PlantACT! - how to tackle the climate crisis.
Greenhouse gas (GHG) emissions have created a global climate crisis which requires immediate interventions to mitigate the negative effects on all aspects of life on this planet. As current agriculture and land use contributes up to 25% of total GHG emissions, plant scientists take center stage in finding possible solutions for a transition to sustainable agriculture and land use. In this article, the PlantACT! (Plants for climate ACTion!) initiative of plant scientists lays out a road map of how and in which areas plant scientists can contribute to finding immediate, mid-term, and long-term solutions, and what changes are necessary to implement these solutions at the personal, institutional, and funding levels.


Size-Dependent Thermal Stability and Optical Properties of Ultra-Small Nanodiamonds Synthesized under High Pressure.
Diamond properties down to the quantum-size region are still poorly understood. High-pressure high-temperature (HPHT) synthesis from chloroadamantane molecules allows precise control of nanodiamond size. Thermal stability and optical properties of nanodiamonds with sizes spanning range from <1 to 8 nm are investigated. It is shown that the existing hypothesis about enhanced thermal stability of nanodiamonds smaller than 2 nm is incorrect. The most striking feature in IR absorption of these samples is the appearance of an enhanced transmission band near the diamond Raman mode (1332 cm-1). Following the previously proposed explanation, we attribute this phenomenon to the Fano effect caused by resonance of the diamond Raman mode with continuum of conductive surface states. We assume that these surface states may be formed by reconstruction of broken bonds on the nanodiamond surfaces. This effect is also responsible for the observed asymmetry of Raman scattering peak. The mechanism of nanodiamond formation in HPHT synthesis is proposed, explaining peculiarities of their structure and properties.


Helping learners in difficulty--the incidence and effectiveness of remedial programmes of the Medical Radiation Sciences Programme at University of Toronto and the Michener Institute for Applied Sciences, Toronto, Ontario, Canada.
Academic difficulty can often be a significant problem for students in health professional programmes. Students in difficulty are often identified late in their training and run the risk of dismissal if remediation is not successful. Since the inception of the Medical Radiation Sciences Program (MRSP) at the University of Toronto, Faculty of Medicine, and the Michener Institute (MI) in 1999, a number of students have required remediation due to problems in the didactic or clinical component of their training. Not all remediation was successful, and a number of students have been dismissed. There is relatively sparse evidence in the educational literature regarding the nature of academic difficulties that health professional students encounter, and what constitutes appropriate remedial education. The purpose of this research was to evaluate the incidence and prevalence of remediation in the MRSP and the nature of the academic problems. In addition, this study looked at the type of remedial instruction that the Radiation Sciences Board of Examiners (BOE) recommended for these students as well as the effectiveness of these recommendations. This study consisted of a review of the academic records of students who failed one or more courses and underwent pre-clinical or clinical remediation, and who were presented at the Medical Radiation Sciences Board of Examiners at the University of Toronto between September 1999 and December 2004. Data extraction forms were developed to obtain demographic information, the nature of the academic problems, the remedial recommendation, and their outcomes. This study identified 69 students who were presented to the BOE 95 times. Forty-four students (44/69, 64%) were from the Radiation Therapy stream, 16 students (16/69, 23%) were from the Nuclear Medicine stream and 9 students (9/69, 13%) were from the Radiographic Technology stream. Most of the remediation occurred due to pre-clinical 50 (50/69, 72%), clinical 15 (15/69, 22%) and both preclinical and clinical problems 4 students (4/69, 6%). Out of 54 students who required pre-clinical remediation, 40 (74%) were promoted. Out of 19 students who required clinical remediation, 10 (10/19, 53%) passed their remediation. Six students (6/69, 9%) were dismissed from the programme due to unsuccessful remediation; 2 due to pre-clinical and 4 due to clinical problems. Based on these results, the remediation process at the MRSP was successful; however, 6 students (6/69, 9%) were dismissed from the programme during the last 4 years despite lengthy unsuccessful remediation. Our study provided an important perspective about the remediation process at the MRSP at the Michener Institute for Applied Health Sciences. Despite its retrospective methodology, it attempted to identify the magnitude of learning problems that lead to remediation, and identified the efficacy of the remedial programmes.


Magnetic and dielectric properties of Ca-substituted BiFeO3 nanoferrites by the sol-gel method.
A multiferroic material can simultaneously show two or more basic magnetic properties, including ferromagnetism, antiferromagnetism, and ferroelectricity. BiFeO3 is a multiferroic material with a rhombohedral distorted perovskite structure. Doping can reduce the volatility of Bi and greatly improve the magnetoelectric properties of BiFeO3. To investigate the influence of the doping content we used the following analytical methods: X-ray powder diffraction (XRD), scanning electron microscopy (SEM), microwave network analysis (PNA-N5244A), and the Superconducting Quantum Interference Device (Quantum Design MPMS) test. With the increase of Ca2+ concentration in the solution, the grain size of Bi1- xCa xFeO3 becomes smaller, showing the role of Ca2+ ions as the dopant for fine grains. The calcination temperatures are the major causes for the saturated magnetization. The residual magnetization ( Mr) and the coercive force ( Hc) decrease linearly with the increase of x value, and due to the effect of Ca2+ substitution at Bi3+ sites, which causes the valence change of Fe and/or the oxygen vacancies. The XRD result indicates that the diffraction peak emerges with the increase of Ca2+ and the main diffraction peak achieves a high angle. The best calcining temperature is 600 °C, and the morphology is very dependent on the calcining temperature.


Fat mass and obesity-associated gene polymorphisms, pre-diagnostic plasma adipokine levels and the risk of colorectal cancer: The Japan Public Health Center-based Prospective Study.
Although their functional outcomes remain largely unknown, single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated gene (FTO) may interact with adipokines, especially leptin and adiponectin, to modify the risk of colorectal cancer. We conducted a prospective study of 375 colorectal cancer cases and 750 matched controls to examine the effects of SNPs in the FTO, either alone or in interaction with pre-diagnostic plasma adipokine levels. Using a conditional logistic regression model, we obtained odds ratios (ORs) and their 95% confidence intervals (CIs) of colorectal cancer. Seven SNPs in strong linkage disequilibrium demonstrated a similarly positive association with colorectal cancer, and most evidently for rs1558902, rs8050136, rs3751812, and rs9939609 (Ptrend = 0.02). Of interest, we observed a statistically significant interaction of rs8050136 with plasma total adiponectin levels (Pinteraction = 0.03). Compared to non-carriers in the lowest quintile of plasma total adiponectin, A allele carriers in the same quintile showed a considerably elevated risk of colorectal cancer, with a body mass index-adjusted OR of 2.54 (95% CI, 1.36-4.75). This investigation of the interaction between SNPs in the FTO and pre-diagnostic plasma adipokine levels has revealed the importance of both genetic and hormonal factors associated with adiposity in colorectal carcinogenesis.


Extraction, separation and kinetics of phenylethanosides from Plantago asiatica L. by an innovative extraction technology-deep eutectic solvent-based ultrasound-assisted extraction.
In this paper, the total phenylethanosides (TPS) were extracted efficiently by an innovative extraction technology--deep eutectic solvent-based ultrasound-assisted extraction (DES-UAE) from Plantago asiatica L. Ten diverse types of DESs were synthesized as alternative extraction solutions. The extraction efficiency of DES-3 (constituted by choline chloride and lactic acid) was much higher than those of other DESs. On the basis of single factor tests and Box-Behnken design (BBD), the optimum processing parameters of DES-UAE as follow: DES-3 with molar ratio of 1:3, extraction temperature 51 °C, solid/liquid 22.5 mg/ml, water content 30%, ultrasonic power 65 W, extraction time 23 min. The extraction efficiency of TPS from Plantago asiatica L. was 8.395 mg/ml, which was more superior than those of organic solvents (water, methanol, 50% methanol, ethanol, 50% ethanol). The extraction kinetics experiment results showed that water content had a significant influence upon the extraction efficiency of TPS. At the same time, AB-8 macroporous resin column was used to efficiently isolate TPS from DES extraction with a recovery rate of 88.5%.


Multifunctional chemical inhibitors of the florigen activation complex discovered by structure-based high-throughput screening.
Structure-based high-throughput screening of chemical compounds that target protein-protein interactions (PPIs) is a promising technology for gaining insight into how plant development is regulated, leading to many potential agricultural applications. At present, there are no examples of using high-throughput screening to identify chemicals that target plant transcriptional complexes, some of which are responsible for regulating multiple physiological functions. Florigen, a protein encoded by FLOWERING LOCUS T (FT), was initially identified as a molecule that promotes flowering and has since been shown to regulate flowering and other developmental phenomena such as tuber formation in potato (Solanum tuberosum). FT functions as a component of the florigen activation complex (FAC) with a 14-3-3 scaffold protein and FD, a bZIP transcription factor that activates downstream gene expression. Although 14-3-3 is an important component of FAC, little is known about the function of the 14-3-3 protein itself. Here, we report the results of a high-throughput in vitro fluorescence resonance energy transfer (FRET) screening of chemical libraries that enabled us to identify small molecules capable of inhibiting FAC formation. These molecules abrogate the in vitro interaction between the 14-3-3 protein and the OsFD1 peptide, a rice (Oryza sativa) FD, by directly binding to the 14-3-3 protein. Treatment with S4, a specific hit molecule, strongly inhibited FAC activity and flowering in duckweed, tuber formation in potato, and branching in rice in a dose-dependent manner. Our results demonstrate that the high-throughput screening approach based on the three-dimensional structure of PPIs is suitable in plants. In this study, we have proposed good candidate compounds for future modification to obtain inhibitors of florigen-dependent processes through inhibition of FAC formation.


Identification of AIDS-Associated Kaposi Sarcoma: A Functional Genomics Approach.
Kaposi sarcoma-associated herpes virus (KSHV) is one of the most common causal agents of Kaposi Sarcoma (KS) in individuals with HIV-infections. The virus has gained attention over the past few decades due to its remarkable pathogenic mechanisms. A group of genes, ORF71, ORF72, and ORF73, are expressed as polycistronic mRNAs and the functions of ORF71 and ORF72 in KSHV are already reported in the literature. However, the function of ORF73 has remained a mystery. The aim of this study is to conduct comprehensive exploratory experiments to clarify the role of ORF73 in KSHV pathology and discover markers of AIDS-associated KSHV-induced KS by bioinformatic approaches. We searched for homologues of ORF-73 and attempted to predict protein-protein interactions (PPI) based on GeneCards and UniProtKB, utilizing Position-Specific Iterated BLAST (PSI-BLAST). We applied Gene Ontology (GO) and KEGG pathway analyses to identify highly conserved regions between ORF-73 and p53to help us identify potential markers with predominant hits and interactions in the KEGG pathway associated with host apoptosis and cell arrest. The protein p53 is selected because it is an important tumor suppressor antigen. To identify the potential roles of the candidate markers at the molecular level, we used PSIPRED keeping the conserved domains as the major parameters to predict secondary structures. We based the FUGE interpretation consolidations of the sequence-structure comparisons on distance homology, where the score for the amino acids matching the insertion/deletion (indels) detected were based on structures compared to the FUGE database of structural profiles. We also calculated the compatibility scores of sequence alignments accordingly. Based on the PSI-BLAST homologues, we checked the disordered structures predicted using PSI-Pred and DISO-Pred for developing a hidden Markov model (HMM). We further applied these HMMs models based on the alignment of constructed 3D models between the known structure and the HMM of our sequence. Moreover, stable homology and structurally conserved domains confirmed that ORF-73 maybe an important prognostic marker for AIDS-associated KS. Collectively, similar variants of ORF-73 markers involved in the immune response may interact with targeted host proteins as predicted by our computational analysis. This work also suggests the existence of potential conformational changes that need to be further explored to help elucidate the role of immune signaling during KS towards the development of therapeutic applications.


Effect of intrathecal octreotide on thermal hyperalgesia and evoked spinal c-Fos expression in rats with sciatic constriction injury.
This study was designed to determine whether intrathecal octreotide (sandostatin), a synthetic octapeptide derivative of somatostatin, relieved thermal hyperalgesia and reduced the evoked spinal c-Fos expression in rats with chronic constriction injury (CCI) of the sciatic nerve. Intrathecal catheters were implanted in rats 7 days before CCI of the sciatic nerve over the left hind limb. After confirmation of the development of thermal hyperalgesia by decreased paw withdrawal latencies (PWL) to heat stimulation 7 days after CCI, intrathecal sandostatin at 20, 40, and 80 microg was administered, respectively. Rats in the control group received saline injections intrathecally. PWLs were evaluated at 30, 60, 120, 180, and 240 min after drug administration. Detection of Fos-like immunoreactivity (Fos-LI) neurons in the dorsal horn of the spinal cord following drug administration was performed after mechanical stimulation (stroking of the hind paws) on the 14th day after CCI. The reduction of PWL was attenuated significantly in the groups that received intrathecal sandostatin at 20, 40, and 80 g when compared with the saline group. However, PWL did not return to pre-CCI values in all groups. In the 40 microg group, PWL returned up to 76% of pre-CCI values 120 min after drug administration. Stroking of the hind paw in CCI-treated (ipsilateral) limbs induced a significantly greater expression of spinal Fos-LI neurons than that of non-CCI treated (contralateral) limbs in each group. The number of Fos-LI neurons in animals receiving intrathecal sandostatin was dose-dependently reduced. Expression of Fos-LI neurons in the 80 microg group was nearly completely inhibited. These data suggest that intrathecal sandostatin significantly relieved thermal hyperalgesia behaviorally but with limited effects and dose-dependently reduced spinal Fos-LI neurons expression evoked by stroking stimulation, which may reflect mechanical allodynia in rats with sciatic constriction injury. This implies that intrathecal sandostatin was effective in the treatment of neuropathic pain.


How can we maximize skills for non-variceal upper gastrointestinal bleeding: injection, clipping, burning, or others?
Endoscopy has its role in the primary diagnosis and management of acute non-variceal upper gastrointestinal bleeding. Main roles of endoscopy are identifying high risk stigmata lesion, and performing endoscopic hemostasis to lower the rebleeding and mortality risks. Early endoscopy within the first 24 hours enables risk classification according to clinical and endoscopic criteria, which guide safe and prompt discharge of low risk patients, and improve outcomes of high risk patients. Techniques including injection therapy, ablative therapy and mechanical therapy have been studied over the recent decades. Combined treatment is more effective than injection treatment, and single treatment with mechanical or thermal method is safe and effective in peptic ulcer bleeding. Specific treatment and correct decisions are needed in various situations depending on the site, location, specific characteristics of lesion and patient's clinical conditions.


Psychomotor slowing in schizophrenia.
Psychomotor slowing (PS) is a cluster of symptoms that was already recognized in schizophrenia by its earliest investigators. Nevertheless, few studies have been dedicated to the clarification of the nature and the role of the phenomenon in this illness. Moreover, slowed psychomotor functioning is often not clearly delineated from reduced processing speed. The current, first review of all existing literature on the subject discusses the key findings. Firstly, PS is a clinically observable feature that is most frequently established by neuropsychological measures assessing speed of fine movements such as writing or tasks that require rapid fingertip manipulations or the maintenance of maximal speed over brief periods of time in manual activities. Moreover, the slowed performance on the various psychomotor measures has been demonstrated independent of medication and has also been found to be associated with negative symptoms and, to a lesser extent, with positive and depressive symptoms. Importantly, performance on the psychomotor tasks proved related to the patients' social, clinical, and functional outcomes. Several imaging studies showed slowed performance to coincide with dopaminergic striatal activity. Finally, conventional neuroleptics do not improve the patients' PS symptoms, in contrast to the atypical agents that do seem to produce modestly improving effects.


[Analysis of disease-causing gene mutation in three Chinese families with congenital inherited cataract].
To identify the disease-causing gene mutations in three Chinese pedigrees affected with congenital inherited cataract, in ordre to provide genetic counseling and prenatal diagnosis. Using exons combined target region capture sequencing chip to screen the candidate disease-causing mutations, Sanger sequencing was used to confirm the disease-causing mutations. Family 1 was polymorphic cataract, family 2 was cerulean cataract, family 3 was coralliform cataract. The inheritance mode of the three pedigrees consisted with autosomal dominant inheritance. In family 1, a nonsense mutation of CRYβB2 gene c.463C>T in exon 6 result in a p.Q155X amino acid change. In family 2, a missense mutation of of CRYGD gene c.43C>T in exon 2 result in a p.R14C amino acid change. In family 3, a missense mutation of CRYGD gene c.70C>A in exon 2 result in a p.P23T amino aid change. No above-mentioned mutations were found in normal individuals. The nonsense mutation c.463C>T (p.Q155X) of CRYβB2 gene, the heterozygous mutations c.43C>T(p.R14C) of CRYGD gene and c.70C>A( p.P23T) of CRYGD gene was the disease-causing gene mutation in family 1, 2 and 3 respectively, our results provid genetic counseling and prenatal diagnosis for these three families.


Genome-Wide Association Studies of Virulent and Avirulent Haemophilus parasuis Serotype 4 Strains.
Haemophilus parasuis is a normal commensal of the upper respiratory tract of healthy pigs. However, in conjunction with stress and/or viral infections, or in immunocompromised animals, H. parasuis can transform into a pathogen causing Glasser's disease, which is typically characterized by fibrinous polyserositis, polyarthritis, meningitis, and sometimes acute pneumonia and septicemia. H. parasuis serotype 5 is highly virulent and more frequently isolated from respiratory and systemic infection in pigs. Recently Newport Laboratories isolated highly virulent H. parasuis serotype 4 strains from the tissues of diseased pigs. This study was undertaken to identify the genes responsible for H. parasuis serotype 4 virulence. To achieve this objective we performed genome-wide association studies (GWAS) across two virulent and three avirulent H. parasuis serotype 4 strains.


Dynamic evaluation of a trilobal capillary-channeled polymer fiber shape for reversed phase protein separations and comparison to the eight-channeled form.
A new, trilobal-shaped capillary-channeled polymer fiber is under development to address the issues of poor A-term performance of the previous eight-channeled form. The trilobal geometry should provide better packing homogeneity due to the fewer potential orientations of the symmetric fiber geometry. Comparisons of separation efficiency and peak shape were made between the two fiber shapes through several dynamic parameters. Column hydrodynamics were investigated with two marker compounds, uracil and bovine serum albumin, with van Deemter plots of those two compounds revealing differences in the packing qualities between the different fiber shapes. Parametric fitting to the van Deemter, Knox, and Giddings equations provides insights into the column physical structures. Separation quality for both shapes was evaluated across differences in fiber packing density, gradient rate, and mobile phase linear velocity for the reversed phase separation of a four protein mixture, containing ribonuclease A, cytochrome c, lysozyme, and myoglobin. The results of this study lay the ground work for future efforts in the use of trilobal fibers for the separation of biomacromolecules.


A Case of Laying Hens Mycosis Caused by Fusarium proliferatum.
In this article, we present the first case report of a chicken mycosis caused by F. proliferatum occurred on a private farm in the Russian Federation. Lesions on the skin of the legs and scallops were reported. The object of this study was samples of feed and pathological material from sick hens-layers. Mycological analysis included determination of the total number of fungi (TNF) and identification and determination of the toxicity and pathogenicity of the isolates. The identification of the isolate was carried out taking into account direct microscopy, morphological features, and the method of molecular genetic analysis. Microscopic fungi of the genus Penicillium and Rhizopus were isolated by mycological analysis of the feed. The test feed was nontoxic. Mycological examination of pathological material (scrapings from the combs and affected legs) identified an isolate of Fusarium proliferatum, which showed toxicity on biological objects (protozoa, rabbits) and pathogenicity (white mice). Dermal application of F. proliferatum suspension was accompanied by reddening of the rabbit skin. Intraperitoneal injection of fungal spores caused mycosis in white mice. Polymerase chain reaction (PCR) made it possible to identify this type of microscopic fungus (F. proliferatum) with high accuracy in the samples under study. The research results allow us to consider F. proliferatum as a cause of poultry disease against the background of predisposing factors in the form of desquamation of the stratum corneum of the skin against the background of immunosuppression and metabolic disorders caused by an imbalance in the diet.


[Diagnostic value of the EEG. Neurologic diagnosis today].
The principal fields of application of the EEG are 1) the identification of transient functional disturbances - especially in cerebral seizures - which cannot always be reliably observed clinically, 2) the tracing of concomitant signs of substantial lesions which in the silent areas are not necessarily associated with isolated neurological defects and 3) the determination of the degree of severity of abnormalities when they do not agree with neurological or psychic disturbances. The discrepancies of the clinical findings themselves sometimes demand attention and benefit the patient when they lead to the identification of disturbances which could not at first be recognized. Selective indications, planned interrogation and thorough correlations with the clinical examinations and other findings are decisive for the value of the EEG in detail.


Tailoring Synthetic Melanin Nanoparticles for Enhanced Photothermal Therapy.
Melanin and its synthetic analogs (i.e., polydopamine nanomaterials) are able to transform a near-infrared (NIR) light energy source to heat for the selective killing of cancer cells. Although many of the effects on these nontoxic photothermal agents have been well documented, a concern has arisen that the extended usage of these natural and synthetic melanins might be hindered by their limited photothermal effects under low-density light irradiation. To address this issue, herein, we propose a rational and green fabrication strategy toward a new class of synthetic melanin nanoparticles (SMNPs) with superior photothermal effects via the one-pot copolymerization of two kinds of naturally occurring monomers (arginine and dopamine). The total photothermal efficiencies of these arginine-doped SMNPs could be significantly improved (i.e., ∼60% increase) by enhancing 808 nm NIR light absorption via the construction of donor-acceptor microstructures within SMNPs and decreasing nonthermal radiative transition processes via the increase of free radical concentrations within SMNPs. The resulting SMNPs demonstrated higher photothermal therapy efficiencies in both killing 4T1 cancer cells in vitro and suppressing tumor growth and recurrence compared with conventional agents. This work offers new opportunities in the structural and functional tailoring of melanin-inspired nanomaterials for cancer treatment via green fabrication strategies.


Supplemental Trichomonas vaginalis testing is required to maintain control following a transition from Pap smear to HPV DNA testing for cervical screening: a mathematical modelling study.
Using mathematical modelling, we have previously shown that the prevalence of infection with Trichomonas vaginalis (TV) is likely to increase in the general population in Australia with the transition from Pap smear-based cervical screening to human papillomavirus (HPV) DNA testing. Here we use the existing model to estimate the level of supplemental testing required to maintain TV control. A compartmental mathematical model describing the transmission of TV in the general heterosexual population in Australia was used to evaluate the impact of a range of screening scenarios on TV prevalence over time following the transition to HPV DNA testing for cervical screening. Scenarios considered were the inclusion of a TV test with the HPV test and the addition of TV testing to routine chlamydia testing conducted in primary care. Our modelling suggests that with sufficient coverage, inclusion of TV testing with routine chlamydia screening in general practice, TV prevalence can be reduced over time, but at the current reported coverage will gradually increase following the transition to HPV testing. Inclusion of TV testing with HPV testing in the cervical screening programme is preferable to no supplemental testing but is considerably less effective in controlling TV. These findings support the inclusion of TV testing with routine chlamydia testing of young people.


[Trends of vegetables and fruits consumption among Chinese adults aged 18 to 44 years old from 1991 to 2011].
To identify the trends of vegetables and fruits consumption among Chinese adults aged 18 to 44 years old from 1991 to 2011. Twenty four hour dietary recall data from China Health and Nutrition Survey (1991, 1993, 1997, 2000, 2004, 2006, 2009 and 2011) were used to identify the trends of vegetables and fruits consumption among Chinese between 18 and 44 years old. From 1991 to 2011, the proportion of daily consumption of vegetables rarely varied, while the vegetables intake declined significantly; and the proportion of daily consumption and intake of fruits kept increasing as follows. By 2011, the proportion of daily consumption and intake of vegetables and fruits among the respondents were 99.7%, 48.0%, 321.6 g/d, and 90.1 g/d respectively. A significant drop was found in the vegetables intake among the respondents against the vegetables intake as recommended by the Chinese dietary guidelines, up to 50.2% in 2011; a significant rise was found in the fruits intake of the respondents against the fruits intake as recommended by the said guidelines, up to 17.4% in 2011. The average daily intake of vegetables and fruits of young and middle-aged residents (18-44 age group) in nine provinces in China was found lower than that recommended in the Chinese dietary guidelines; in view of the high proportion of people having less vegetables and fruits intake that those recommended by the Chinese dietary guidelines, further measures are expected to encourage their vegetables and fruits intake.


[Does cancer preventive care on the cervix need to be reformed? Gynecological preventive care and early diagnosis--current knowledge on cervix neoplasms].
A comparative study shows high incidence of preclinical cancerous lesions of the uterine cervix in women under thirty years of age. The rate of positive cytology in this age group was the same as in the group of women over thirty (0.3 per cent each). The histological findings revealed intraepithelial lesions like dysplasia and carcinoma in situ in the younger group compared to more advanced lesions like microinvasive cancer in the higher-aged group. The use of colposcopy rendered optical evidence--predominantly in the younger group--of lesions which under long-term observation preceded positive cytology for years as well as the consequent histological proof of dysplasia and preclinical carcinoma. As a result of the given and discussed clinical data in both compared age groups the value of colposcopy is stressed in improving the quality of detection of preclinical neoplasia in the uterine cervix and the necessity of cancer-screening in younger-aged women is emphasized.


A blueprint for electronic utilization of ambiguous molecular HLA typing data in organ allocation systems and virtual crossmatch.
Virtual crossmatch (VXM) compares a transplant candidate's unacceptable antigens to the HLA typing of the donor before an organ offer is accepted and, in selected cases, supplant a prospective physical crossmatch. However, deceased donor typing can be ambiguous, leading to uncertainty in compatibility prediction. We have developed a prototype web application that utilizes ambiguous HLA molecular typing data to predict which unacceptable antigens are present in the donor HLA genotype as donor-specific antibodies (DSA). The application compares a candidate's listed unacceptable antigens to computed probabilities of all possible two-field donor HLA alleles and UNOS antigens. The VIrtual CrossmaTch for mOleculaR HLA typing (VICTOR) tool can be accessed at http://www.transplanttoolbox.org/victor. We reanalyzed historical VXM cases where a transplant center's manual interpretation of molecular typing results influenced offer evaluation. We found that interpretation of ambiguous donor molecular typing data using imputation could one day influence VXM decisions if the DSA predictions were rigorously validated. Standardized interpretation of molecular typing data, if applied to the match run, could also change which offers are made. HLA typing ambiguity has been an underappreciated source of immunological risk in organ transplantation. The VICTOR tool can serve as a testbed for development of allocation policies with the aim of decreasing offers refused due to HLA incompatibility.


Absorbable Plate-Related Infection after Facial Bone Fracture Reduction.
Absorbable plates are used widely for fixation of facial bone fractures. Compared to conventional titanium plating systems, absorbable plates have many favorable traits. They are not palpable after plate absorption, which obviates the need for plate removal. Absorbable plate-related infections are relatively uncommon at less than 5% of patients undergoing fixation of facial bone fractures. The plates are made from a mixture of poly-L-lactic acid and poly-DL-lactic acid or poly-DL-lactic acid and polyglycolic acid, and the ratio of these biodegradable polymers is used to control the longevity of the plates. Degradation rate of absorbable plate is closely related to the chance of infection. Low degradation is associated with increased accumulation of plate debris, which in turn can increase the chance of infection. Predisposing factors for absorbable plate-related infection include the presence of maxillary sinusitis, plate proximity to incision site, and use of tobacco and significant amount of alcohol. Using short screws in fixating maxillary fracture accompanied maxillary sinusitis will increase the rate of infection. Avoiding fixating plates near the incision site will also minimize infection. Close observation until complete absorption of the plate is crucial, especially those who are smokers or heavy alcoholics. The management of plate infection is varied depending on the clinical situation. Severe infections require plate removal. Wound culture and radiologic exam are essential in treatment planning.


Sleep and multisystem biological risk: a population-based study.
Short sleep and poor sleep quality are associated with risk of cardiovascular disease, diabetes, cancer, and mortality. This study examines the contribution of sleep duration and sleep quality on a multisystem biological risk index that is known to be associated with morbidity and mortality. Analyses include a population-based sample from the Midlife Development in the United States survey recruited to the Biomarker substudy. A total of 1,023 participants aged 54.5 years (SD = 11.8), 56% female and 77.6% white, were included in the analyses. A multisystem biological risk index was derived from 22 biomarkers capturing cardiovascular, immune, lipid-metabolic, glucose-metabolic, sympathetic, parasympathetic, and hypothalamic-pituitary-adrenal systems. Self-reported average sleep duration was categorized as short (<5 hrs), below normal (5 to <6.5 hrs), normal (6.5 to <8.5 hrs), and long sleepers (8.5+ hrs). Sleep quality was determined using the Pittsburgh Sleep Quality Index categorized as normal (≤5) and poor quality (>5) sleep. Linear mixed effect models adjusting for age, gender, race, education, income, BMI, and health status were performed. As compared to normal sleepers, multisystem biological risk in both short (B(SE) = .38(.15), p<.01) and long sleepers (B(SE) = .28(.11), p<.01) were elevated. Poor quality sleep alone was associated with elevated multisystem biological risk (B(SE) = .15(.06), p = .01), but was not significant after adjustment for health status. All short sleepers reported poor sleep quality. However in the long sleepers, only those who reported poor sleep quality exhibited elevated multisystem biological risk (B(SE) = .93(.3), p = .002). Self-reported poor sleep quality with either short or long sleep duration is associated with dysregulation in physiological set points across regulatory systems, leading to elevated multisystem biological risk. Physicians should inquire about sleep health in the assessment of lifestyle factors related to disease risk, with evidence that healthy sleep is associated with lower multisystem biological risk.


Efficacy of teicoplanin as antimicrobial treatment of severe nosocomial infections caused by gram-positive bacteria: a preliminary study.
We used single daily intravenous teicoplanin as therapy for 12 severe nosocomial infections caused by gram-positive bacteria. A daily dosage of 3-6 mg/kg was usually adopted; however, in selected cases the dosage was increased to 8-9.5 mg/day on the basis of serum bactericidal monitoring. Most of these infections were life-threatening and included ventriculitis/meningitis (3 cases), sepsis (3 cases), mediastinitis (1 case) and extensive burn wound infection (1 case). Staphylococcus aureus was by far the most frequent pathogen and methicillin-resistant strains were isolated in 7 out of 9 infections caused by this organism. The remaining isolates were Staphylococcus epidermidis, JK Corynebacterium, Streptococcus agalactiae and Propionilbacterium acnes. Additional antibiotics were used in 5 cases for concomitant gram-negative bacillus etiology (2 cases), granulocytopenia (2 cases), superinfection (1 case). Overall a clinical success and microbial eradication were documented in 100% and 91% of 12 cases, respectively. Except one case of fever, no other major adverse effect was observed and no patient required trial therapy discontinuation. In conclusion, our preliminary data seem to suggest a satisfactory activity of teicoplanin against nosocomial gram-positive infections.


Breast myeloid sarcoma after allogeneic stem cell transplantation for acute myelomonocytic leukemia - case report.
Defined as a rare extramedullary tumor, myeloid sarcoma (MS) is in the attention of specialists, although the information in the literature is represented especially through case reports. MS can precede acute myeloid leukemia (AML), appear simultaneous and can be the only manifestation of leukemia relapse after allogeneic stem cell transplantation (allo-SCT). We present the case of a 30-year-old female diagnosed with acute myelomonocytic leukemia (AML M4), with complete remission (CR) after chemotherapy, followed by allo-SCT for consolidation. After five months, the patient presented right breast tumors. Ultrasound-guided biopsy of the breast lesion displayed diffuse infiltration of undifferentiated tumor cells, with blastic granulocytic features, strongly immunopositive for cluster of differentiation (CD) 45, CD99, CD34 and myeloperoxidase (MPO) and negative for all epithelial markers [MNF116, cytokeratin 7 (CK7), estrogen receptor (ER), progesterone receptor (PR), E-cadherin]. The final diagnosis was AML relapse with breast MS. After multiple leukemia relapses with breast MS, the patient died with cerebral bleeding secondary to severe thrombocytopenia.


Functional constipation in patients with hemorrhoids: a systematic review and meta-analysis.
Hemorrhoids are common anorectal pathology, with high recurrence rates after surgical treatment. It is hypothesized that high straining forces during paradoxical contractions and inadequate relaxation are causally related to hemorrhoids. This review aimed to assess the coprevalence of functional constipation and dyssynergic defecation in a population with hemorrhoids. Moreover, the effects of rubber band ligation (RBL) were analyzed. Sources included Pubmed, Embase and CENTRAL . Randomized trials, cohort and case-control studies that investigated the prevalence of constipation in patients with hemorrhoids or the prevalence of hemorrhoids in patients with constipation compared to healthy subjects were included. Manometric studies were also eligible. Quality assessment was performed by using the Newcastle Ottawa Quality Assessment Scale. The primary outcome was the prevalence of functional constipation or dyssynergic defecation in patients with hemorrhoids. Nineteen studies were included. Prevalence of constipation was significantly higher in patients with hemorrhoids compared to controls [OR (odds ratio), 2.09; 95% CI (confidence interval), 1.27-3.44]. No significant difference in the prevalence of hemorrhoids between patients with constipation compared to controls was found (OR, 2.37; 95% CI, 0.67-8.44). Anal pressures in patients with hemorrhoids were significantly higher compared to healthy controls in all manometric studies. After RBL, these pressures remained significantly higher in patients with hemorrhoids ( P = 0.001). Functional constipation, dyssynergic defecation and higher basal anal pressures are more prevalent in patients with hemorrhoids compared to controls. Improvement of therapy for functional constipation, especially dyssynergic defecation patterns, might lead to better long-term outcomes and reduce recurrence.


Integration of the Metabolomic and Transcriptome Analysis Reveals the Remarkable Compounds of G. bicolor Young and Mature Leaves under Different Iron Nutrient Conditions.
Gynura bicolor (Roxb. ex Willd.) DC. (G. bicolor) is a functional vegetable rich in iron (Fe) and widely grown in Asia (e.g., Japan and China). Because most Fe in the soil exists in the form of insoluble oxides or hydroxides, it is difficult for plants to obtain Fe from the soil. A comparative metabolomic and transcriptome study was carried out to investigate the effect of Fe deficiency on metabolite synthesis and gene expression in young and mature leaves of G. bicolor. Fe deficiency caused chlorosis and decreased the chlorophyll content in young leaves. The metabolomic results for young leaves showed that l-glutamate and 4-hydroxybutanoic acid lactone significantly increased and decreased, respectively. The transcriptome results showed that the expression levels of genes involved in ferric reduction oxidase 7 and 14-kDa proline-rich protein DC2.15-like were significantly upregulated and downregulated, respectively. However, Fe deficiency had little effect on mature leaves.


Genetics of behavioural evolution in giant mice from Gough Island.
The evolution of behaviour on islands is a pervasive phenomenon that contributed to Darwin's theory of natural selection. Island populations frequently show increased boldness and exploration compared with their mainland counterparts. Despite the generality of this pattern, the genetic basis of island-associated behaviours remains a mystery. To address this gap in knowledge, we genetically dissected behaviour in 613 F2s generated by crossing inbred mouse strains from Gough Island (where they live without predators or human commensals) and a mainland conspecific. We used open field and light/dark box tests to measure seven behaviours related to boldness and exploration in juveniles and adults. Across all assays, we identified a total of 41 quantitative trait loci (QTL) influencing boldness and exploration. QTL have moderate effects and are often unique to specific behaviours or ages. Function-valued trait mapping revealed changes in estimated effects of QTL during assays, providing a rare dynamic window into the genetics of behaviour often missed by standard approaches. The genomic locations of QTL are distinct from those found in laboratory strains of mice, indicating different genetic paths to the evolution of similar behaviours. We combine our mapping results with extensive phenotypic and genetic information available for laboratory mice to nominate candidate genes for the evolution of behaviour on islands.


Glutamate release by an Na+ load and oxidative stress in nerve terminals: relevance to ischemia/reperfusion.
Previously we have reported that oxidative stress induced by hydrogen peroxide exacerbates the effect of an Na+ load in isolated nerve terminals, with a consequence of an ATP depletion, [Ca2+]i and [Na+]i deregulation, and collapse of mitochondrial membrane potential. In the present study, the release of glutamate in response to a combined effect of an [Na+] load and oxidative stress was measured in isolated nerve terminals over an incubation for 15 min. Exposure to hydrogen peroxide (100 micro m) had no effect on the release of glutamate, but significantly enhanced the Ca2+-independent glutamate release induced by a small [Na+] load achieved with 10 micro m veratridine. The effect of a larger Na+ load induced by 40 micro m veratridine was not further increased by hydrogen peroxide; in contrast the external Ca2+-dependent glutamate release was completely eliminated by the oxidant under this condition. The effects of oxidative stress superimposed on a Na+ load are consistent with at least two factors: (i) a relatively modest Na+ load induced by veratridine is augmented by H2O2 giving rise to an increased Ca2+-independent release of glutamate (ii) oxidative stress in combination with a larger Na+ load causes severe ATP depletion limiting the Ca2+-dependent vesicular glutamate release. Given the concurrent presence of an Na+ load and oxidative stress in ischemia/reperfusion these results indicate that the extent of the Na+ load developing during the ischemic period could determine the release of glutamate induced by an oxidative stress during reperfusion.


Endometrial CRISP3 is regulated throughout the mouse estrous and human menstrual cycle and facilitates adhesion and proliferation of endometrial epithelial cells.
The endometrium (the mucosal lining of the uterus) is a dynamic tissue that undergoes extensive remodeling, secretory transformation in preparation for implantation of an embryo, inflammatory and proteolytic activity during menstruation, and rapid postmenstrual repair. A plethora of local factors influence these processes. Recently, a cysteine-rich protein, CRISP3, a clade of the CRISP, antigen 5, pathogenesis-related (CAP) protein superfamily, has been implicated in uterine function. The localization, regulation, and potential function of CRISP3 in both the human and mouse endometrium is described. CRISP3 localizes to the luminal and glandular epithelium of the endometrium within both species, with increased immunoreactivity during the proliferative phase of the human cycle. CRISP3 also localizes to neutrophils, particularly within the premenstrual human endometrium and during the postbreakdown repair phase of a mouse model of endometrial breakdown and repair. Endometrial CRISP3 is produced by primary human endometrial epithelial cells and secreted in vivo to accumulate in the uterine cavity. Secreted CRISP3 is more abundant in uterine lavage fluid during the proliferative phase of the menstrual cycle. Human endometrial epithelial CRISP3 is present in both a glycosylated and a nonglycosylated form in vitro and in vivo. Treatment of endometrial epithelial cells in vitro with recombinant CRISP3 enhances both adhesion and proliferation. These data suggest roles for epithelial and neutrophil-derived CRISP3 in postmenstrual endometrial repair and regeneration.


Intravascular ultrasound and drug-eluting stents. Where are we now?
Drug-eluting stents (DES) have revolutionized interventional cardiology. The profound ability of DES to suppress neointimal hyperplasia results in a reduced need for revascularization and improved clinical outcomes. DES, however, are not immune to in-stent restenosis. This problem particularly affects DES implanted for "off-label" indications and in challenging clinical and anatomic scenarios. In addition, as compared to bare-metal stents, DES do not reduce the incidence of stent thrombosis. Therefore, optimization of DES deployment is becoming increasingly important and, in this regard, intravascular ultrasound (IVUS) provides unique insights. IVUS assessment of neointimal growth has been of major value to understand the mechanisms of action of DES and also to compare different DES. Notably, IVUS enables optimization of DES implantation. DES underexpansion, edge-restenosis, residual dissections, plaque prolapse, stent fracture, incomplete stent apposition and DES-related aneurysms, are readily assessed by IVUS. The use of IVUS to study and manage DES failures (namely in-stent restenosis and DES thrombosis) is of major value. In conclusion, IVUS provides unique insights during DES implantation, allows DES optimization and should always be used during the management of DES failures: in-stent restenosis and DES thrombosis.


The application of polyvinyl alcohol in the technology of modern drug form.
The following presentation is a review of literature related to application of nonionic polymer, polyvinyl alcohol, in the technology of modern drug form. The review contains the description of physical-chemical properties of this polymer, such as hydrolysis degree, solubility, swelling capacity. Each characteristic is followed by the description of its application as a therapeutical substance carrier in the pharmacy.


[Efforts toward harmony within the scope of the European Community. What has been accomplished, what remains to be done?].
Report about harmonization of surgical training in the E.C. countries. Responsibility of the U.E.M.S. (European Union of Medical Specialists), in particular of the section of surgery. Each country is represented by two members. Annual meetings. A harmonization committee has been founded under direction of Prof. Gruwez, Leuwen/Belgium. A first report on the harmonization of surgical training in the E.C. countries is available. Standards of quality shall be reached. Consideration to found a European Board of Surgery.


Proton permeation into single vesicles occurs via a sequential two-step mechanism and is heterogeneous.
This article describes the first single-vesicle study of proton permeability across the lipid membrane of small (approximately 100 nm) uni- and multilamellar vesicles, which were composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). To follow proton permeation into the internal volume of each vesicle, we encapsulated carboxyfluorescein, a pH-sensitive dye whose fluorescence was quenched in the presence of excess protons. A microfluidic platform was used for easy exchange of high- and low-pH solutions, and fluorescence quenching of single vesicles was detected with single-molecule total internal reflection fluorescence (TIRF) microscopy. Upon solution exchange and acidification of the extravesicular solution (from pH 9 to 3.5), we observed for each vesicle a biphasic decay in fluorescence. Through single-vesicle analysis, we found that rate constants for the first decay followed a Poisson distribution, whereas rate constants for the second decay followed a normal distribution. We propose that proton permeation into each vesicle first arose from formation of transient pores and then transitioned into the second decay phase, which occurred by the solubility-diffusion mechanism. Furthermore, for the bulk population of vesicles, the decay rate constant and vesicle intensity (dependent on size) correlated to give an average permeability coefficient; however, for individual vesicles, we found little correlation, which suggested that proton permeability among single vesicles was heterogeneous in our experiments.


A systematic comparison of rheumatoid arthritis and ankylosing spondylitis: structural outcomes.
Rheumatoid arthritis and ankylosing spondylitis are both chronic diseases with inflammation as a hallmark. Both diseases are characterized by structural abnormalities of the peripheral joints (RA) or the spine (AS) that can be visualized on conventional radiographs. RA is associated with destruction (erosions, joint space narrowing) whilst AS is dominated by bone formation (syndesmophytes). The causative relationship between inflammation and structural damage in RA is well established, whilst this relation is largely unknown but certainly less strong in AS. Progression of structural damage in RA is inhibited by disease modifying anti-rheumatic drugs and especially by TNF-blockade, whilst progression of structural damage in AS seems insensitive to TNF-blockade but sensitive to non-steroidal inflammatory drugs.In this article, similarities and dissimilarities with respect to structural damage in RA and AS are discussed and set against a background.


Fine-Tuned Reactivity of N-Containing Naphthol Analogues.
6-Hydroxyquinoline and 3-hydroxyisoquinoline as N-containing naphthol analogues were tested in modified Mannich reactions (mMr's). In the case of 6-hydroxyquinoline, the outcomes of the attempted Mannich reactions were strongly influenced by the amine components. Aminoalkylation of this substrate with reagents 1-naphthaldehyde and N-benzylmethylamine led to the isolation of a diol regarded as a stabilised water adduct of an ortho-quinone methide (o-QM), of which formation can be ascribed to the presence of a hydroxide ion in a relatively higher concentration generated by the bulky and basic amine component with decreased nucleophilicity. The classical Mannich base was isolated as a single product when the amine component was replaced for morpholine, featuring nucleophilicity rather than basic character under the applied reaction conditions. Starting from the isomer substrate 3-hydroxyisoquinoline, independently on the nucleophile (methanol or morpholine) besides the formation of the classical Mannich base, the nucleophilic attack at position one of the heterocyclic substrate was also observed. The DFT analysis of the acceptor molecular orbitals of the potential electrophilic components and the thermodynamics of the assumed-possible transformations demonstrated that this regioselective addition is a feasible process on the investigated heterocyclic skeleton. DFT modelling studies also suggest that besides the steric bulk, the orbital-controlled electronic properties of the aryl group, originating from the aldehyde components, have a strong influence on the ratios and the NMR-monitored interconversions of the C-1-substituted 3-hydroxyisoquinolines and the classical Mannich bases formed in multistep reaction sequences. On the basis of the DFT analysis of the thermodynamics of alternative pathways, a reaction mechanism was proposed for the rationalization of these characteristic substrate-controlled interconversions.


[Functional assessment of infiltrating immunocytes in patients with primary hepatocellular carcinoma after percutaneous microwave coagulation therapy].
To assess the function local immune cells in patients with primary hepatocellular carcinoma (HCC) after percutaneous microwave coagulation therapy (PMCT). Thirty-eight patients with histologically proved primary HCC underwent ultrasound guided PMCT. Specimens were taken from the lesion site before and 17 days after PMCT respectively using 18-guage core needle through US-guide biopsy, embedded in paraffin, and stained by immunohistochemistry. The panel of monoclonal antibodies of CD3, CD56, CD68 and Fas-L were used to detect the CD3+, CD56+, CD68+ cells and T lymphocyte Fas-ligand. The positive cells were detected under light microscopy. Their diameter and area and the Fas-L expression rate of T lymphocytes and changes of secondary lysosomes in macrophages were measured by computer. Before PMCT, only a few infiltrating immunocytes were seen in the tumor specimens; the diameter of most CD3+ and CD56+ cells was less than 10 microns and the diameter of CD68+ cells was less than 18 microns. The amount and volume of CD3+, CD56+, and CD68+ cells significantly increased after PMCT (t = 3.48, P = 0.025 for CD3+ cells, t = -4.76, P = 0.000 for CD56+ cells, and t = -2.46, P = 0.028 for CD68+ cells). The percentage of CD3+ and CD56+ cells with the largest diameter > 10 microns increased from 10.4% and 20.1% respectively before PMCT to 24.9% and 30.2% respectively after PMCT. The percentage of CD68+ cells with the largest diameter > 18 microns increased from 10.2% before PMCT to 33.4% after PMCT. The Fas-l expression rate of T lymphocytes increased from 7.2% to 20.1% (t = -19.12, P = 0.000). The secondary lysosomes and cellular debris within microphages and the cellular organs in T lymphocytes significantly increased. The function of intratumaral infiltrating immunocytes is significantly enhanced after PMCT.


[Sound affects the discrimination of weak intensities of light in the visual cortex of the rabbit depending on time intervals between sound and light].
In this paper, we researched an influence of sound (2000 Hz, 70 dB, 40 ms) to the discrimination of low-light intensities (0.3 and 1 cd/m2) in the visual cortex of the rabbit. We used a recording of evoked potentials from the visual cortex of awaked rabbits in chronic experiments. The sound was switched on with different time slots before and after the replacement of the light intensities at each other (range from -750 to +150 ms). Sound itself caused no response. In 42 experiments on 3 rabbits we revealed that' he sound has a significant modulating effect on the discrimination of low-light intensities in the range of time shifts from -300 to +50 ms. Maximum sound effect was manifested in the transition of light from a high-intensity (1 cd/m2) to lower (0.3 cd/m2). Analyses of the phases of visual evoked potentials revealed that significant influence of sound to the light occurs in the intervals -300, -100, -60, -40, -20, 0, -20 and + 50 ms. We found that phase P2 (120-150 ms from the moment of replacement of the light stimuli) is most affected by sound in response to the replacement of low-light intensities both in the number of significant (p < 0.05) time slots (7) and the impact of sound on the light response. In phase P2 the impact of sound was almost exclusively facilitating (by 19-36%) compared with the responses to the light, whereas in phases N1 80-110 ms) and N2 (180-250 ms) were only 2-3 intervals with the significant influence of the sound. And the degree of response facilitation to light was ranged by 8-12%. We assumed that the effect of sound on the light response in visual cortex is delayed that caused by the passage of auditory signal through the auditory,parietal cortex, superior colliculus.


Intestinal Organoids as a Novel Complementary Model to Dissect Inflammatory Bowel Disease.
Inflammatory bowel diseases (IBDs) include colitis ulcerosa and Crohn's disease, besides the rare microscopic colitis. Both diseases show a long-lasting, relapsing-remitting, or even chronic active course with tremendous impact on quality of life. IBDs frequently cause disability, surgical interventions, and high costs; as in other autoimmune diseases, their prevalent occurrence at an early phase of life raises the burden on health care systems. Unfortunately, our understanding of the pathogenesis is still incomplete and treatment therefore largely focuses on suppressing the resulting excessive inflammation. One obstacle for deciphering the causative processes is the scarcity of models that parallel the development of the disease, since intestinal inflammation is mostly induced artificially; moreover, the intestinal epithelium, which strongly contributes to IBD pathogenesis, is difficult to assess. Recently, the development of intestinal epithelial organoids has overcome many of those problems. Here, we give an overview on the current understanding of the pathogenesis of IBDs with reference to the limitations of previous well-established experimental models. We highlight the advantages and detriments of recent organoid-based experimental setups within the IBD field and suggest possible future applications.


Anthocyanidin synthase in non-anthocyanin-producing Caryophyllales species.
Red colors in flowers are mainly produced by two types of pigments: anthocyanins and betacyanins. Although anthocyanins are widely distributed in higher plants, betacyanins have replaced anthocyanins in the Caryophyllales. There has been no report so far to find anthocyanins and betacyanins existing together within the same plant. This curious phenomenon has been examined from genetic and evolutionary perspectives, however nothing is known at the molecular level about the mutual exclusion of anthocyanins and betacyanins in higher plants. Here, we show that spinach (Spinacia oleracea) and pokeweed (Phytolacca americana), which are both members of the Caryophyllales, have functional anthocyanidin synthases (ANSs). The ability of ANSs of the Caryophyllales to oxidize trans-leucocyanidin to cyanidin is comparable to that of ANSs in anthocyanin-producing plants. Expression profiles reveal that, in spinach, dihydroflavonol 4-reductase (DFR) and ANS are not expressed in most tissues and organs, except seeds, in which ANS may contribute to proanthocyanidin synthesis. One possible explanation for the lack of anthocyanins in the Caryophyllales is the suppression or limited expression of the DFR and ANS.


Feasibility of supercritical fluid chromatography/mass spectrometry of polypeptides with up to 40-mers.
Supercritical fluid chromatography (SFC) provides a number of advantages over traditional HPLC such as speed, practical use of longer columns, a normal-phase retention mechanism, and reduced use of organic solvents. Yet, it has been a technique traditionally limited to relatively nonpolar compounds. The nature of SFC mobile and stationary phases did not allow the elution of ionic compounds or of peptides, except, in the latter case, for the most hydrophobic peptides. The characterization of peptides is critically important for drug discovery and development in the pharmaceutical industry, as well as for a variety of other important applications. Here, for the first time to our knowledge, we show that relatively large peptides (at least 40 mers), containing a variety of acidic and basic residues, can be eluted in SFC. We used trifluoroacetic acid as additive in a CO2/methanol mobile phase to suppress deprotonation of peptide carboxylic acid groups and to protonate peptide amino groups. A 2-ethylpyridine bonded silica column, which was specifically developed for SFC, was used for the majority of this work. The relatively simple mobile phase was compatible with mass spectrometric detection.


Mechanism of nonphotochemical quenching in green plants: energies of the lowest excited singlet states of violaxanthin and zeaxanthin.
The xanthophyll cycle is an enzymatic, reversible process through which the carotenoids violaxanthin, antheraxanthin, and zeaxanthin are interconverted in response to the need to balance light absorption with the capacity to use the energy to drive the reactions of photosynthesis. The cycle is thought to be one of the main avenues for safely dissipating excitation energy absorbed by plants in excess of that needed for photosynthesis. One of the key factors needed to elucidate the molecular mechanism by which the potentially damaging excess energy is dissipated is the energy of the lowest excited singlet (S(1)) state of the xanthophyll pigments. Absorption from the ground state (S(0)) to S(1) is forbidden by symmetry, making a determination of the S(1) state energies of these molecules by absorption spectroscopy very difficult. Fluorescence spectroscopy is potentially the most direct method for obtaining the S(1) state energies. However, because of problems with sample purity, low emission quantum yields, and detection sensitivity, fluorescence spectra from these molecules, until now, have never been reported. In this work these technical obstacles have been overcome, and S(1) --> S(0) fluorescence spectra of violaxanthin and zeaxanthin are presented. The energies of the S(1) states deduced from the fluorescence spectra are 14 880 +/- 90 cm(-)(1) for violaxanthin and 14 550 +/- 90 cm(-)(1) for zeaxanthin. The results provide important insights into the mechanism of nonphotochemical dissipation of excess energy in plants.


Allergic sensitization in patients with rhinitis and bronchial asthma in Ningxia region of China.
Allergic rhinitis and bronchial asthma are common allergic diseases. The pattern of dominant allergens depends on the degree of urbanization and the geographic region. The present study characterized the allergens of patients with allergic rhinitis and bronchial asthma in Ningxia region of China. A total of 309 patients were enrolled in this study. Western blotting assays were performed of the serum samples to evaluate allergen-specific IgE antibody for inhaled and ingested allergens. Statistical analysis was performed to compare the positive rate among different subgroups. Among the 309 patients, 221 of them had positive test results. There were 157 positive cases for ingested allergens and 174 positive cases for inhaled allergens. No significant differences in positive rates were found between the ingested and inhaled allergens. Among the inhaled allergens, Artemisia was the most frequent allergen, followed by fungi and dog hair. Cashew was the most common ingested allergen, followed by crab, mango, and beef. Further analysis showed no significant differences in positive rate between males and females. However, significant differences in positive rate of inhaled and ingested allergens were found between children (1-13 years old) and adults (above 18 years old) (P < .05), while no significant differences were found between the children and teenagers (14-18 years old). For the comparison between teenagers and adults, significant difference in positive rate was found only in the ingested allergen. This study provided the characteristics of allergens in Ningxia population, providing clinical and epidemiological data for prevention and treatment of the diseases in the region.


Navigated femoral shaft fracture treatment: current status.
Femoral malrotation is a common complication after internal fixation of a femoral shaft fracture. The only valid, objective monitoring method is computer tomography-assisted torsion measurement between the proximal and distal femur; unfortunately, this can only be carried out postoperatively. A difference of 15° compared to the contralateral femur is seen as an indication for revision. With the development of computer-assisted surgery, new possibilities for performing torsion control and correction intraoperatively has been introduced. These methods also allow for navigation-assisted definition of the optimal incision site, intramedullary access, femoral nail and interlocking. The main problem lies in the extra time of surgery, which is due to performing all the steps of the surgery navigated. The solution for this problem is "hybrid navigation", in which the surgeon can select the steps he needs from the navigation system, depending on his experience or surgical technique.


Potential effectiveness of pelvic floor rehabilitation treatment for postradical prostatectomy incontinence, climacturia, and erectile dysfunction: a case series.
Radical prostatectomy is the treatment of choice for prostate cancer; although novel techniques have significantly reduced its side effects, the procedure can provoke urinary incontinence of various degrees and/or erectile dysfunction. We evaluate the effect of a complete pelvic floor rehabilitation program on both incontinence and erectile dysfunction, including climacturia, in a preliminary case series. Pad usage and International Index of Erectile Function (IIEF-15) Questionnaire. Three male patients, previously submitted to nerve and bladder neck sparing radical prostatectomy, presented with urinary incontinence, climacturia and erectile dysfunction of new onset. We decided to manage those subjects with a pelvic-floor rehabilitation program consisting of active pelvic-floor muscle exercises, electromyography biofeedback for strength and endurance, electrical stimulation. The whole program lasted 4 months, with weekly sessions, including general advices on lifestyle changes. Pad usage for incontinence and IIEF-15 were used to assess symptoms before and after the procedure. Before a complete rehabilitation program, pad usage was 1 per day in all the subjects, and the score for erectile function was set at 17 (range 15-20). After the procedure, all the patients experienced a satisfying urinary continence and an improvement in erectile function (mean IIEF score: 22, range 19-24). Similarly, climacturia seems to be subjectively reduced in all the subjects. Pelvic floor muscles exercises seem to result in an improved urinary continence and erectile function after radical prostatectomy. Since this is the first clinical case series dealing with this topic, our outcomes are encouraging and suggest the potential usefulness of such noninvasive treatment modality.


Replisome dysfunction upon inducible TIMELESS degradation synergizes with ATR inhibition to trigger replication catastrophe.
The structure of DNA replication forks is preserved by TIMELESS (TIM) in the fork protection complex (FPC) to support seamless fork progression. While the scaffolding role of the FPC to couple the replisome activity is much appreciated, the detailed mechanism whereby inherent replication fork damage is sensed and counteracted during DNA replication remains largely elusive. Here, we implemented an auxin-based degron system that rapidly triggers inducible proteolysis of TIM as a source of endogenous DNA replication stress and replisome dysfunction to dissect the signaling events that unfold at stalled forks. We demonstrate that acute TIM degradation activates the ATR-CHK1 checkpoint, whose inhibition culminates in replication catastrophe by single-stranded DNA accumulation and RPA exhaustion. Mechanistically, unrestrained replisome uncoupling, excessive origin firing, and aberrant reversed fork processing account for the synergistic fork instability. Simultaneous TIM loss and ATR inactivation triggers DNA-PK-dependent CHK1 activation, which is unexpectedly necessary for promoting fork breakage by MRE11 and catastrophic cell death. We propose that acute replisome dysfunction results in a hyper-dependency on ATR to activate local and global fork stabilization mechanisms to counteract irreversible fork collapse. Our study identifies TIM as a point of replication vulnerability in cancer that can be exploited with ATR inhibitors.


Bis(CBT)palladium(II) Derivatives (CBT = m-carborane-1-thiolate): Synthesis, Molecular Structure, and Physicochemical Properties of cis-[(bipy)Pd(CBT)2] and trans-[(py)2Pd(CBT)2].
The new synthesized PdII complex cis-[(bipy)Pd(CBT)2] (bipy = 2,2'-bipyridyl; CBT = m-carborane-1-thiolate anion), which is a potential BNCT (boron neutron capture therapy) agent and of structure elucidated by single-crystal X-ray work, has been studied by infrared (IR) and ultraviolet-visible light (UV-vis) spectra and its properties compared with those of the previously reported and also the structurally characterized analogue trans-[(py)2Pd(CBT)2]. This trans species, prepared via a direct method, was previously isolated from a pyridine solution, consequent to the occurring releasing of the external Pd(CBT)2 moieties of the porphyrazine macrocycle [{Pd(CBT)2}4LZn]·xH2O (L = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato anion), which is an active photosensitizer in photodynamic therapy (PDT) and a potential bimodal PDT/BNCT agent. The UV-vis spectral behavior of both cis and trans species in CHCl3 solution and in the gas phase has been examined in detail by density functional theory (DFT) and time-dependent density functional theory (TDDFT) studies devoted to explain their distinct behavior observed in the region of 400-500 nm, as determined by the presence in the cis structure of a vicinal arrangement of the two CBT groups, an ensemble of results closely similar to those observed for the macrocycles [{Pd(CBT)2}4LM]·xH2O (M = MgII(H2O), ZnII, PdII). It has also been experimentally proved the tendency of the cis isomer in CHCl3/pyridine solution to be changed to the respective trans analogue, with conversion occurring in two steps, as interpreted by detailed DFT studies.


Local SAR enhancements in anatomically correct children and adult models as a function of position within 1.5 T MR body coil.
Usage of magnetic resonance imaging (MRI) is continuously increasing due to its excellent soft-tissue contrast and improving diagnostic values. MRI also has the advantage that it operates without ionizing radiation. The main safety concerns are torque, acceleration by the static field, nerve stimulation by the gradient fields, and tissue heating by the radio-frequency (RF) fields. This paper investigates if children and fetuses are at higher risks than adults when the current RF regulations are applied. We analyzed and compared local absorption hotspots, i.e., the peak spatial specific absorption rate averaged over any 10 g (psSAR10g) for five adults, three children of ages 5, 11 and 14 years, and 1 pregnant female (36 weeks' gestation) in 10 different Z-positions (head to calves). In the First Level Operating Mode (4 W/kg whole-body averaged exposure), the psSAR10g values found for adults were as large as 60 W/kg in the trunk and 104 W/kg in the extremities. The corresponding values for children were 43 and 58 W/kg, respectively, and 14 W/kg for the unborn child. Modeling of worst case anatomical RF loops can substantially increase the psSAR10g values, i.e., by factor >>2. The results suggest that local exposure for children and fetuses is smaller than for adults (15-75%), i.e., no special considerations for children and the unborn child are needed regarding psSAR10g due to RF. However, the local thermal load of the unborn may be significantly increased due to the high exposure average (up to 4 W/kg) of the non-perfused amniotic fluid.


Versatile Medium Entropy Ti-Based Bulk Metallic Glass Composites.
An ultra-strong Ti-based bulk metallic glass composite was developed via the transformation-induced plasticity (TRIP) effect to enhance both the ductility and work-hardening capability of the amorphous matrix. The functionally graded composites with a continuous gradient microstructure were obtained. It was found that the austenitic center possesses good plasticity and toughness. Furthermore, the amorphous surface exhibited high strength and hardness, as well as excellent wear corrosion resistance. Compared with the Ti-6Al-4V alloy, bulk metallic glass composites (BMGCs) exhibit better spontaneous passivation behavior during the potential dynamic polarization. No crystallization was observed on the friction surface, indicating their good friction-reduction and anti-wear properties.


Injuries and Strength Training Practices in Collegiate Tennis.
Strength and conditioning practices may influence injury rates in the sport of tennis. Methods: Coaches reported the number injuries over the past year. Coaches were also surveyed on whether their training program included training related to upper-body or lower-body strength, power, muscle growth, and eccentric exercise. Separate regression analyses were run in the upper and lower body to examine the relationship between injuries and participation in training focused on strength, power, growth, and maximal eccentric exercise. A total of 111 coaches were surveyed. The most frequent injuries observed were ankle sprains (144 injures), followed by paraspinal muscle strains (126 injuries). When pooled, there were a total of 355 lower-body and 260 upper-body injuries. Strength and conditioning practices explained 9.9% of the variance of injury rates in the upper body (R2 = 0.099). The only significant predictor of upper-body injury was participation in upper-body muscle growth training (β = 1.613, p = 0.013). In addition, training practices explained 11.1% of the variance of injury in the lower body (R2 = 0.111). Coaches value injury prevention exercise, sports-specific training and flexibility and mobility training the most, with muscle growth and maximal power ranked lowest. Additionally, the most frequent injuries observed in collegiate tennis players were ankle sprains (144 injures), followed by paraspinal muscle strains (126 injuries).


Search for Neutrinoless Double-Beta Decay of (130)Te with CUORE-0.
We report the results of a search for neutrinoless double-beta decay in a 9.8 kg yr exposure of (130)Te using a bolometric detector array, CUORE-0. The characteristic detector energy resolution and background level in the region of interest are 5.1±0.3 keV FWHM and 0.058±0.004(stat)±0.002(syst)counts/(keV kg yr), respectively. The median 90% C.L. lower-limit half-life sensitivity of the experiment is 2.9×10(24) yr and surpasses the sensitivity of previous searches. We find no evidence for neutrinoless double-beta decay of (130)Te and place a Bayesian lower bound on the decay half-life, T(1/2)(0ν)>2.7×10(24) yr at 90% C.L. Combining CUORE-0 data with the 19.75 kg yr exposure of (130)Te from the Cuoricino experiment we obtain T(1/2)(0ν)>4.0×10(24) yr at 90% C.L. (Bayesian), the most stringent limit to date on this half-life. Using a range of nuclear matrix element estimates we interpret this as a limit on the effective Majorana neutrino mass, m(ββ)<270-760 meV.


Poor prognosis and SATB1 overexpression in solid tumors: a meta-analysis.
Several previous studies have reported the prognostic value of special AT-rich sequence-binding protein 1 (SATB1) in solid tumors. However, these studies produced inconsistent results because of their various limitations, including small sample sizes. Here, we describe a meta-analysis based on 17 studies including 3144 patients to search for connections between SATB1 overexpression and overall survival (OS) of patients with solid tumors. Seventeen studies (n = 3144) were assessed in the meta-analysis. Both univariate and multivariate analysis for survival indicated that high SATB1 reactivity significantly predicted poor prognosis. In the multivariate analysis, the combined hazard ratio (HR) for OS was 1.82 (95% confidence interval [CI]: 1.59-2.08, P < 0.0001). The pooled HR of the univariate analysis for OS was 1.96 (95% CI: 1.65-2.34, P < 0.0001). Studies were identified by an electronic search of PubMed, EMBASE, and Web of Science, including publications prior to April 2017. Pooled HR values for OS were aggregated and quantitatively analyzed in the meta-analysis. The meta-analysis indicated that high SATB1 reactivity is significantly correlated with decreased survival in most cases of solid tumors. In addition, SATB1 shows promise as a prognostic biomarker and novel therapeutic target on the basis of its expression level in solid tumors.


GPR171 activation regulates morphine tolerance but not withdrawal in a test-dependent manner in mice.
A newly deorphanized G protein-coupled receptor, GPR171, is found to be highly expressed within the periaqueductal gray, a pain-modulating region in the brain. Our recent research has shown that a GPR171 agonist increases morphine antinociception in male mice and opioid signaling in vitro . The objective of this study was to evaluate the effects of combination treatment in females as well as whether chronic treatment can be used without exacerbating morphine-induced tolerance and withdrawal in female and male mice. Our results demonstrate that activation of GPR171 with an agonist attenuates morphine tolerance in both female and male mice on the tail-flick test, but not the hotplate test. Importantly, the GPR171 agonist in combination with morphine does not exacerbate morphine-induced tolerance and withdrawal during long-term morphine treatment. Taken together, these data suggest that the GPR171 agonist may be combined with morphine to maintain antinociception while reducing the dose of morphine and therefore reducing side effects and abuse liability. The outcome of this study is clearly an important step toward understanding the functional interactions between opioid receptors and GPR171 and developing safer therapeutics for long-term pain management.


Dosing errors of empirical antibiotics in critically ill patients with severe sepsis or septic shock: A prospective observational study.
Effective antibiotic therapy is crucial in sepsis management. Studies have emphasized on antibiotic administration timing more than dosing. We evaluated the frequency and risk factors of antibiotic dosing errors in sepsis. This prospective observational study compared the doses of intravenous empirical antibiotics in the 1st day of sepsis diagnosis with those recommended by Micromedex, considering sepsis source and glomerular filtration rate estimated by the modification of diet in renal disease equation. The doses were classified as under-dosed, over-dosed, or appropriate. We excluded antibiotics which did not need a dose adjustment. The under-dosing rate was retrospectively evaluated according to the creatinine clearance estimated by the Cockcroft-Gault equation. Between October 1, 2013, and April 30, 2014, 189 patients were evaluated (age 61.6 ± 18.6 years, acute physiology and chronic health evaluation II score 22.8 ± 7.0, 58.7% septic shock) with 415 antibiotic prescriptions (2.2 ± 0.9 prescriptions per patient). Antibiotic dosing was appropriate in 50.8% of patients; under-dosing in 30.7% and overdosing in 25.9%. Under-dosing prevalence was 39.4% when kidney function was assessed by the Cockcroft-Gault equation. Vancomycin was associated with the highest under-dosing rate (39.4%), followed by piperacillin/tazobactam (12.1%). The cohort mortality was 35.4%. Age, shock, chronic kidney disease, and cirrhosis independently predicted mortality on multivariable logistic regression analysis. Antibiotic dosing error was not associated with mortality: Over-versus appropriate dosing (odds ratio [OR], 1.41; 95% confidence interval [CI], 0.57-3.47), under-versus appropriate dosing (OR, 0.57; 95% CI, 0.24-1.35). Antibiotic dosing errors were common in patients with sepsis. Vancomycin had the highest under-dosing rate. Antibiotic dosing errors were not associated with increased mortality.


Theoretical investigation of the binding energies of the iodide ion and xenon atom with decaborane.
The interaction of decaborane (B(10)H(14)) with the I(-) ion and the (isoelectronic) Xe atom is investigated using a number of theoretical methods: MP2, CCSD(T), CCSD, spin-orbit CISD, and DFT using the B3LYP, B3PW91, PW91PW91, and PBE0 methods. All non-DFT and some DFT methods agree that B(10)H(14)I(-) is bound by charge-dipole electrostatic forces, charge- and dipole-induced-dipole forces, and dispersion forces, while B(10)H(14)Xe is bound by dipole-induced-dipole forces and dispersion forces. Counterpoise corrections are necessary to obtain reliable results. Relativistic effective core potentials were used for the I, Xe, and B atoms. Basis sets for use with these potentials are discussed as is the question of basis set balance in molecules. We find B(10)H(14)I(-) to be bound by 19.8 kcal/mol and B(10)H(14)Xe by 1.1 kcal/mol, indicating that the charge and polarizability of I(-) play the major role in the interaction energy.


Effect of calvarial burring on resorption of onlay cranial bone graft.
Variable resorption occurs whenever calvarial bone graft is used for onlay cranioplasty. The recipient ectocortex may be burred to expose vessels and osteocytes to maximize healing. The purpose of this study was to determine whether abrading the recipient site improves the volume of onlay graft. The parietal bones of 17 rabbits were sectioned into split-thickness and full-thickness grafts. The right frontal cortex was abraded with a bur to punctate bleeding. Pairs of split-thickness (n = 48) or full-thickness (n = 20) grafts were onlayed to the burred right frontal bone and to the nonburred left frontal bone. Micro-computed tomography was used to determine graft volume immediately postoperatively and 16 weeks later. Histology, including tartrate-resistant acid phosphatase staining, was performed to quantify vascular channels and osteoclasts per high-power field 10 days postoperatively. Split-thickness graft volume decreased 58.0% when placed on the burred calvarial site, compared with grafts on the nonburred cortex (28.4%) (P = 0.01). Full-thickness grafts showed a similar trend: greater resorption (39.1%) when onlayed onto abraded calvaria compared with nonburred ectocortex (26.0%) (P = 0.11). Split-thickness graft orientation (cortical vs cancellous side in contact with the recipient site) did not affect resorption (P = 0.67). Onlay grafts placed on the burred recipient site had more vascular channels (11.8) and osteoclasts (5.7), compared with grafts over nonabraded cortex (3.4 and 4.2, respectively) (P < 0.05). Burring the recipient site cortex before onlay cranial bone grafting promotes resorption, possibly by increasing vascularization and osteoclastic activity. This technique cannot be recommended.


Application of the Extreme Value Distribution to Estimate the Uncertainty of Peak Sound Pressure Levels at the Workplace.
The purpose of this article is to develop a method for the statistical inference of the maximum peak sound pressure level and of the associated uncertainty. Both quantities are requested by the EU directive 2003/10/EC for a complete and solid assessment of the noise exposure at the workplace. Based on the characteristics of the sound pressure waveform, it is hypothesized that the distribution of the measured peak sound pressure levels follows the extreme value distribution. The maximum peak level is estimated as the largest member of a finite population following this probability distribution. The associated uncertainty is also discussed, taking into account not only the contribution due to the incomplete sampling but also the contribution due to the finite precision of the instrumentation. The largest of the set of measured peak levels underestimates the maximum peak sound pressure level. The underestimate can be as large as 4 dB if the number of measurements is limited to 3-4, which is common practice in occupational noise assessment. The extended uncertainty is also quite large (~2.5 dB), with a weak dependence on the sampling details. Following the procedure outlined in this article, a reliable comparison between the peak sound pressure levels measured in a workplace and the EU directive action limits is possible. Non-compliance can occur even when the largest of the set of measured peak levels is several dB below such limits.


An enzyme immunoassay of estrone in swine serum.
An enzyme immunoassay for estrone in swine serum was established. For this, beta-galactosidase from E. coli was conjugated through estrone-17 (O-carboxymethyl)oxime using a mixed anhydride reaction. The percentage of immunoreactive estrone-17 (O-carboxymethyl)oxime-beta-galactosidase conjugate was estimated to be about 70%. The recovery rate of estrone (25-500 pg) added to 0.05 ml of swine serum averaged 91.4%. The sensitivity of the present enzyme immunoassay was 5 pg/tube. The coefficients of variation (CV) were 5.9-8.2% (within assays) and 4.1-5.9% (between assays), respectively. Estrone values determined by the present enzyme immunoassay were highly correlated with those determined by radioimmunoassay (r = 0.99, P less than 0.005). This method of enzyme immunoassay was determined to be suitable for the routine assay of serum estrone.


Effects of DHU001, a Mixed Herbal Formula on Acute Inflammation in Mice.
The effects of DHU001, a mixed herbal formula consisted of 7 types aqueous extracts for treating respiratory disorders were observed on xylene-induced acute inflammation. The xylene was topically applied 60 min after administration of 500, 250 and 125 mg/kg of DHU001, and all animals were sacrificed 2 hrs after xylene application. The changes on ear weights, histolopathological analyses of ear were evaluated and compared to those of indomethacin and dexamethasone (15 mg/kg treated) - Both of drugs are well-known by anti-inflammatory agents. Xylene application resulted in marked increases in induced ear weights as compared with intact control ear. Severe vasodilation, edematous changes of ear skin and increase in the thickness of the ear tissues, neutrophil infiltration as acute inflammation were detected in xylene-treated control ears at histopathological observation. However, these xylene-induced acute inflammatory changes were dose-dependently decreased by oral treatment of DHU001. Therefore, it is concluded that DHU001 has favorable anti-inflammatory effects on xylene-applicated acute ear inflamed mice.


Novel precision therapies for cholangiocarcinoma: an overview of clinical trials.
The treatment landscape of biliary cancers is rapidly changing. Inhibitors against the actionable targets FGFR and IDH1 are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma. However, there remains an unmet need in identifying the mechanisms of resistance and treatment strategies involving possible tumor sequencing. In this review article, we address clinical trials evaluating FGFR, IDH, BRAF and HER2 inhibitors in advanced cholangiocarcinoma. We also review the mechanisms of resistance described thus far and approaches to overcome them. Articles selected for this review were based on reported studies indexed in PubMed (2010-2022). Precision medicine in biliary cancers has already been incorporated into the treatment landscape of the disease in many countries. Fusions of FGFR2 and mutations in IDH1 are the first drivers with targetable treatments approved in these cancers. HER2 and BRAF would be the next drivers with possible tumor-agnostic or cholangiocarcinoma-specific approvals. The advent of ctDNA could improve the accessibility of sequencing and recruitment in these clinical trials. However, limitations of detecting fusions should be considered and addressed in these platforms.


Cerebral state monitoring in Beagle dogs sedated with medetomidine.
To provide experience of monitoring the level of hypnosis with the Cerebral State Monitor (CSM), a device extracting a single numerical variable between 0 and 100 from the electroencephalogram in dogs sedated with medetomidine during dental scale removal. Prospective observational study. Animals Nine female Beagle dogs weighing 13.3 +/- 1.3 kg. Cerebral state index (CSI) and burst suppression ratio (BSR) were recorded from sub-dermal needle electrodes in dogs sedated after subcutaneous injection of 114 +/- 11 microg kg(-1) medetomidine. Ten minutes after injection CSI monitoring began, and after 5 minutes, dental scale removal with an ultrasonic probe was started. After approximately 30 minutes, the effects of medetomidine were antagonized with atipamezole. The CSI had a median value of 43 (range 40-56) in undisturbed sedated dogs. During dental scale removal, CSI increased to a median value of 99 (range 92-100). The BSR in undisturbed sedated dogs ranged from 2 to 15, but fell to zero during dental scale removal. Stimulation during dental scale removal might be expected to reduce the level of sedation and hypnosis in dogs to which medetomidine had been administered. The concurrent increase in CSI and decrease in BSR suggested that a higher CSI was associated with arousal from sedation and a reduction in the depth of hypnosis. More studies are needed to validate CSI in order to better understand the functioning of this monitor. The CSM shows promise for monitoring the degree of sedation and hypnosis during anaesthesia, and after adequate validation, could contribute to the refinement of anaesthetic techniques in animals.


Proposal for the Application of a Quality Indicator to Medico-legal Consultations in the Field of Medical Liability.
In recent decades, the number of professional liability disputes has increased, especially in the civil sector. In these liability assessments, medico-legal experts have become the linchpin. Law No. 24/2017, concerning professional liability in Italy, requires that guidelines and best practices be established to identify the necessary elements for writing expert reports in the legal sector. The authors have created a numerical indicator to be applied to 150 legal expert reports on professional liability, enabling them to evaluate the methodological quality of those reports. The results are then compared with the outcome of the legal proceedings in order to establish the suitability of this quality index for evaluating the work of medico-legal experts. Of the 150 reports considered, 14 were scored inadequate, 75 adequate and 31 good. These inadequate (according to the indicator) reports presented a higher probability of being scored inadequate in court proceedings, compared to the risk of inadequacy of all the reports; OR 4.6 (95% CI 1.25-16.90). This probability significantly increased on comparing the inadequate reports with the adequate; OR 5.6 (95% CI 1.28-24.41), and the inadequate with the good; OR 7.73 (95% CI 1.50- 39.87). Application of the proposed indicator is simple and produces a high-quality result, thus ensuring an accurate and tenable appraisal of methodological quality. The indicator proposed serves as a useful starting point for creating the necessary methodological standards for medico-legal experts in the field of professional liability as recommended by Law No. 24/2017.


Wollaston's effect in infants: Do infants integrate eye and head information in gaze perception?
The current study examined infants' sensitivity to Wollaston's effect: When identical eyes are placed in differently angled faces, the perceived gaze direction shifts toward the orientation of the face such that physically, the direct gaze is perceived as averted toward the orientation of the face. Consistent with Wollaston's effect, we found that looking toward direct and averted gaze by 4- to 5- and 7- to 8-month-olds (n = 40) was affected by the head orientation context. These results demonstrate that infants aged 4 to 5 and 7 to 8 months integrate eye and head information to perceive another's gaze direction. In light of recent psychophysical findings, the current results suggest that the visual function supporting constant gaze perception across head rotation is already at work by 4 to 5 months of age.


Use of a surgical preparation and sterile dressing change during office visit treatment of chronic foot and ankle wounds decreases the incidence of infection and treatment costs.
Foot and ankle surgeons work with a patient population burdened by multiple factors that adversely affect wound healing and the ability to combat infection. As a result, many of these patients are seen for treatment of chronic ulcerations on their lower extremities that are highly susceptible to colonization and possible progression to a limb- and/or life-threatening infection. The Limb Preservation Service at the Madigan Army Medical Center hypothesized that implementation of a standardized protocol involving a formal physician-directed surgical preparation of the affected lower extremity and a physician-applied sterile dressing at each outpatient clinic appointment would reduce the incidence of infection, use of systemic antibiosis, and thus the requirement for frequent follow-up office appointments. Initiation of this protocol resulted in the reduction of infection to the extent that antibiotic need was eliminated. The frequency of office visits required for follow-up was also significantly reduced. This is key in treating a patient population in which the financial burden to treat chronic wounds and associated infections represents a large portion of the health care money spent for their medical care.


Effect of Vanadium Content on the Microstructure and Mechanical Properties of IN718 Alloy by Laser Cladding.
Microalloying vanadium can change the segregation state of Nb element in IN718 alloy, reduce the formation of harmful Laves phase and refine the dendritic structure of IN718 alloy during the laser process. Therefore, IN718 alloys with V content from 0.081 to 1.88 wt.% were prepared and evaluated. Metallographic microscopy and scanning electron microscopy were used to observe the corresponding morphology, structure, and distribution of elements. First of all, it was found that the addition of V refines the grain size of IN718 alloy and reduces the primary dendrite arm spacing. Secondly, adding V to IN718 alloy can reduce the porosity of the cladding layer. The elements are uniformly distributed in the cladding layer, and the addition of vanadium reduces the segregation degree of the Nb element, which is conducive to homogenization. In addition, microhardness and residual stress were also investigated. Finally, the addition of vanadium was shown to have no apparent effect on the tensile strength and yield strength but can significantly improve the elongation of IN718 alloy. In conclusion, the microstructure and mechanical properties of IN718 alloy with 0.081 wt.% vanadium content provide a new solution to improve the application level of IN718 alloy in laser cladding.


Prevalence of tetracycline resistance genes in oral bacteria.
Tetracycline is a broad-spectrum antibiotic used in humans, animals, and aquaculture; therefore, many bacteria from different ecosystems are exposed to this antibiotic. In order to determine the genetic basis for resistance to tetracycline in bacteria from the oral cavity, saliva and dental plaque samples were obtained from 20 healthy adults who had not taken antibiotics during the previous 3 months. The samples were screened for the presence of bacteria resistant to tetracycline, and the tetracycline resistance genes in these isolates were identified by multiplex PCR and DNA sequencing. Tetracycline-resistant bacteria constituted an average of 11% of the total cultivable oral microflora. A representative 105 tetracycline-resistant isolates from the 20 samples were investigated; most of the isolates carried tetracycline resistance genes encoding a ribosomal protection protein. The most common tet gene identified was tet(M), which was found in 79% of all the isolates. The second most common gene identified was tet(W), which was found in 21% of all the isolates, followed by tet(O) and tet(Q) (10.5 and 9.5% of the isolates, respectively) and then tet(S) (2.8% of the isolates). Tetracycline resistance genes encoding an efflux protein were detected in 4.8% of all the tetracycline-resistant isolates; 2.8% of the isolates had tet(L) and 1% carried tet(A) and tet(K) each. The results have shown that a variety of tetracycline resistance genes are present in the oral microflora of healthy adults. This is the first report of tet(W) in oral bacteria and the first report to show that tet(O), tet(Q), tet(A), and tet(S) can be found in some oral species.