays a significant role. The purpose of this study was to compare the microbiota makeup of CRC patients with that of healthy control and to identify upregulated and downregulated proteins and metabolites in CRC patients. Using a next-generation sequencing approach, fecal samples of five females (4 CRC patients and one healthy control) were analyzed by BGI DNBSEQ-T7, Hong Kong, China. Furthermore, proteomics and metabolomics analysis were performed using LC-MS/MS technique. Dysbiosis of gut microbiota has been observed in patients with CRC, with an increase in microbiota diversity at all taxonomic levels relative to healthy control. Where, at the functional level the bacterial species participate in many different pathways among them de novo nucleotide synthesis and amino acids pathways were aberrantly upregulated in CRC patients. Proteomics and metabolomics profiles of CRC patients showed different proteins and metabolites, a total of 360 and 158 proteins and metabolites, respectively were highly expressed compared to healthy control with fold change ≥ 1.2. Among the highly expressed proteins were transketolase, sushi domain-containing protein, sulfide quinone oxidoreductase protein, AAA family ATPase protein, carbonic anhydrase, IgG Fc-binding protein, nucleoside diphosphate kinase protein, arylsulfatase, alkaline phosphatase protein, phosphoglycerate kinase, protein kinase domain-containing protein, non-specific serine/threonine protein kinase, Acyl-CoA synthetase and EF-hand domain-containing protein. Some of the differential metabolites, Taurine, Taurocholic acid, 7-ketodeoxycholic acid, Glycochenodeoxycholic acid, Glycocholic acid, and Taurochenodeoxycholic acid that belong to bile acids metabolites. Some bacterial species, proteins, and metabolites could be used as diagnostic biomarkers for CRC. Our study paves an insight into using multi-omics technology to address the relationship between gut microbiota and CRC.


Synchronous Superficial Middle Cerebral Vein Outflow Correlates Favorable Tissue Fate After Mechanical Thrombectomy for Acute Ischemic Stroke.
The purpose of this study was to determine the association between hemispheric synchrony in venous outflow at baseline and tissue fate after mechanical thrombectomy (MT) for acute ischemic stroke (AIS). A two-center retrospective analysis involving AIS patients who underwent MT was performed. The four cortical veins of interest include the superficial middle cerebral vein (SMCV), sphenoparietal sinus (SS), vein of Labbé (VOL), and vein of Trolard (VOT). Baseline computed tomography perfusion data were used to compare the following outflow parameters between the hemispheres: first filling time (△FFT), time to peak (△TTP) and total filling time (△TFT). Synchronous venous outflow was defined as △FFT = 0. Multivariable regression analyses were performed to evaluate the association of venous outflow synchrony with penumbral salvage, infarct growth, and intracranial hemorrhage (ICH) after MT. A total of 151 patients (71.4 ± 13.2 years, 65.6% women) were evaluated. Patients with synchronous SMCV outflow demonstrated significantly greater penumbral salvage (41.3 mL vs. 33.1 mL, P = 0.005) and lower infarct growth (9.0 mL vs. 14.4 mL, P = 0.015) compared to those with delayed SMCV outflow. Higher △FFTSMCV (β = -1.44, P = 0.013) and △TTPSMCV (β = -0.996, P = 0.003) significantly associated with lower penumbral salvage, while higher △FFTSMCV significantly associated with larger infarct growth (β = 1.09, P = 0.005) and increased risk of ICH (odds ratio [OR] = 1.519, P = 0.047). Synchronous SMCV outflow is an independent predictor of favorable tissue outcome and low ICH risk, and thereby carries the potential as an auxiliary radiological marker aiding the treatment planning of AIS patients.


Predictors and Rate of Progression of Aortic Root and Ascending Aorta Dilatation.
In the absence of risk factors like bicuspid aortic valve, connective tissue disorder, or family history of aortic dissections, degenerative thoracic aortic aneurysm appears to be an indolent disease. Most American and European societies recommend yearly or biannual imaging of the thoracic aorta with computed tomographic (CT) imaging, magnetic resonance (MRI) imaging, and transthoracic echocardiographic (TTE) examination. We aimed to identify the rate of progression and predictors of early degenerative aortic root dilatation (ARD) and ascending aortic dilatation (AAD) over a period of 10 years on the basis of echocardiographic measurements. A retrospective chart analysis was performed on 340 patients (mean age 67.4 ± 11.6 years; 85.6% men; 83.8% White) with known ARD and AAD. Aortic root and ascending aorta measurements were followed by serial echocardiograms from the time of the first diagnosis for a total of 10 years. During this time, the mean change in ARD was 0.28 ± 0.71 mm and AAD was 0.15 ± 0.18 mm. On multivariate regression after adjusting for baseline demographics, risk factors, and medication use, there was no statistically significant increase in their unit change in mean ARD or AAD. In conclusion, mild to moderate degenerative thoracic aortic aneurysm has a minimal change in dimensions over time, and current guidelines recommending yearly surveillance imaging of ARD and AAD need to be revisited to allow a more liberal follow-up interval.


"Fatal adsorption" of brushlike macromolecules: high sensitivity of C-C bond cleavage rates to substrate surface energy.
Adsorption-induced degradation of brushlike macromolecules was monitored through molecular imaging by atomic force microscopy. The rate constant for C-C bond cleavage was shown to be extremely sensitive to the substrate surface energy. A few percent increase in the surface energy from 69.2 to 71.2 mN/m led to an order of magnitude increase of the scission rate. The absolute values of the rupture forces ranging from 2.57 to 2.47 nN are in agreement with previously calculated and measured values for stretching surface-tethered molecules.


Smoking clinic failures and recent life stress.
To test the assumption that people with greater current life stress would more likely fail at quitting smoking in stop smoking clinics, 231 smokers who attended at least one session of an ongoing series of clinics were given a "Life Change Inventory" and had their smoking status assessed at the clinic's end. A high life stress score was a strong predictor for men (n = 88) of continuing smoking and dropping out of the clinics, but not for the women (n = 143). No difference in the numbers of life change items was reported between the sexes. Younger, lighter-smoking women did significantly better at stopping than older, heavier-smoking females, a relationship not found in the males. For this sample's males, life stress appears to be an important factor reducing motivation when undertaking changing another habit. It seems reasonable to counsel males under high life stress about their low chances of stopping smoking before subjecting themselves to a failure experience in a clinic.


Diagnostic value of quantification of circulating free DNA for gall bladder cancer using a chemiluminescence DNA biosensor system based on DNA G-quadruplex/ hemin enzyme.
Gall bladder cancer (GBC) is an insidious but rapidly progressed disease with a poor prognosis and high mortality rate. To explore a novel method for GBC diagnosis, we quantified circulating free DNA (cfDNA) in serum samples from 228 participants, including 83 patients with GBC, 75 patients with cholecystitis, and 70 healthy donors, using a chemiluminescence DNA biosensor system based on DNA G-quadruplex/hemin enzyme. We measured β-actin gene expression to evaluate serum cfDNA levels representing as chemiluminescence intensity with the addition of sufficient probes. We analyzed associations of cfDNA quantities in serum samples and corresponding pathological stages and found that the concentration of cfDNA was significantly higher in GBC group than in the healthy control and cholecystitis groups. The levels of cfDNA were significantly associated with TNM stage, lymph node involvement, metastasis, and jaundice. The ROC curves showed that the diagnostic value of chemiluminescence DNA biosensor system was nearly equivalent to that of qPCR. Our method can distinguish patients with GBC from healthy donors and patients with cholecystitis clearly; however, this method was not available to distinguish patients with cholecystitis from the healthy controls. In summary, cfDNA maybe serve as a new diagnostic and noninvasive marker for the diagnosis of GBC using chemiluminescence DNA biosensor system based on DNA G-quadruplex/hemin enzyme.


Dormancy phases in seeds ofVerbascum thapsus L.
Seeds ofVerbascum thapsus were imbibed on filter papers in Petri dishes and were exposed to a series of temperatures of 4°C→10°C→20°C→10°C→4°C in darkness. After each temperature treatment lasting one month, samples were removed and tested in light and darkness over a range of alternating temperatures. The results showed us that the dormancy state changes gradually according to the imbibition temperatures simulating the seasonal cycle. The ecological implications of the dormancy phases for the regulation of germination in natural conditions are discussed.


Humeral shaft fractures: a cost-effectiveness analysis of operative versus nonoperative management.
Humeral shaft fractures can be managed operatively or nonoperatively with functional bracing in the absence of neurovascular injury, open fracture, or polytrauma. A consensus on optimal management has not been reached, nor has the cost-effectiveness perspective been investigated. A decision tree was constructed describing the management of humeral shaft fractures with open reduction-internal fixation (ORIF), intramedullary nailing (IMN), and functional bracing in a non-elderly population. Probabilities were defined using weighted averages determined from systematic review of the literature. Cost-effectiveness was evaluated with incremental cost-effectiveness ratios, measured in cost per quality-adjusted life-year (QALY). Willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY were evaluated. Eighty-six studies were included. Using bracing as the referent in the health care model, we observed that bracing was the preferred strategy at both incremental cost-effectiveness ratio thresholds. ORIF and IMN had higher overall effectiveness (0.917 QALYs and 0.913 QALYs, respectively) compared with bracing (0.877 QALYs). The cost-effectiveness of bracing was driven by a substantially lower overall cost. In the societal model-accounting for both health care and societal costs-the cost difference narrowed between bracing, ORIF, and IMN. Bracing remained the preferred strategy at the $50,000/QALY threshold; ORIF was preferred at the $100,000/QALY threshold. ORIF and IMN were comparable strategies across a range of probability values in sensitivity analyses. Functional bracing, with its low cost and satisfactory clinical outcomes, is often the most cost-effective strategy for humeral shaft fracture management. ORIF becomes preferable at the higher willingness-to-pay threshold when societal burden is considered. QALY values for ORIF and IMN were comparable.


The policy of public health genomics in Italy.
Italy has a monitoring system for genetic testing, consisting in a periodic census of clinical and laboratory activities performed in the country. The experience is limited, however, concerning the translation of genomic testing for complex diseases into clinical practice. For the first time the Italian Ministry of Health has introduced a policy strategic plan on genomics and predictive medicine within the 2010-2012 National Prevention Plan. This achievement was supported by the Italian Network for Public Health Genomics (GENISAP) and will likely contribute to the integration of public health genomics into health care in the country. Our experience might be of interest not only in Italy, but in other high-income countries, struggling to keep a healthy economy and healthy citizens.


Prevalence of Diabetes, Prediabetes, and Obesity in the Indigenous Kuna Population of Panamá.
Diabetes is a burgeoning disease affecting more than 8% of the world population. Indigenous communities are disproportionately impacted by diabetes; however, limited data is available on prevalence and correlates of diabetes. Data was collected from 211 Indigenous Kuna adults off the coast of Panamá in the San Blas region of the Caribbean. Diabetes and prediabetes were measured by HbA1c. Obesity was defined using the US BMI categories as well as categories defined by the WHO to assess obesity among Asian populations. Univariate analyses (chi2 tests) were used to investigate diabetes status and obesity by demographic factors. Logistic regression was used to examine the correlates of diabetes and obesity. Of the 211 adults, 13% had diabetes, 35% had prediabetes, and approximately 39% were obese. Using the Asian cut point for obesity, this number increased to 61%. Income was statistically significantly related to an HbA1c cut point of 6.5 (p = 0.005). Individuals who reported a monthly income of greater than $250 had increased odds of prediabetes and diabetes nearly sixfold for HbA1c of > 6.5 (OR 6.3; CI 1.43-28.45) and HbA1c of > 5.7 (OR 5.1; CI 1.03-26.14). These findings represent one of the first studies examining diabetes and prediabetes in indigenous Kuna of the San Blas region. Our findings suggest Kuna Indians may be at an increased risk for diabetes and prediabetes. Current national estimates for diabetes is considered low in this population. Greater understanding of determinants of diabetes and obesity are needed in order to address diabetes in this indigenous community.


Early Life Antibiotic Exposure Is Not Associated with Growth in Young Children of Vellore, India.
To estimate the effects of antibiotic exposures in the first 6 months of life on short- and long-term growth. In a prospective observational cohort study of 497 children from Vellore, India, we estimated short-term effects of antibiotics during the first 6 months using longitudinal general linear regression to model weight-for-age, height-for-age, and weight-for-height z-scores in monthly intervals. To estimate long-term effects, we modeled growth from 6 months to 3 years as a function of antibiotic use in the first 6 months. We also estimated the effects of antibiotics on the monthly relative risks of underweight, stunting, and wasting in the first 6 months and to 3 years. Underweight, stunting, and wasting were common in this population: 31%, 32%, and 15% on average after 6 months of age, respectively. There was no association between antibiotic exposures before 6 months and growth during that period. From 6 months to 3 years, adjusted absolute differences in weight and height were small (approximately -100 g and no more than -2 mm overall, respectively) and not statistically significant. Antibiotic exposures early in life were not associated with increased or decreased growth. The combination of malnutrition and recurrent illness likely complicate the relationship between antibiotic exposures and growth among children in low and middle-income countries.


A scoring system for basic cardiac life support skills in training situations.
A valid and reproducible system for determining basic cardiac life support (BCLS) skills can help to evaluate the effect of instruction courses and to estimate the results of educational activities. The aim of this study was to develop and test such a system in accordance with the Standards and Guidelines of the American Heart Association (AHA). Five criteria were defined in advance towards such a system (1) Inadequate techniques must be reflected by a fail score. (2) Skilled persons should achieve a pass score. (3) The effect of training must be reflected by an improvement of the score. (4) Inter- and intra-observer variability must be negligible. (5) The system should be simple to apply. The system was developed, and in order to test the system, the BCLS skills of 40 ambulance nurses were tested once and those of 148 lay people twice. All cardiopulmonary resuscitation (CPR) attempts were performed on a mannequin. The relevant parameters of the attempt were continuously recorded and printed. Penalty points were assigned in a predefined way for aberrations of the techniques advised in the Standards and Guidelines. The system satisfied the five criteria mentioned above. It therefore offers a reliable and reproducible evaluation of BCLS skills.


How to MEK the best of uveal melanoma: A systematic review on the efficacy and safety of MEK inhibitors in metastatic or unresectable uveal melanoma.
BRAF and MEK inhibitors have demonstrated significant survival benefits for patients with cutaneous melanoma. However, their use for uveal melanoma (UM) is less established. The aim of this systematic review was to summarise the current evidence on the efficacy and safety of MEK inhibitors in metastatic UM. We performed a systematic literature search in MEDLINE, Embase and the Cochrane Library CENTRAL from 1946 through 17 April 2018. Abstracts of oncologic conferences, trial registers and reference lists were handsearched for relevant publications. The risk of bias was assessed with the Cochrane Risk of Bias Tool. Of 590 records identified, six studies met the eligibility criteria and were included in the qualitative synthesis. Data were available for selumetinib ± dacarbazine (n = 3), trametinib ± AKT inhibitor (n = 2) and binimetinib plus sotrastaurin (n = 1) from three open-label phase II, two open-label phase I and one placebo-controlled phase III trial. The overall response rate was available in five studies and ranged from 0 to 14% with an average of 2.5%. The median progression-free survival ranged from 3.1 weeks to 16 weeks. Data on overall survival and 1-year survival rates were not consistently reported. Severe treatment-related adverse events were observed most commonly for the combination use of selumetinib plus dacarbazine (62%) and binimetinib plus sotrastaurin (75%). UM is little responsive to MEK inhibition, regardless of the inhibiting agent and combination partner. Our results do not support the use of MEK inhibitors in UM. Novel treatment options are urgently needed in this patient population.


The Role of Hyperthermic Intraperitoneal Chemotherapy for Non-colorectal Peritoneal Surface Malignancies.
Peritoneal carcinomatosis, from a variety of gastrointestinal and gynecological malignancies, has been historically challenging to treat and there remains a wide range of biologic aggressiveness in these patients. Malignancies commonly associated with PC include those of colorectal, appendiceal, gastric, ovarian, sarcoma, small intestinal, and primary peritoneal origin among others. Advances in our understanding of this unique disease process have led to significant interest in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) as an emerging treatment option. The goal of CRS-HIPEC is to remove all visible macroscopic disease while preserving organ function, and then treat microscopic disease through perfusion of the peritoneal cavity with heated chemotherapy. Although recent reviews have focused on the management of peritoneal carcinomatosis secondary to colorectal cancer given the publication of several recent randomized controlled trials, the purpose of the current review is to summarize the evidence on CRS-HIPEC for non-colorectal peritoneal surface malignancies, including appendiceal neoplasms, malignant peritoneal mesothelioma, gastric cancer, and ovarian cancer. While retrospective studies have clarified the importance of prognostic factors such as the peritoneal carcinomatosis index, completeness of cytoreduction, histopathological characteristics, and lymph node positivity, the lack of convincing level 1 evidence for the use of CRS-HIPEC has led to it remaining a highly controversial topic. The decision to utilize CRS-HIPEC should involve a multidisciplinary team approach and evaluation of prognostic factors to balance the short-term morbidity of the operation with maximum long-term benefits. Large, multi-institutional groups and ongoing trials hold promise for clarifying the role of CRS-HIPEC in peritoneal surface malignancies.


Acute short-term effect of VVI pacing mode on P wave dispersion in patients with dual chamber pacemakers.
The acute or chronic effect of VVI pacing on P wave duration in the same patient with dual chamber pacemaker has not been studied before. Hence, with the purpose of determining whether VVI pacing increases dispersion of atrial refractoriness, we undertook a comparative study with the aid of a simple noninvasive approach, namely P wave dispersion (PWD) determined from surface electrocardiogram in the same patients who were implanted with dual chamber pacemakers. Pmax duration calculated in VVI paced mode was significantly higher than in VDD paced mode (121+/-21 vs. 111+/-17 ms, P=0.021). PWD (33+/-15 vs. 40+/-23 ms, P=0.062) did not demonstrate any significant difference between VDD and VVI paced modes, respectively. In conclusion, the findings of our study suggest that short-term VVI pacing itself does not have any direct effect on PWD in patients with dual chamber pacemakers. Different pacing modes in the long term might be responsible for altering PWD and the occurrence of atrial fibrillation while affecting the autonomic nervous system.


The comparison of VEGFR-1-binding domain of VEGF-A with modelled VEGF-C sheds light on receptor specificity.
Receptor specificity determines the role of vascular endothelial growth factors (VEGFs), which either induce angiogenesis via VEGFR-1 and VEGFR-2 receptors or lymphangiogenesis via the VEGFR-3 receptor. Among the VEGFs, VEGF-A and VEGF-B predominantly induce angiogenesis while VEGF-C and VEGF-D induce lymphangiogenesis. The answer for the question of why VEGF-C and VEGF-D are not able to bind VEGFR-1 and behave as angiogenic growth factors may hide behind the details of the tertiary structures of these proteins. In the present study, the tertiary structure of human VEGF-C protein was modelled and the model was compared with the known human VEGF-A tertiary structure. In overall, the modelled structure highly resembled the structure of VEGF-A. The respective key residues that are involved in cysteine-knot motif formation in VEGF-A are similarly located and identically oriented in VEGF-C, indicating the presence of a VEGF-A-like homodimer. However, a VEGF-C homodimer created via monomer docking did not superimpose well with the VEGF-A homodimer. Rigid docking models of VEGF-C with the VEGFR-1 receptor revealed that in the VEGF-C-VEGFR-1 complex, the receptor-protein-interacting residues were not correctly oriented to induce angiogenesis via VEGFR-1. Mapping the electrostatic surface potentials to the protein surfaces revealed noteworthy number of dissimilarities between VEGF-A and VEGF-C, indicating that overall both proteins differ in their folding properties and stability.


Geriatrics, emergencies, and visible light-cured dentures.
This article will cover several aspects involved with the routine prosthodontic care of an elderly patient. One of these patients is ambulatory and the other institutionalized. The article will also cover emergency treatment rendered to a patient requiring unexpected care because of trauma.


Magnetic resonance imaging: controlled interstitial laser therapy in children with vascular malformations.
Interstitial laser therapy (ILT) is a minimally invasive treatment method for congenital vascular malformations (CVM). This study was intended to show whether or not open magnetic resonance imaging (MRI) offers a means of on-line thermometry and procedure control. ILT using a bare fiber and an Nd:YAG laser was applied in 20 children with CVM under open MR control. With the open MR systems, needle placement and advancement was excellent in all cases. On-line thermometry was possible in 90% of the therapy spots. The 6 week MR follow-up revealed a 76% reduction in tumor size in 14 patients. Clinical symptoms improved in 85% of the patients. MR-guided ILT could become a safe method to treat selected types or selected regions of CVM.


Patient involvement in decision-making in surgical and orthopaedic practice: the Project Perioperative Risk.
As part of the Project Perioperative Risk (PROPER), which is a clinical and epidemiological study of surgical complications, patient involvement in the decision to operate was evaluated by means of a questionnaire. The sample of 666 patients, on the waiting list for an operation, received a questionnaire on a broad range of issues concerning their involvement in the decision-making process one week before the operation. The results show that 41% regarded the decision to have an operation as a joint patient-doctor decision, in 29% of the cases the doctor advocated an operation and in 8% the patient asked to be operated. A clear majority, 73% felt involved in the decision-making as much as they wished. Two groups--women and immigrants from non-European countries--were least satisfied with their involvement and they also found the decision more difficult to make. In the discussion, it is argued that the comparatively high degree of patient satisfaction with involvement in the decision-making process cannot be taken as evidence of a high level of influence in an absolute sense. In a normative perspective--and considering the fact that the increased responsibility of the health sector is aimed at involving patients in decision-making in health matters--patient satisfaction can just as well be understood as resulting from low expectations with respect to one's own influence. The results also indicate that patient's information needs when facing surgery relate to three issues; possible complications, precise nature of the operation as such, and nature and consequences of anaesthetic procedures.


[Lymph node biopsy in the study of lymphomas: from the incisional biopsy to videolaparoscopic lymphadenectomy].
The role of the surgeon in the treatment of lymphoproliferative diseases is mainly addressed to histological diagnosis and staging. The aim of this study was to analyze the results of lymph node biopsies in patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma NHL). Between January 1992 and March 2003, 37 patients (17 males and 20 females, mean age 57 years, range 17-90) were submitted to a node biopsy to determine type of lymphoma and clinical staging: there were 8 HD and 29 NHL. In a single case laparoscopy was adopted to remove abdominal nodes; the procedure was uneventful and the patients discharged in the third postoperative day. The Authors stress the importance of the minimally invasive approach in the management of lymphoproliferative diseases.


[Analysis by reflection. A new method of observing human chromosomes].
When metaphase preparations of human cells are stained with Giemsa and submitted to epi-illumination with white light a brilliant yellow-green reflexion from the chromosomes is produced, quite comparable to fluorescence after acridine orange staining. Beside a remarkable stability of the image during repeated observations, this method yields excellent resolution.


Insights into non-symbiotic plant growth promotion bacteria associated with nodules of Sphaerophysa salsula growing in northwestern China.
In addition to rhizobia, other non-symbiotic endophytic bacteria also have been simultaneously isolated from the same root nodules. The existence of non-symbiotic endophytic bacteria in leguminous root nodules is a universal phenomenon. The vast majority of studies have detected endophytic bacteria in other plant tissues. In contrast, little systemic observation has been made on the non-symbiotic endophytic bacteria within leguminous root nodules. The present investigation was carried out to isolate plant growth-promoting endophytic non-symbiotic bacteria from indigenous leguminous Sphaerophysa salsula and their influence on plant growth. A total of 65 endophytic root nodule-associated bacteria were isolated from indigenous legume S. salsula growing in the northwestern arid regions of China. When combining our previous work with the current study, sequence analysis of the nifH gene revealed that the strain belonging to non-nodulating Bacillus pumilus Qtx-10 had genes similar to those of Rhizobium leguminosarum Qtx-10-1. The results indicated that horizontal gene transfer could have occurred between rhizobia and non-symbiotic endophyties. Under pot culture conditions, out of the 20 representative endophytic isolates, 15 with plant growth-promoting traits, such as IAA production, ACC deaminase, phosphate solubilization, chitinase, siderophore, and fungal inhibition activity showed plant growth-promoting activity with respect to various plant parameters such as chlorophyll content, fresh weight of plant, shoot length, nodule number per plant and average nodule weight per plant when co-inoculated with rhizobial bioinoculant Mesorhizobium sp. Zw-19 under N-free culture conditions. Among them, Bacillus pumilus Qtx-10 and Streptomyces bottropensis Gt-10 were excellent plant growth-promoting bacteria, which enhanced the seeding fresh weight by 87.5% and the shoot length by 89.4%, respectively. The number of nodules grew more than 31.89% under field conditions. Our findings indicate the frequent presence of these non-symbiotic endophytic bacteria within root nodules, and that they help to improve nodulation and nitrogen fixation in legume plants through synergistic interactions with rhizobia.


The effect of sodium meclofenamate in premenstrual asthma: a controlled clinical trial.
We speculated that changes in endogenous prostaglandin synthesis might be responsible for the syndrome of premenstrual asthma (worsening of asthma in relation to menstruation). To test our hypothesis, we compared the effects of sodium meclofenamate, a prostaglandin synthesis inhibitor, and placebo on premenstrual asthma in a 4-month, double-blind, crossover study of 17 women with asthma. Day-by-day evaluation revealed that peak expiratory flow reached a nadir during menstruation on both meclofenamate and placebo therapy and varied inversely with menstrual symptoms and asthma symptoms. Meclofenamate therapy resulted in significant improvement in peak expiratory flow during the early premenstrual period but had no treatment effect on the exacerbation of asthma during the late premenstrual period and early menstruation. The overall improvement in pulmonary function caused by meclofenamate therapy was correlated with the treatment effect on menstrual symptoms. Meclofenamate caused a small, nonsignificant decrease in use of theophylline and oral beta-agonist agents, whereas corticosteroid use increased slightly but not significantly. This study demonstrates the temporal relationship between menstrual symptoms and asthma. The study also demonstrates that inhibition of prostaglandin synthesis does not prevent exacerbation of asthma in relation to menstruation.


Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.
Mitochondrial dysfunction has been suggested to contribute to Parkinson's disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson's patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson's neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson's neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson's neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis.


Safety and efficacy of galantamine in subjects with mild cognitive impairment.
To assess the safety of galantamine in subjects with mild cognitive impairment (MCI), the ability of galantamine to benefit cognition and global functioning in subjects with MCI, and the ability of galantamine to delay conversion to dementia. In two studies, 2,048 subjects, 990 in Study 1 and 1,058 in Study 2, with a Clinical Dementia Rating (CDR) = 0.5, CDR memory score > or =0.5, without dementia were randomized to double-blind galantamine (16-24 mg/day) or placebo for 24 months. Primary efficacy endpoint at month 24 was number (%) of subjects who converted from MCI to dementia (CDR > or = 1.0). There were no differences between galantamine and placebo in 24-month conversion rates (Study 1: 22.9% [galantamine] vs 22.6% [placebo], p = 0.146; Study 2: 25.4% [galantamine] vs 31.2% [placebo], p = 0.619). Mean CDR-sum of boxes declined less with galantamine than placebo at 12 and 24 months in Study 1 (p = 0.024 [12 months] and p = 0.028 [24 months]), but not in Study 2 (p = 0.662 [12 months] and p = 0.056 [24 months]). Digit Symbol Substitution Test scores improved with galantamine in Study 1 at 12 months and in Study 2 at 24 months (Study 1: p = 0.009 [month 12] and p = 0.079 [Month 24]; Study 2: p = 0.154 [month 12] and p = 0.020 [month 24]). The most frequently reported adverse event was nausea (galantamine, 29%; placebo, 10%). Serious AEs occurred in 19% of each group. Mortality of the cohort after retrospectively determining the status of subjects (98.3%) at 24 months was 1.4% (galantamine) and 0.3% (placebo); RR (95% CI), 1.70 (1.00, 2.90). Galantamine failed to significantly influence conversion to dementia. Galantamine was generally well tolerated. Whereas recorded mortality was greater in the galantamine group than in the placebo group in the original per-protocol assessment, a post hoc analysis of the cohort was consistent with no increased risk.


Mucosal complications of modified osteo-odonto keratoprosthesis in chronic Stevens-Johnson syndrome.
To describe clinical outcomes of complications afflicting the autologous oral mucous membrane graft after modified osteo-odonto keratoprosthesis surgery in chronic Stevens-Johnson syndrome (SJS). Prospective case series. This study included 30 eyes of 30 patients with SJS-induced dry keratinized ocular surfaces; the patients underwent various stages of this procedure between August 2009 and February 2012. Mucosal complications were classified as either necrosis or overgrowth. Mucosal necrosis was managed according to a predesigned algorithm based on timing (pre- and postimplantation) and location (central or peripheral) of necrosis. Cases with mucosal overgrowth underwent mucosal debulking and trimming. Mucosal necrosis developed in 15 (50%) eyes and overgrowth in 4 (13.3%) eyes. Preimplantation necrosis (n = 7) was initially managed conservatively, but 2 eyes required free labial-mucous membrane grafting for persistent corneal exposure. Free labial-mucous membrane grafting was performed in all cases of postimplantation necrosis (n = 10), but 8 eyes required additional tarsal pedicle flaps (n = 6, for peripheral necrosis) or through-the-lid revisions (n = 2, for central necrosis). Debulking and trimming effectively managed all cases of mucosal overgrowth, but 3 eyes required repeat procedures. At 24.1 ± 6.5 months postimplantation, the keratoprosthesis was retained in all eyes, and the probability of maintaining 20/60 or better vision was similar in eyes with or without mucosal necrosis (86 ± 8.8% vs 80 ± 10.3%). Mucosal complications, especially necrosis, occurred commonly following modified osteo-odonto keratoprosthesis surgery in dry keratinized post-SJS eyes. The algorithm-based management approach described in this study was successful in treating these complications, retaining the prosthesis and preserving useful vision.


Time-resolved single-turnover of ba3 oxidase from Thermus thermophilus.
The kinetics of the oxidation of fully-reduced ba(3) cytochrome c oxidase from Thermus thermophilus by oxygen were followed by time-resolved optical spectroscopy and electrometry. Four catalytic intermediates were resolved during this reaction. The chemical nature and the spectral properties of three intermediates (compounds A, P and O) reproduce the general features of aa(3)-type oxidases. However the F intermediate in ba(3) oxidase has a spectrum identical to the P state. This indicates that the proton taken up during the P-->F transition does not reside in the binuclear site but is rather transferred to the covalently cross-linked tyrosine near that site. The total charge translocation associated with the F-->O transition in ba(3) oxidase is close to that observed during the F-->O transition in the aa(3) oxidases. However, the P(R)-->F transition is characterized by significantly lower charge translocation, which probably reflects the overall lower measured pumping efficiency during multiple turnovers.


Androgen receptor expression in ductal carcinoma in situ of the breast: relation to oestrogen and progesterone receptors.
Ductal carcinoma in situ (DCIS) of the breast has been diagnosed increasingly since the advent of mammographic screening. In contrast to the situation in invasive breast carcinoma, there are no reports on androgen receptor (AR) status in DCIS and few reports on oestrogen (ER) and progesterone (PR) receptors. AR expression was examined in 57 cases of DCIS of the breast and correlated to the degree of differentiation and ER/PR status using immunohistochemical methods. AR positivity was noted in 19 of the cases, whereas the other 38 cases were negative. There was no significant association between AR expression and the degree of differentiation of DCIS; three of the 13 well differentiated DCIS cases, 10 of the 19 intermediately differentiated cases, and six of the 25 poorly differentiated cases were positive (p = 0.093). However, a strong association was shown between the expression of ER (p < 0.0001) and PR (p = 0.002) and the degree of differentiation of DCIS. In addition, no significant association was found between the expression of AR and the expression of ER (p = 0.26) or PR (p = 0.57) in DCIS of the breast. A large number of cases of DCIS of the breast express AR and this may be associated with apocrine differentiation, which may impact on accurate typing of DCIS. Moreover, the expression of AR (but not ER or PR) in DCIS does not appear to be associated with the degree of differentiation.


Safety of High-Dose Vitamin D Supplementation: Secondary Analysis of a Randomized Controlled Trial.
More than 3% of adults report vitamin D intakes of 4000 IU/day or more, but the safety of this practice is unknown. The objective of this work is to establish whether vitamin D doses up to 10 000 IU/day are safe and well tolerated. The Calgary Vitamin D Study was a 3-year, double-blind, randomized controlled trial. A single-center study was conducted at the University of Calgary, Canada. Participants included healthy adults (n = 373) ages 55 to 70 years with serum 25-hydroxyvitamin D 30 to 125 nmol/L. Participants were randomly assigned 1:1:1 to vitamin D3 400, 4 000, or 10 000 IU/day. Calcium supplementation was initiated if dietary calcium intake was less than 1200 mg/day. In these prespecified secondary analyses, changes in serum 25-hydroxyvitamin D, calcium, creatinine, 24-hour urine calcium excretion, and incidence of adverse events were assessed. Between-group differences in adverse events were examined using incident rate differences and logistic regression. Of 373 participants (400: 124, 4000: 125, 10 000: 124), 49% were male, mean (SD) age was 64 (4) years, and 25-hydroxyvitamin D 78.0 (19.5) nmol/L. Serum calcium, creatinine, and 24-hour urine calcium excretion did not differ between treatments. Mild hypercalcemia (2.56-2.64 mmol/L) occurred in 15 (4%) participants (400: 0%, 4000: 3%, 10 000: 9%, P = .002); all cases resolved on repeat testing. Hypercalciuria occurred in 87 (23%) participants (400: 17%, 4000: 22%, 10 000: 31%, P = .01). Clinical adverse events were experienced by 365 (97.9%) participants and were balanced across treatment arms. The safety profile of vitamin D supplementation is similar for doses of 400, 4000, and 10 000 IU/day. Hypercalciuria was common and occurred more frequently with higher doses. Hypercalcemia occurred more frequently with higher doses but was rare, mild, and transient.


Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.
α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson's disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.


Effect of two new PBN-derived phosphorylated nitrones against postischaemic ventricular dysrhythmias.
Spin traps might exert antioxidant cardioprotective effects during myocardial ischaemia-reperfusion where free radicals are thought to be responsible for the occurrence of reperfusion injury. The aim of our study was to investigate the effects of two new alpha-phenyl N-tert-butylnitrone (PBN)-derived beta-phosphorylated nitrones: 2-N-oxy-N-[benzylidène amino] diéthyl propyl-2-phosphate (PPN) and 1-diethoxyphosphoryl-1-methyl-N-[(1-oxido-pyridin-1-ium-4-yl) methylidene] ethylamine N-oxide (4-PyOPN) compared with PBN on (1) the evolution of cardiovascular parameters and (2) the postischaemic recovery. Anaesthetized rats were injected with 120 micro mol/kg of the nitrones or 14 micro mol/kg of amiodarone, used as a reference antidysrhythmic drug. Ischaemia was induced in vivo through ligation of the left anterior descending coronary artery for 5 min followed by 15 min of reperfusion after release. Cardiovascular parameters and occurrence of ventricular premature beats (VPB), ventricular tachycardia (VT) and fibrillation (VF) were recorded throughout the experiment. Under nonischaemic conditions, none of the three spin traps was shown to modify cardiovascular parameters during the 25-min measurement period. Solvent-treated (NaCl 0.9%) animals challenged with ischaemia-reperfusion exhibited 39 +/- 10 VPB, 156 +/- 39 s of VT and 60% mortality caused by sustained VF. Nitrones improved slightly postischaemic recovery, reducing the occurrence of VF and mortality to 33% whereas amiodarone injection totally suppressed rhythm disturbances and mortality. Our study has shown only limited antidysrhythmic cardioprotective effects of PBN-derived beta-phosphorylated nitrones during reperfusion after a regional myocardial ischaemia but also minor antioxidant properties of these spin trapping agents.