Predictive Value of Serum Cytokeratin 19 Level for the Feasibility of Conserving Ovaries in Endometrial Cancer.
Objective: To determine the predictive value of cytokeratin 19 (CK19) for evaluating the safety of ovarian preservation in patients with endometrial cancer (EC). Methods: Five hundred and seventeen EC patients hospitalized from November 2010 to June 2016 were reviewed retrospectively. Pre-operative tumor biomarkers including CA125, HE4, CK19, and CA19-9 were obtained. Predictive biomarkers associated with ovarian metastasis were selected using univariate and multivariate Logistic regression. The cut-off values were determined by receiver operating characteristic (ROC) curves. Kaplan-Meier method and Cox multivariate regression model was used to perform survival analysis. Results: Among clinical parameters and biomarkers included, age > 65, type II EC, CA125 ≥ 35 u/ml, CK19 > 3.3 ng/ml, and myometrial invasion ≥ 50% depth appeared as significant predictors of the risk of ovarian involvement in univariable logistic analysis. In multivariable analysis, CK19 > 3.3 ng/ml (OR = 11.541, 95%CI: 1.968-67.668, P = 0.007) and Type II EC (OR = 8.336, 95%CI: 1.456-47.722, P = 0.017) were independent risk predictors of ovarian metastasis in pre-menopausal women. In pre-menopausal women with Type I EC (n = 142), CK19 level could satisfactorily predict the risk of ovarian metastasis (AUC = 0.860, 95%CI: 0.792-0.912, P < 0.001), and when the cut-off point was set as 2.45 ng/ml, the negative predictive value and negative likelihood ratio were 99% and 0.19, with the maximum Youden index of 0.598. Conclusions: The present study advocates the necessity of incorporating serum CK19 measurement into the pre-operative evaluation of EC, especially as extension of current standard approach with ovarian preservation counseling.


Elevated soluble thrombomodulin in the febrile stage related to patients at risk for dengue shock syndrome.
Children with dengue hemorrhagic fever (DHF) are at risk to develop dengue shock syndrome (DSS) for which neither marker has been demonstrated. The study was designed to investigate the markers of vascular endothelial cell injuries and dysfunction that might be used as early predictors of the subsequent manifestation of DSS. The blood samples from 111 patients with dengue fever, DHF and other febrile illness (OFI) were collected daily from the day of admission until discharge and at convalescent stage. The sample from the day of defervescence was defined as day 0, 1 day before defervescence was defined as day -1 and so on. Also, 1 day after defervescence was defined as day +1 and so on. Increased soluble thrombomodulin (sTM) was demonstrated in dengue-infected patients via an enzyme-linked immunosorbent assay. Patients with DSS (DHF grades III and IV) had higher concentrations of sTM than those with dengue fever, DHF grade I, II and OFIs from day -3 until day +2. Increased circulating endothelial cells were detected from day 0 until day +2 in DSS patients as compared with other groups. In addition, increased soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and soluble E-selectin were also found in dengue virus-infected patients as compared with OFIs. Blood sTM may be useful as an early predictor of DSS in dengue infected patients in the febrile stage. However, a further evaluation in a large prospective series is needed.


Lycopene Protects Keratinocytes Against UVB Radiation-Induced Carcinogenesis via Negative Regulation of FOXO3a Through the mTORC2/AKT Signaling Pathway.
Lycopene, one of the most potent anti-oxidants, has been reported to exhibit potent anti-proliferative properties in a wide range of cancer cells through modulation of the cell cycle and apoptosis. Forkhead box O3 (FOXO3a) plays a pivotal role in modulating the expression of genes involved in cell death. Herein, we investigated the role of FOXO3a signaling in the anti-cancer effects of lycopene. Results showed that lycopene pretreatment attenuated UVB-induced cell hyper-proliferation and promoted apoptosis, accompanied by decreased cyclin-dependent kinase 2 (CDK2) and CDK4 complex in both human keratinocytes and SKH-1 hairless mice. FOXO3a is phosphorylated in response to UVB irradiation and sequestered in the cytoplasm, while lycopene pretreatment rescued this sensitization. Gene ablation of FOXO3a attenuated lycopene-induced decrease in cell hyper-proliferation, CDK2, and CDK4 complex, indicating a critical role of FOXO3a in the lycopene-induced anti-proliferative effect of keratinocytes during UVB irradiation. Transfection with FOXO3a siRNA inhibited the lycopene-induced increase in cell apoptosis, BAX and cleaved PARP expression. Moreover, loss of AKT induced further accelerated lycopene-induced FOXO3a dephosphorylation, while loss of mechanistic target of rapamycin complex 2 (mTORC2) by transfection with RICTOR siRNA induced levels of AKT phosphorylation comparable to those obtained with lycopene. In contrast, overexpression of AKT or mTORC2 decreased the effects of lycopene on the expression of FOXO3a as well as AKT phosphorylation, suggesting that lycopene depends on the negative modulation of mTORC2/AKT signaling. Taken together, our findings demonstrate that the mTORC2/AKT/FOXO3a axis plays a critical role in the anti-proliferative and pro-apoptotic effects of lycopene in UVB-induced photocarcinogenesis. J. Cell. Biochem. 119: 366-377, 2018. © 2017 Wiley Periodicals, Inc.


Cell-type specific metabolic profiling of Arabidopsis thaliana protoplasts as a tool for plant systems biology.
Flow cytometry combined with cell sorting of protoplasts has previously been used successfully for transcript profiling of the Arabidopsis thaliana root. We have developed the technique further, and in this paper we present a robust and reliable method for metabolite profiling in specific cell types isolated from Arabidopsis roots. The method uses a combination of fluorescence-activated cell sorting and gas chromatography-time of flight-mass spectrometry analysis. Cortical and endodermal cells from the green fluorescent protein (GFP)-expressing enhancer trap line J0571 were analysed and compared with non-GFP-expressing cells and intact root tissue. Of the metabolites identified, several showed significant differences in concentration between cell types. Multivariate statistical analysis was used to compare metabolite patterns between cell and tissue types, showing that the patterns differed substantially. Isolation of specific cell populations combined with highly sensitive MS-analysis will be a powerful tool for future studies of plant metabolism, and can also be combined with transcript and protein profiling for in-depth analyses of cellular processes.


Long-term menstrual and reproductive function in patients with bulimia nervosa.
Menstrual dysfunction occurs frequently in patients with bulimia nervosa. Whether this is associated with diminished fertility is unknown. This study examined menstrual and reproductive function in bulimia nervosa patients retrospectively, with 10-15-year follow-ups. A total of 173 women with bulimia nervosa were interviewed an average of 11.5 years (SD=1.9) after initial assessment with the Structured Clinical Interview for DSM-IV and a questionnaire about menstruation, pregnancy, and eating disorder symptoms. At baseline assessment, 38.2% of the subjects reported regular menses, and 4.6% reported amenorrhea. At follow-up, the rate of amenorrhea was 16.8% (2.9% because of pregnancy). At baseline, 34.7% of the subjects had experienced at least one pregnancy. At follow-up, 74.6% had been pregnant at least once, and 1.7% reported an inability to conceive. These results suggest that while menstrual irregularities are common, bulimia nervosa appears to have little impact on later ability to achieve pregnancy.


[The practice guideline 'Urolithiasis' (first revision) from the Dutch College of General Practitioners; a response from the perspective of urology].
The Dutch College of General Practitioners has made a useful revision of its practice guideline 'Urolithiasis', in which new imaging techniques and medical treatment modalities are implemented. Sonography is useful but CT has now become the gold standard imaging technique. CT images should be examined by both the radiologist and the urologist. Therefore, requests for CT should preferably be made by urologists. This guideline should focus more on the differential diagnosis of urolithiasis in the acute phase, and in particular on aortic aneurysm in the elderly patient. Complaints of irritative micturition should be considered to indicate a distal localization ofa ureteral stone rather than a urinary tract infection. When prescribing selective alpha-1 blocking agents, the doctor should inform the patient that both retrograde ejaculation and orthostatic hypotension are side effects.


Comment on "Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation".
The cause of contamination and dissemination of leiomyoma tissue particles and cells in the peritoneal cavity during myomectomy is a challenging issue for both clinicians and researchers. Therefore, the article by Huang et al. recently published in your journal is the subject of this letter. We comment on the role of laparoscopic condition in xenograft implantation and also highlighted the shortcomings of this study. The surgical technique of intramural fibroid enucleation, cell spillage during morcellation and postsurgical hormonal impact on the development of parasitic myomas become evident, while the contribution of CO2 insufflation, the fibroid's nature, mutations and pseudocapsule impacts on angiogenesis are not clear. In addition, an exploration of the exact origin of implanted fragments harvested from the fibroid tissue and their nature might play a significant role in the implantation and the angiogenesis induction ability of xenografts. Taking into account the current literature in the scope of this study, we suggest that the factors involved in development of parasitic myomas can be classified as confirmed and doubtful contributions.


Unequal physical activity among children with cerebral palsy in Sweden-A national registry study.
To examine the extent to which sex, country of birth, and functional aspects influence participation in physical education and physical leisure activity among children with cerebral palsy (CP) in Sweden. This national cross-sectional registry study included children with CP aged 6 to 18 years who participated in the Swedish national quality registry, the Cerebral Palsy Follow-up Program, CPUP, in 2015. Comparisons and associations between sex, country of birth, and functional aspects and physical leisure/physical education were examined using chi-squared and multivariable logistic regression analysis. The study included 1935 children. Of them, 1625 (87%) reported participating in physical education and 989 (53%) reported participating in physical leisure activity. Children born in Sweden had higher odds of participating in physical education (OR: 1.99; 95% CI: 1.20-3.28) and physical leisure activity (OR: 2.51; 95% CI: 1.70-3.72) compared with children born outside Europe. Greater impairment of gross motor function was associated with lower participation levels. Boys participated slightly more frequently in leisure activities than girls. Enhancing social inclusion with regard to disability, birth country, and sex are important and achievable goals for policymakers and practitioners for promoting participation in physical activity for children and adolescents with CP.


Fitch ratings. Health care special report.
Fitch Ratings continues to believe that the current and projected personnel shortages, especially among registered nurses (RNs). present one of the greatest operating challenges for health care providers nationwide. As noted in Fitch Research on "Health Care Staffing Shortage," dated June 21, 2001 (available on Fitch's web site at www.fitchratings. com), staffing is an area that is creating enormous expense inflation for health care providers and presenting one of the biggest areas of uncertainty in assessing an organization's credit quality. Shortages are becoming increasingly widespread, affecting health care providers in urban and rural areas regardless of size. Since health care is a labor intensive business, salary and benefit costs are key determinants of profitability. Fitch believes the attention given to the nursing shortage and potential looming crisis has created a sense of urgency, with many hospitals developing innovative strategies for work force development. In addition, federal, state, and local governments are creating programs and/or providing financial support to help alleviate shortages. Yet, the benefits of many of these initiatives may not be realized for many years, and Fitch expects health care providers to continue experiencing inflating salary and benefit expenses with growing temporary staffing usage and competitive pressure to increase overall compensation. Fitch believes managing labor costs is critical to achieving profitability, especially as the ability to increase revenue diminishes. Fitch believes the nursing shortage will continue to represent an area of extreme expense pressure for health care providers for years to come. Imbalanced supply and demand, which is expected to worsen as retiring nurses outstrip replacements, should create financial strain for many providers in an industry that is gearing up to meet the aging population's anticipated demand for more services. Fitch plans to closely monitor management strategies for dealing with vacancy and turnover rates, as well as trends in agency spending, to determine financial implications among its rated portfolio.


eIF3k regulates apoptosis in epithelial cells by releasing caspase 3 from keratin-containing inclusions.
Keratins 8 and 18 (collectively referred to as K8/K18) are the major components of intermediate filaments of simple epithelial cells. Recent studies have revealed the function of K8/K18 in apoptosis modulation. Here, we show that eIF3k, originally identified as the smallest subunit of eukaryotic translation initiation factor 3 (eIF3) complexes, also localizes to keratin intermediate filaments and physically associates with K18 in epithelial cells. Upon induction of apoptosis, eIF3k colocalizes with K8/K18 in the insoluble cytoplasmic inclusions. Depletion of endogenous eIF3k de-sensitizes simple epithelial cells to various types of apoptosis through a K8/K18-dependent mechanism and promotes the retention of active caspase 3 in cytoplasmic inclusions by increasing its binding to keratins. Consequently, the cleavage of caspase cytosolic and nuclear substrates, such as ICAD and PARP, respectively, is reduced in eIF3k-depleted cells. This study not only reveals the existence of eIF3k in a subcellular compartment other than the eIF3 complex, but also identifies an apoptosis-promoting function of eIF3k in simple epithelial cells by relieving the caspase-sequestration effect of K8/K18, thereby increasing the availability of caspases to their non-keratin-residing substrates.


Mineralized, obstructive cardiac myxoma with chondroid differentiation in a cocker spaniel.
A 12-year-old castrated male cocker spaniel dog was referred for evaluation of signs consistent with right-sided heart failure. Thoracic radiography revealed mineralization in the region of the right atrium. Echocardiography identified a mass partially filling the right atrium and right ventricle and obstructing flow through the right heart. These findings were confirmed at necropsy and histopathologic features were consistent with myxoma with chondroid differentiation.


Determination of Nanogram Microparticles from Explosives after Real Open-Air Explosions by Confocal Raman Microscopy.
Explosives are increasingly being used for terrorist attacks to cause devastating explosions. The detection of their postblast residues after an explosion is a high challenge, which has been barely investigated, particularly using spectroscopic techniques. In this research, a novel methodology using confocal Raman microscopy has been developed for the analysis of postblast residues from 10 open-air explosions caused by 10 different explosives (TNT, RDX, PETN, TATP, HMTD, dynamite, black powder, ANFO, chloratite, and ammonal) commonly used in improvised explosive devices. The methodology for the determination of postblast particles from explosives consisted of examining the samples surfaces with both the naked eye, first, and microscopically (10× and 50×), immediately afterward; and finally, analyzing the selected residues by confocal Raman spectroscopy in order to identify the postblast particles from explosives. Interestingly, confocal Raman microscopy has demonstrated to be highly suitable to rapidly, selectively, and noninvasively analyze postblast microscopic particles from explosives up to the nanogram range.


Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants.
The three pan-genotypic HCV NS3/4A protease inhibitors (PIs) currently in clinical use-grazoprevir, glecaprevir, and voxilaprevir-are quinoxaline-based P2-P4 macrocycles and thus exhibit similar resistance profiles. Using our quinoxaline-based P1-P3 macrocyclic lead compounds as an alternative chemical scaffold, we explored structure-activity relationships (SARs) at the P2 and P4 positions to develop pan-genotypic PIs that avoid drug resistance. A structure-guided strategy was used to design and synthesize two series of compounds with different P2 quinoxalines in combination with diverse P4 groups of varying sizes and shapes, with and without fluorine substitutions. Our SAR data and cocrystal structures revealed the interplay between the P2 and P4 groups, which influenced inhibitor binding and the overall resistance profile. Optimizing inhibitor interactions in the S4 pocket led to PIs with excellent antiviral activity against clinically relevant PI-resistant HCV variants and genotype 3, providing potential pan-genotypic inhibitors with improved resistance profiles.


Oxidative cyclizations: the asymmetric synthesis of (-)-alliacol A.
A tandem anodic coupling-Friedel-Crafts alkylation strategy has been used to rapidly complete the asymmetric synthesis of alliacol A. The anodic oxidation reaction allowed for the generation of a new bond between two nucleophiles. In the synthesis, the absolute stereochemistry of the final natural product is set relative to a methyl group that is incorporated early in the sequence using an asymmetric Michael reaction.


Liothyronine for Depression: A Review and Guidance for Safety Monitoring.
Objective: The objective of this review is to discuss triiodothyronine's (T3, liothyronine) mechanism of action, efficacy in enhancement and augmentation trials, and dosing and safety considerations for the treatment of depression. Method: A literature search of PubMed was performed using search terms depression, augmentation, antidepressant, and liothyronine. Only English-language studies of subjects with unipolar depression were included from the past 50 years. Results: Most studies have shown that liothyronine is an efficacious enhancement and augmentation strategy for depression in combination with antidepressants, primarily tricyclic antidepressants and selective serotonin reuptake inhibitors. Conclusion: With appropriate baseline and follow-up safety monitoring, liothyronine augmentation can be a safe and effective treatment for unipolar depression. Larger studies of longer duration assessing liothyronine efficacy with serotonin norepinephrine reuptake inhibitors and multimodal antidepressants are needed.


Analysis of Noun Phrase Ambiguity in Narratives Reveals Differences in Referential Establishment But Not Cohesion for Older Autistic Children.
Stories told by autistic narrators often contain relatively frequent use of ambiguous references. However, it remains unclear whether this ambiguity is driven by ambiguous character establishment (e.g., "Once upon a time, she/the girl…") and/or ambiguous cohesion (e.g., "Two girls lived in a castle. She/The girl…"). In this study, we directly compared rates of each type of ambiguity within and between narratives told by autistic and non-autistic children, to determine which type of ambiguity is relatively more common in narratives told by autistic children. Thirty-three 10- to 17-year-old autistic participants (n = 17) and non-autistic peers (n = 16), who were not statistically different in age, standardized language scores, and IQ scores (p > .8 for all), watched two short animated videos alone and then described the videos' events to two listeners who were openly unfamiliar with the videos. We transcribed video recordings of narratives and coded all referential noun phrases (NPs) as either clear or ambiguous. We further categorized ambiguous NPs as either ineffective introduction or ineffective cohesion. Autistic children produced significantly higher rates of ambiguous establishment than non-autistic peers, whereas between-group comparisons' rates of ambiguous cohesion were not statistically significant. Older children on the autism spectrum show differences in the way they introduce characters, selecting NP types that are only appropriate when their listener is already familiar with the referent. In contrast, once they have introduced characters, they show cohesive skills that are comparable to those of non-autistic peers. Findings support theories arguing that autistic children show differences in their application of social pragmatic principles (listener/context-specific pragmatic rules), whereas their use of linguistic pragmatics (context-independent rules) is similar to that of non-autistic peers.


Does orthodontic treatment before the age of 18 years improve oral health-related quality of life? A systematic review and meta-analysis.
Orthodontics aims to improve oral health-related quality of life (OHRQoL). In this systematic review, we examined the evidence for changes in OHRQoL after orthodontic treatment for patients treated before they were 18 years old. The participants were patients aged less than 18 years. The interventions were nonorthognathic and cleft orthodontic treatment. The comparisons were before and after orthodontic treatment, or nonorthodontic control. The outcomes were validated measures of OHRQoL. The study designs were randomized controlled trials, controlled clinical trials, prospective cohort studies, and cross-sectional or case-control studies. Multiple electronic databases were searched, with no language restrictions; authors were contacted, and reference lists screened. The Newcastle-Ottawa scale was used for quality assessments. Screening, data extraction, and quality assessments were performed by 2 investigators independently. We found 1590 articles and included 13 studies (9 cohort, 3 cross sectional, and 1 case control), with 6 in the meta-analyses. All were judged of low or moderate quality. A moderate improvement in OHRQoL was observed before and after orthodontic treatment (n = 243 participants; standardized mean difference, -0.75; 95% CI, -1.15 to -0.36) particularly in the dimensions of emotional well-being (n = 213 participants; standardized mean difference, -0.61; 95% CI, -0.80 to -0.41) and social well-being (n = 213 participants; standardized mean difference, -0.62; 95% CI, -0.82 to -0.43). Orthodontic treatment during childhood or adolescence leads to moderate improvements in the emotional and social well-being dimensions of OHRQoL, although the evidence is of low and moderate quality. More high quality, longitudinal, prospective studies are needed.


[Homicide and mutilation of the body--review of the literature].
In two hitherto not elucidated murders of two young women the bodies were devastated in a peculiar way and some organs were removed. The author presents a review of literature focused on manipulation with the human body and also with regard to the ability to commit such operations.


Sports training enhances visuo-spatial cognition regardless of open-closed typology.
The aim of this study was to investigate the effects of open and closed sport participation on visuo-spatial attention and memory performance among young adults. Forty-eight young adults-16 open-skill athletes, 16 closed-skill athletes, and 16 non-athletes controls-were recruited for the study. Both behavioral performance and event-related potential (ERP) measurement were assessed when participants performed non-delayed and delayed match-to-sample task that tested visuo-spatial attention and memory processing. Results demonstrated that regardless of training typology, the athlete groups exhibited shorter reaction times in both the visuo-spatial attention and memory conditions than the control group with no existence of speed-accuracy trade-off. Similarly, a larger P3 amplitudes were observed in both athlete groups than in the control group for the visuo-spatial memory condition. These findings suggest that sports training, regardless of typology, are associated with superior visuo-spatial attention and memory performance, and more efficient neural resource allocation in memory processing.


Long-term results with cisapride in Parkinson's disease.
In this study, we examined whether there is a long-term effect of cisapride on colonic transit in Parkinson's disease. Twenty-five patients (11 women, 14 men; average age, 64.4 years; moderate symptoms) were studied and treated initially with cisapride, 5 mg, twice a day, and after the first week with cisapride, 10 mg, twice a day. Colonic transit was measured by radioopaque markers at various stages: after 1 week, 6 months, and 1 year. In untreated patients, transit took 131 h; after 1 week with cisapride, it was accelerated to 81 h. After 6 months, colonic transit time amounted to 99 and 118 h, respectively, after 1 year. Cisapride seems to be highly effective initially. After 6 months, a significant but reduced effect was seen, and after 1 year, only a small effect could be demonstrated.


Health impact of the Anthropocene: the complex relationship between gut microbiota, epigenetics, and human health, using obesity as an example.
The growing prevalence of obesity worldwide poses a public health challenge in the current geological epoch, the Anthropocene. Global changes caused by urbanisation, loss of biodiversity, industrialisation, and land-use are happening alongside microbiota dysbiosis and increasing obesity prevalence. How alterations of the gut microbiota are associated with obesity and the epigenetic mechanism mediating this and other health outcome associations are in the process of being unveiled. Epigenetics is emerging as a key mechanism mediating the interaction between human body and the environment in producing disease. Evidence suggests that the gut microbiota plays a role in obesity as it contributes to different mechanisms, such as metabolism, body weight and composition, inflammatory responses, insulin signalling, and energy extraction from food. Consistently, obese people tend to have a different epigenetic profile compared to non-obese. However, evidence is usually scattered and there is a growing need for a structured framework to conceptualise this complexity and to help shaping complex solutions. In this paper, we propose a framework to analyse the observed associations between the alterations of microbiota and health outcomes and the role of epigenetic mechanisms underlying them using obesity as an example, in the current context of global changes within the Anthropocene.


Expression of GULP1 in bronchial epithelium is associated with the progression of emphysema in chronic obstructive pulmonary disease.
GULP1 functions as a cytoplasmic adaptor protein involved in the engulfment of apoptotic cells. The aim of this study was to investigate the expression and/or promoter methylation of GULP1 in the bronchial tissue and the lung parenchyma of chronic obstructive pulmonary disease (COPD) patients and control subjects without COPD (non-smokers and smokers). Using a case-control design, we selected a group of 15 subjects with non-small cell lung carcinoma (NSCLC), 15 subjects with COPD, 9 subjects of without COPD (4 non-smokers and 5 smokers) as controls. We studied the expression of GULP1 in the bronchial tissue and the lung parenchyma by means of immunohistochemistry (IHC). To understand the mechanistic aspect of GULP1 expression in COPD and NSCLC, we performed quantitative methylation specific PCR (QMSP) in cases and controls of COPD and NSCLC. Our IHC analysis revealed that GULP1 was not expressed in pneumocytes or alveolar macrophages of COPD patients, however, GULP1 expression was detected at different levels in bronchial epithelium. GULP1 expression statistically correlated with severity of COPD-emphysema (p = 0.001, χ2 test). GULP1 promoter methylation was not observed by QMSP assay in any of the samples thereby excluding the role of promoter methylation in differential expression of GULP1 in COPD and NSCLC. This study provides preliminary observations on the differences in GULP1 expression in different cellular components of lung tissues from COPD and control subjects. Our findings suggest a potential role for GULP1 in the pathogenesis and progression of COPD-emphysema that warrants further investigation.


Quantum amplified isomerization in polymers based on triplet chain reactions.
Photoinitiated triplet quantum amplified isomerizations (QAI) of substituted Dewar benzene derivatives in polymeric media are reported. The quantum efficiencies and the ultimate extents of reactant-to-product conversions increase significantly with the incorporation of appropriate co-sensitizers; compounds whose triplet energies are similar to or lower than that of the sensitizer and close to that of the reactant. These co-sensitizers serve to promote chain-propagating energy transfer processes and thereby increase the action sphere of photosensitization. Isomerization quantum yields increase, as predicted, with increasing concentrations of the reactants and the co-sensitizers. Chain amplifications as large as approximately 16 and extents of conversion that approach 100% have been achieved. Mechanistic schemes are proposed to account for the dynamics of the inherent energy transfer processes and provide a predictively useful model for the design of a new class of photoresponsive polymers based on changes in the refractive index of the materials.


Annual banned-substance review: analytical approaches in human sports drug testing.
The annual update of the list of prohibited substances and doping methods as issued by the World Anti-Doping Agency (WADA) allows the implementation of most recent considerations of performance manipulation and emerging therapeutics into human sports doping control programmes. The annual banned-substance review for human doping controls critically summarizes recent innovations in analytical approaches that support the efforts of convicting cheating athletes by improved or newly established methods that focus on known as well as newly outlawed substances and doping methods. In the current review, literature published between October 2008 and September 2009 reporting on new and/or enhanced procedures and techniques for doping analysis, as well as aspects relevant to the doping control arena, was considered to complement the 2009 annual banned-substance review.


Does medical students' diagnostic performance improve by observing examples of self-explanation provided by peers or experts?
Educational strategies that promote the development of clinical reasoning in students remain scarce. Generating self-explanations (SE) engages students in active learning and has shown to be an effective technique to improve clinical reasoning in clerks. Example-based learning has been shown to support the development of accurate knowledge representations. The purpose of this study was to investigate the effect of combining student's SE and observation of peer's or expert's SE examples on diagnostic performance. Fifty-three third-year medical students were assigned to a peer SE example, an expert SE example or control (no example) group. All participants solved a set of the same four clinical cases (training cases), 1-after SE, 2-after listening to a peer or expert SE example or after a control task, and 3-1 week later. They solved a new set of four different cases (transfer cases) also 1 week later. For training cases, students improved significantly their diagnostic performance overtime but the main effect of group was not significant suggesting that students' SE mainly drives the observed effect. On transfer cases, there was no difference between the three groups (p > .05). Educational implications are discussed and further studies on different types of examples and additional strategies to help students actively process examples are proposed.


Digital multiple correlation for pattern recognition.
A method of digital multiple correlation for rotation-invariant recognition has been developed. It is also a computer simulation of an incoherent optodigital hybrid system previously introduced. Speed and flexibility of the digital system are investigated.


Medial approach for fixation of displaced supracondylar fractures of the humerus in children.
This study aimed at evaluating our protocol for displaced Gartland Type 3 supracondylar fractures of the humerus in children. Forty-eight children had 49 fractures during the study period, from 1997 to 2002; they were included in the study. Their mean age was 7.02 years. They all were treated with crossed K-wires. The medial wire was always put under direct vision through a medial approach. All fractures were manipulated maximum twice. Ten patients (23.25%) required open reduction which was done through the same medial approach which we use for medial pin placement. No patient had iatrogenic ulnar nerve neuropathy. At final review radiographs were taken of the normal and operated sides and films were compared with immediate post-op films. The postoperative mean value of Bauman's angle in the affected elbow was 76.7 degrees with a range of +/- 1.0 degrees and 74.8 degrees with a range of +/- 0.6 degrees on the unaffected elbow. Carrying angle and movements of operated and normal sides were measured at review. According to Flynn's criteria, all patients showed satisfactory results. We conclude that cross K-wiring gives excellent results; the medial approach provides an excellent view of the supracondylar area, leaves a cosmetically acceptable scar and enables to avoid iatrogenic injury to the ulnar nerve.


Ribosomal selection of mRNAs with degenerate initiation triplets.
To assess the influence of degenerate initiation triplets on mRNA recruitment by ribosomes, five mRNAs identical but for their start codon (AUG, GUG, UUG, AUU and AUA) were offered to a limiting amount of ribosomes, alone or in competition with an identical AUGmRNA bearing a mutation conferring different electrophoretic mobility to the product. Translational efficiency and competitiveness of test mRNAs toward this AUGmRNA were determined quantifying the relative amounts of the electrophoretically separated wt and mutated products synthesized in vitro and found to be influenced to different extents by the nature of their initiation triplet and by parameters such as temperature and nutrient availability in the medium. The behaviors of AUAmRNA, UUGmRNA and AUGmRNA were the same between 20 and 40°C whereas the GUG and AUUmRNAs were less active and competed poorly with the AUGmRNA, especially at low temperature. Nutrient limitation and preferential inhibition by ppGpp severely affected activity and competitiveness of all mRNAs bearing non-AUG starts, the UUGmRNA being the least affected. Overall, our data indicate that beyond these effects exclusively due to the degenerate start codons within an optimized translational initiation region, an important role is played by the context in which the rare start codons are present.


Effects of prolonged poisoning by Russell's viper venom on blood coagulation, platelets and fibrinolysis.
The effects of Russell's viper venom on blood coagulation, platelets and the fibrinolytic enzyme system were studied in rabbits after injecting repeated doses of 0.05 MLD of the venom. Thrombocytopenia was the earliest change to appear. It was followed by rise in serum fibrinogen degradation products and prolongation of prothrombin time, activated partial thromboplastin time and thrombin time indicating a progressive consumption coagulopathy and activation of fibrinolysis. Red blood cell morphology was unchanged during the first three weeks; whereas the fragmentation appeared after the fourth week and it increased in severity with further envenomations, i.e. when chronic DIC was established.


Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection.
Present study outlines a comprehensive view of published information about the underlying mechanisms operational for progression of chronic hepatitis C virus (HCV) infection to development of hepatocellular carcinoma (HCC). These reports are based on the results of animal experiments and human based studies. Although, the exact delineated mechanism is not yet established, there are evidences available to emphasize the involvement of HCV induced chronic inflammation, oxidative stress, insulin resistance, endoplasmic reticulum stress, hepato steatosis and liver fibrosis in the progression of HCV chronic disease to HCC. Persistent infection with replicating HCV not only initiates several liver alterations but also creates an environment for development of liver cancer. Various studies have reported that HCV acts both directly as well as indirectly in promoting this process. Whereas HCV related proteins, like HCV core, E1, E2, NS3 and NS5A, modulate signal pathways dysregulating cell cycle and cell metabolism, the chronic infection produces similar changes in an indirect way. HCV is an RNA virus and does not integrate with host genome and therefore, HCV induced hepatocarcinogenesis pursues a totally different mechanism causing imbalance between suppressors and proto-oncogenes and genomic integrity. However, the exact mechanism of HCC inducement still needs a full understanding of various steps involved in this process.


The globally invasive small Indian mongoose Urva auropunctata is likely to spread with climate change.
Invasive alien species represent one of the major factors of global loss of biodiversity and disruption of natural ecosystems. The small Indian mongoose, Urva auropunctata, is considered one of the wild carnivore species with the greatest negative impact on global biodiversity. Understanding of the factors underpinning the species' distribution and potential dispersion in a context of climate change thus appears crucial in the conservation of native ecosystems. Here we modelled the current and future climatically favourable areas for the small Indian mongoose using Ecological Niche Modelling based on data sets filtrated in environmental spaces. Projections from these models show extensive current favourable geographical areas, covering continental and insular regions within tropical and sub-tropical latitudes. Moreover, predictions for 2050 reveal that climate change is likely to expand current favourable areas north of the current favourable spaces, particularly in Eastern Europe. This climate-induced expansion is particularly worrisome given that the species is already spreading in the Balkan region. Our projections suggest that it is very likely that the small Indian mongoose will have an increasing influence on ecosystems and biodiversity in Europe by 2050.


Gli3 in fetal thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of Shh.
Gli3 is a Hedgehog (Hh)-responsive transcription factor that can function as a transcriptional repressor or activator. We show that Gli3 activity in mouse thymic epithelial cells (TECs) promotes positive selection and differentiation from CD4+ CD8+ to CD4+ CD8- single-positive (SP4) cells in the fetal thymus and that Gli3 represses Shh Constitutive deletion of Gli3, and conditional deletion of Gli3 from TECs, reduced differentiation to SP4, whereas conditional deletion of Gli3 from thymocytes did not. Conditional deletion of Shh from TECs increased differentiation to SP4, and expression of Shh was upregulated in the Gli3-deficient thymus. Use of a transgenic Hh reporter showed that the Hh pathway was active in thymocytes, and increased in the Gli3-deficient fetal thymus. Neutralisation of endogenous Hh proteins in the Gli3-/- thymus restored SP4 differentiation, indicating that Gli3 in TECs promotes SP4 differentiation by repression of Shh Transcriptome analysis showed that Hh-mediated transcription was increased whereas TCR-mediated transcription was decreased in Gli3-/- thymocytes compared with wild type.


Understanding Transcription Factor Regulation by Integrating Gene Expression and DNase I Hypersensitive Sites.
Transcription factors are proteins that bind to DNA sequences to regulate gene transcription. The transcription factor binding sites are short DNA sequences (5-20 bp long) specifically bound by one or more transcription factors. The identification of transcription factor binding sites and prediction of their function continue to be challenging problems in computational biology. In this study, by integrating the DNase I hypersensitive sites with known position weight matrices in the TRANSFAC database, the transcription factor binding sites in gene regulatory region are identified. Based on the global gene expression patterns in cervical cancer HeLaS3 cell and HelaS3-ifnα4h cell (interferon treatment on HeLaS3 cell for 4 hours), we present a model-based computational approach to predict a set of transcription factors that potentially cause such differential gene expression. Significantly, 6 out 10 predicted functional factors, including IRF, IRF-2, IRF-9, IRF-1 and IRF-3, ICSBP, belong to interferon regulatory factor family and upregulate the gene expression levels responding to the interferon treatment. Another factor, ISGF-3, is also a transcriptional activator induced by interferon alpha. Using the different transcription factor binding sites selected criteria, the prediction result of our model is consistent. Our model demonstrated the potential to computationally identify the functional transcription factors in gene regulation.


Condylar intramedullary intraosseous lipoma: Contribution of a new case and review of the literature.
Lipoma is the most common benign tumour of the human body, being intraosseous involvement very rare. Just 1 to 4% of all cases of lipoma are located in the oral cavity, only 0.1% being intraosseous. The jaw is its most uncommon bone location. Etiology of intraosseous lipoma (IOL) is unknown, although several theories have been proposed. Usually asymptomatic, the symptoms, when present, will depend on its location and size. Its origin may be intraosseous or juxtacortical. A biopsy is essential for diagnosis, and definitive treatment involves resection or curettage of the lesion. The aim of this paper is to present a new case of intramedullary intraosseous lipoma of the mandible with involvement of the left mandibular ramus and condylar neck. A case of intramedullary intraosseous lipoma (IOL) on the left mandibular ramus and condyle is presented. No history of trauma in temporomandibular joint existed. The radiology showed a radiolucent multi-lobulated lesion with values of attenuation in the range of fat. Curettage is performed and the histopathology showed a conglomerate of adipocytes without trabeculae, calcifications or atypia. According to the bibliography 24 cases of mandibular IOL have been described. This is the second reported case of condylar involvement and the first with cortical expansion. Lipoma intraosseous is a very rare benign bone neoplasm. Histology is required for the differential diagnosis from other radiolucent lesions. The IOL treatment is the curettage with a good prognosis, although malignant transformation to liposarcoma has been reported in other locations. It is a disease with a difficult differential diagnosis, therefore the publication of new cases is important. Key words:Intraosseous lipoma, lipoma, jaw tumour, condylar tumour.


Medical Education During the COVID-19 Pandemic: A Single Institution Experience.
Social distancing to curb the COVID-19 pandemic has caused suspension of classroom teaching in all educational institutions. We implemented a novel online classroom platform at our institute to continue medical education. The program attracted encouraging feedback from the students. It may serve as a model for uninterrupted teaching and training during times of crisis.


Predictors of breast cancer mortality among white and black women in large United States cities: an ecologic study.
We employed a city-level ecologic analysis to assess predictors of race-specific (black and white) breast cancer mortality rates. We used data from the National Center for Health Statistics and the US Census Bureau to calculate 2010-2014 race-specific breast cancer mortality rates (BCMR) for 47 of the largest US cities. Data on potential city-level predictors (e.g., socioeconomic factors, health care resources) of race-specific BCMR were obtained from various publicly available datasets. We constructed race-specific multivariable negative binomial regression models to estimate rate ratios (RR) and 95% confidence intervals (CIs). Predictors of the white BCMR included white/black differences in education (RR 0.95; CI 0.91-0.99), number of religious congregations (RR 0.87; CI 0.77-0.97), and number of Medicare primary care physicians (RR 1.15; CI 1.04-1.28). Predictors of the black rate included white/black differences in household income (RR 1.03; CI 1.01-1.05), number of mammography facilities (RR 1.07; CI 1.03-1.12), and mammogram use (RR 0.93; CI 0.89-0.97). Our ecologic analysis found that predictors of breast cancer mortality differ for the black and white rate. The results of this analysis could help inform interventions at the local level.


Quasielastic neutron scattering experiments including activation energies and mathematical modeling of methyl halide dynamics.
Quasielastic neutron scattering experiments were carried out using the multichopper time-of-flight spectrometer V3 at the Hahn-Meitner Institut, Germany and the backscattering spectrometer at Forschungszentrum Julich, Germany. Activation energies for CH(3)X, X=F, Cl, Br, and I, were obtained. In combination with results from previous inelastic neutron scattering experiments the data were taken to describe the dynamics of the halides in terms of two different models, the single particle model and the coupling model. Coupled motions of methyl groups seem to explain the dynamics of the methyl fluoride and chloride; however, the coupling vanishes with the increase of the mass of the halide atom in CH(3)Br and CH(3)I.


Changing the Context Is Important and Necessary, but Not Sufficient, for Reducing Adolescent Risky Sexual Behavior: A Reply to Steinberg (2015).
Starting school later, keeping adolescents busy with structured programming, and making free condoms available, as Steinberg (2015) suggests, are important and necessary steps, but they are simply not sufficient if the goal is reducing sexually transmitted infections and unplanned pregnancy. We agree that the current state of affairs, which in many schools involves sexuality education using programs that are not empirically supported, is unacceptable. However, abandoning sexuality education entirely would leave adolescents ill equipped to protect themselves. Despite the fact that current intervention technology is neither perfect nor optimally effective, there are empirically supported, school-based sexual risk reduction interventions that teach these skills and are readily available. In addition, even though we agree that structured afternoon programs for school-aged adolescents would reduce the opportunity for sexual risk behavior during the school years, such programs would not address the demographic reality of sexual risk that continues for adolescents and emerging adults far past the end of traditional secondary education. We believe Steinberg's suggestions are an excellent start and ought to be implemented. But complementary to this approach should be the use of existing empirically supported sexual risk reduction interventions and research into the development of even more effective interventions.


A study to investigate women's experiences of radiation enteritis following radiotherapy for cervical cancer.
Radiotherapy remains the standard treatment for cervical cancer, especially for more advanced disease. It is estimated that the prevalence of chronic radiation enteritis (CRE) post-radiotherapy is in the region of 5-15%. However, preliminary studies at the study hospital suggest the problem to be more widespread (C. Israel, unpublished data). This qualitative study of 10 cervical cancer patients investigates experiences of CRE and its impact on quality of life. Informed volunteers participated in one-to-one tape-recorded in-depth interviews exploring experiences following treatment. These interviews were transcribed verbatim and analysed using NUD*IST Nvivo. The majority of women reported side-effects from radiotherapy, predominantly diarrhoea. CRE had a significant impact upon the physical, psychological and social aspects of life of sufferers, enforcing some to be virtually housebound. Other sufferers were managing their symptoms with regular medication and/or self-imposed restricted diets. Few of these women had ever sought professional help in dealing with their problems because of embarrassment or reluctance to complain. If untreated the side-effects of CRE have a disabling affect on sufferers, who may be reluctant to seek help about their symptoms. Health professionals need to be more pro-active in identifying and caring for sufferers of CRE.


[Simultaneous determination of principal components and related substances of raw material drug of ammonium glycyrrhizinate by reversed-phase high performance liquid chromatography].
An analytical method for the simultaneous determination of 18alpha-glycyrrhizic acid, 18beta-glycyrrhizinic acid, related substances A and B and drug quality standard by reversed-phase high performance liquid chromatography (RP-HPLC) was established. The assay was carried out on a Durashell-C18 column (250 mm x 4.6 mm, 5 microm) with 10 mmol/L ammonium perchlorate (the pH value was adjusted to 8.20 with ammonia)-methanol (48:52, v/v) as mobile phase at a flow rate of 0.80 mL/min, and the detection wavelength was set at 254 nm. The column temperature was 50 degrees C and the injection volume was 10 microL. Under the separation conditions, the calibration curves of the analytes showed good linearities within the mass concentrations of 0.50 -100 mg/L (r > 0.999 9). The detection limits for 18alpha-glycyrrhizic acid, 18beta-glycyrrhizinic acid, related substances A and B were 0.15, 0.10, 0.10, 0.15 mg/L, respectively. The average recoveries were between 97.32% and 99.33% (n = 3) with the relative standard deviations (RSDs) between 0.05% and 1.06%. The method is sensitive, reproducible, and the results are accurate and reliable. The method can be used for the determination of principal components and related substances of ammonium glycyrrhizinate for the quality control of raw material drug of ammonium glycyrrhizinate.


Flavoenzyme-mediated reduction reactions and antitumor activity of nitrogen-containing tetracyclic ortho-quinone compounds and their nitrated derivatives.
Nitrogen-based tetracyclic ortho-quinones (naphtho[1'2':4.5]imidazo[1,2-a]pyridine-5,6-diones, NPDOs) and their nitro-substituted derivatives (nitro-(P)NPDOs) were obtained by condensation of substituted 2,3-dichloro-1,4-naphthoquinones with 2-amino-pyridine and -pyrimidine and nitration at an elevated temperature. The structural features of the compounds as well as their global and regional electrophilic potency were characterized by means of DFT computation. The compounds were highly reactive substrates of single- and two-electron (hydride) - transferring P-450R (CPR; EC 184.108.40.206) and NQO-1 (DTD; EC 188.8.131.52), respectively, concomitantly producing reactive oxygen species. Their catalytic efficiency defined in terms of the apparent second-order rate constant (kcat/KM (Q)) values in P-450R- and NQO-1-mediated reactions varied in the range of 3-6 × 107 M-1 s-1 and 1.6-7.4 × 108 M-1 s-1, respectively. The cytotoxic activities of the compounds on tumor cell lines followed the concentration-dependent manner exhibiting relatively high cytotoxic potency against breast cancer MCF-7, with CL50 values of 0.08-2.02 µM L-1 and lower potency against lung cancer A-549 (CL50 = 0.28-7.66 µM L-1). 3-nitro-pyrimidino-NPDO quinone was the most active compound against MCF-7 with CL50 of 0.08 ± 0.01 µM L-1 (0.02 µg mL-1)) which was followed by 3-nitro-NPDO with CL50 of 0.12 ± 0.03 µM L-1 (0.035 µg mL-1)) and 0.28 ± 0.08 µM L-1 (0.08 µg mL-1) on A-549 and MCF-7 cells, respectively, while 1- and 4-nitro-quinoidals produced the least cytotoxic effects. Tumor cells quantified by AO/EB staining showed that the cell death induced by the compounds occurs primarily through apoptosis.


Ocular surface squamous neoplasia in HIV-infected patients: current perspectives.
Ocular surface squamous neoplasia (OSSN) refers to a spectrum of conjunctival and corneal epithelial tumors including dysplasia, carcinoma in situ, and invasive carcinoma. In this article, we discuss the current perspectives of OSSN associated with HIV infection, focusing mainly on the epidemiology, pathophysiology, clinical manifestations, diagnosis, and treatment of these tumors in patients with HIV. Upsurge in the incidence of OSSN with the HIV pandemic most severely affected sub-Saharan Africa, due to associated risk factors, such as human papilloma virus and solar ultraviolet exposure. OSSN has been reported as the first presenting sign of HIV/AIDS in 26%-86% cases, and seropositivity is noted in 38%-92% OSSN patients. Mean age at presentation of OSSN has dropped to the third to fourth decade in HIV-positive patients in developing countries. HIV-infected patients reveal large aggressive tumors, higher-grade malignancy, higher incidence of corneal, scleral, and orbital invasion, advanced-stage T4 tumors, higher need for extended enucleation/exenteration, and increased risk of tumor recurrence. Current management of OSSN in HIV-positive individuals is based on standard treatment guidelines described for OSSN in the general population, as there is little information available about various treatment modalities or their outcomes in patients with HIV. OSSN can occur at any time in the disease course of HIV/AIDS, and no significant trend has been discovered between CD4 count and grade of OSSN. Furthermore, the effect of highly active antiretroviral therapy on OSSN is controversial. The current recommendation is to conduct HIV screening in all cases presenting with OSSN to rule out undiagnosed HIV infection. Patient counseling is crucial, with emphasis on regular follow-up to address high recurrence rates and early presentation to an ophthalmologist for of any symptoms in the unaffected eye. Effective evidence-based interventions are needed to allow early diagnosis and treatment, as well as prevention of the disease.


[Progress in molecular diagnosis of fragile X syndrome].
Fragile X mental retardation 1 is the gene underlying fragile X syndrome (FXS). Its product, fragile X mental retardation protein, is closely involved with development of brain and neurons. PCR and Southern blotting have been the major methods for laboratory diagnosis of FXS. In this article, the progress in the molecular diagnosis of FXS is reviewed.


Effects of inspiratory muscle training on respiratory function and repetitive sprint performance in wheelchair basketball players.
There is considerable evidence that respiratory muscle training improves pulmonary function, quality of life and exercise performance in healthy athletic populations. The benefits for wheelchair athletes are less well understood. Therefore, in the present study, influence of inspiratory muscle training (IMT) on respiratory function and repetitive propulsive sprint performance in wheelchair basketball players was examined. Using a placebo-controlled design, 16 wheelchair athletes were divided to an experimental (IMT; n=8) or placebo (sham-IMT; n=8) group based on selective grouping criteria. 30 dynamic breaths were performed by the IMT group twice daily at a resistance equivalent to 50% maximum inspiratory pressure (MIP), and 60 slow breaths were performed by the sham-IMT group once a day at 15% MIP for a period of 6 weeks. In the IMT group, both MIP and maximum expiratory pressure (17% and 23%, respectively; p< or =0.03) were improved. Similar improvements were noted for the sham-IMT group with 23% and 33% from baseline for MIP and maximum expiratory pressure, respectively (p< or =0.03). There were no significant changes in pulmonary function at rest and any of the performance parameters associated with the repetitive sprint test (sprint and recovery times, peak heart rate and peak blood lactate concentration). Reported experiences of using the IMT training device suggested "less breathlessness" and "less tightness in the chest during the training". Although there was no improvement in sprint performance, an improved respiratory muscle function and quality of life were reported by participants in both the IMT and sham-IMT groups.


Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.
NKp46+CD3- natural killer lymphocytes isolated from blood, lymphoid organs, lung, liver and uterus can produce granule-dependent cytotoxicity and interferon-gamma. Here we identify in dermis, gut lamina propria and cryptopatches distinct populations of NKp46+CD3- cells with a diminished capacity to degranulate and produce interferon-gamma. In the gut, expression of the transcription factor RORgammat, which is involved in the development of lymphoid tissue-inducer cells, defined a previously unknown subset of NKp46+CD3- lymphocytes. Unlike RORgammat- lamina propria and dermis natural killer cells, gut RORgammat+NKp46+ cells produced interleukin 22. Our data show that lymphoid tissue-inducer cells and natural killer cells shared unanticipated similarities and emphasize the heterogeneity of NKp46+CD3- cells in innate immunity, lymphoid organization and local tissue repair.


External fixation for phalangeal and metacarpal fractures.
From 1987 to 1993 we treated 33 patients with 29 phalangeal and seven metacarpal fractures by external fixation using a mini-Hoffmann device. There were 27 open and 25 comminuted fractures. In 12 patients one or more tendons was involved. The mean follow-up was 4.4 years. Complications occurred in ten fractures; two required repositioning of the fixator. All the fractures healed. The functional results after metacarpal fractures were better than those after phalangeal fractures and fractures of the middle phalanx had better recovery than those of the proximal phalanx. Twenty-eight of the 33 patients were satisfied with their result. External fixation proved to be a suitable technique for stabilising unstable, open fractures with severe soft-tissue injuries.


Liposomal Grb2 antisense oligodeoxynucleotide (BP1001) in patients with refractory or relapsed haematological malignancies: a single-centre, open-label, dose-escalation, phase 1/1b trial.
Activating mutations of tyrosine kinases are common in leukaemias. Oncogenic tyrosine kinases use the growth factor receptor-bound protein 2 (Grb2) for signal transduction, leading to activation of mitogen-activated protein kinase (MAPK) 1 and MAPK3 (ERK2 and ERK1). We hypothesised that inhibition of Grb2 would suppress ERK1 and ERK2 activation and inhibit leukaemia progression. To inhibit Grb2, a liposome-incorporated antisense oligodeoxynucleotide that blocks Grb2 protein expression, BP1001, was developed. We report the first phase 1 findings of BP1001. In this single-centre, open-label, dose-escalation phase 1/1b trial, we enrolled participants (aged ≥18 years) with refractory or relapsed acute myeloid leukaemia, Philadelphia-chromosome-positive chronic myeloid leukaemia (in chronic, accelerated, or blast phase), acute lymphoblastic leukaemia, or myelodysplastic syndrome, at MD Anderson Cancer Center (Houston, TX, USA). We used a 3 + 3 dose escalation strategy, with at least three patients enrolled at each dose level. We administered BP1001 intravenously, twice weekly, for 28 days, with a starting dose of 5 mg/m2. If two or more patients developed toxic effects of grade 3 or higher, that dose level was deemed toxic. The dose was escalated if it did not produce dose-limiting toxic effects, and patients would be sequentially enrolled into cohort 2 (10 mg/m2), cohort 3 (20 mg/m2), cohort 4 (40 mg/m2), cohort 5 (60 mg/m2), or cohort 6 (90 mg/m2). After completion of monotherapy, we assessed the safety and toxicity of BP1001 (60 or 90 mg/m2) in combination with 20 mg low-dose cytarabine (twice-daily subcutaneous injections) in a phase 1b study in patients with refractory or relapsed acute myeloid leukaemia (ie, those who were refractory to at least one previous therapy regimen and no more than one previous salvage regimen). The objectives of this study were to establish the toxicity and tolerance of escalating doses of BP1001 monotherapy in patients with refractory or relapsed leukaemia, to assess the maximum tolerated dose of BP1001, and to determine the optimal biologically active dose of BP1001, defined as a 50% reduction in Grb2 expression in circulating leukaemia cells. We also aimed to assess the in-vivo pharmacokinetics of BP1001 and tumour response. The study is completed and is registered with ClinicalTrials.gov, number NCT01159028. Between July 23, 2010, and Feb 23, 2016, we enrolled and treated 39 patients, of whom 27 were assessable for dose-limiting toxicity. The first patient treated had mucositis and hand-foot syndrome, which were assessed as possibly related to BP1001 and counted as a dose-limiting toxicity. We noted no other dose-limiting toxicities, and a maximum tolerated dose was not identified. The highest tested dose of BP1001 was 90 mg/m2. The most common grade 3-4 adverse events were cardiopulmonary disorders (25 [64%] of 39 patients), and fever (including neutropenic fever) and infections (17 [44%] patients). Grade 5 adverse events were cardiopulmonary disorders (two [5%] of 39 patients), fever (including neutropenic fever) and infections (two [5%] of 39 patients), and multi-organ failure (one [3%] of 39 patients). Nine (33%) of 27 patients who had peripheral blood blasts at the start of therapy had a reduction of 50% or more in peripheral blood blasts while receiving BP1001 montherapy. Three (10%) of 29 patients who had bone marrow blasts at the start of therapy had a reduction in bone marrow blasts of 50% or more while receiving BP1001 monotherapy. Per investigator's assessment, seven (22%) of 32 patients benefited from BP1001 monotherapy and had extended cycles of treatment. Of seven patients receiving BP1001 plus low-dose cytarabine combination therapy, two had complete remission, one had complete remission with incomplete haematological recovery, and two had stable disease with no dose-limiting toxicity; one patient died and one withdrew, both because of disease progression. There were eight deaths; none were treatment related. BP1001 is well tolerated, with early evidence of anti-leukaemic activity in combination with low-dose cytarabine. To further explore this anti-leukaemic activity, the efficacy of BP1001 plus low-dose cytarabine combination is being investigated in an ongoing phase 2 study in patients with previously untreated acute myeloid leukaemia who are ineligible for intensive induction therapy. Bio-Path Holdings Inc.


Social and community theatre as a response to the stress experienced by nurses, health professionals, and the relatives of those treated during the pandemic: the experience of the Mauriziano Hospital.
Medical Humanities and participatory experiences connect Culture, Art and Health promoting well-being, health. The Social and Community Theater is part of this approach. From the data collected by health care professionals and family members, it emerged the great fragility to which we were exposed in time of pandemic. Describing the experience of care, connection and empathic understanding of health care professionals and family members' fragility and pain during the Covid period, in order to highlight the importance of an health and social community that takes care of itself. Qualitative descriptive study conducted according to the methodology of the Social and Community Theatre with the involvement of internal networks: Directions, nursing and health groups and external partneship (anthropologists, psychologists, artists). Dramatic/theatrical approach autobiographical narration's one. Five hundred people involved in two events in which they shared stories of care professionals and patients' families. The great pain obtained a new human and symbolical meaning. Connection of different symbolical levels : body, relationship, olive tree, ground, water.The book "An olive tree to remember and celebrate life" was published: it enriches narrations with human value. Moreover recurring and common themes and emotions emerged from the analysis. The experience created the conditions for the structured use of the methodology in order to strengthen life skills in health care professionals for events management, that generates high levels of work stress. Reflection on the importance of giving voice and sharing the experiences in multiprofessional and social communities to give meaning to the ethical and human sense of one's action in the relationship of care.


Electroregenerable anion-exchange resin with triiodide carbon paste electrode for the voltammetric determination of adrenaline.
An electroregenerable carbon paste electrode modified with triiodide ions immobilized in an anion-exchange resin (Lewatit M500) is proposed for the determination of adrenaline in pharmaceutical products by differential-pulse voltammetry (DPV). Adrenaline was chemically converted into adrenochrome by the I3- ions at the electrode surface. The electrochemical reduction back to adrenaline was obtained at a potential of -0.16 V vs. Ag/AgCl (3 mol l(-1) KCl). A 20% decrease of the initial analytical signal was observed after 350-400 determinations; the carbon paste electrode was 100% electroregenerated at a fixed potential of +0.65 V vs. Ag/AgCl (3 mol l(-1) KCl) in 0.1 mol l(-1) KI solution for 20 min. The differential-pulse voltammograms were obtained by applying a sweep potential between 0.0 and -0.34 V, following the adrenochrome reduction at -0.16 V. Under the optimum conditions established, such as pH 6.0; scan rate 20 mV s(-1) and pulse amplitude 50 mV, the calibration curve was linear from 2.0 x 10(-5) to 3.1 x 10(-4) mol l(-1) adrenaline with a detection limit of 3.9 x 10(-6) mol l(-1). The recovery of adrenaline ranged from 99.8 to 103.1% and the RSD was 2.6% for the solution containing 1.0 x 10(-4) mol l(-1) adrenaline (n = 10). The results obtained for adrenaline in pharmaceutical samples using the proposed carbon paste electrode are in agreement with those obtained using a pharmacopoeial procedure at the 95% confidence level.


Creating an Assessment Indicator of Quality Culture Development in the Generic Pharmaceutical Industry in Japan.
In the past few years, there have been several instances of illicit pharmaceutical manufacturing in Japan, and there is a growing awareness of the importance of corporate compliance and pharmaceutical manufacturing and quality controls. One cause of illicit manufacturing is the inadequate development of quality culture. This study focuses on the degree of quality culture development in Japanese pharmaceutical companies manufacturing generic drugs. Since no evaluation index for Japan can visualize the degree of quality culture development in each company, this study sought to establish this index to utilize it as a tool for evaluating the degree of quality culture development that would enable each company to continuously monitor and improve its own. We conducted a questionnaire survey among Japan Generic Medicines Association members to evaluate the degree of their quality culture development. The questionnaire contained 28 questions in five evaluation categories. Potential indicators of quality culture development included ″Employee growth and satisfaction″; ″Management commitment″; ″Improvement activities″; ″Communication ″; and ″Environment, health, and safety.″ We obtained 294 responses from 37 Marketing Authorization Holder (MAH) and 61 manufacturing sites. Respondents were classified by roles of management, manager, and non-manager. The results confirmed the current status of quality culture development efforts, showing that important messages such as the corporate philosophy as communicated by the management is well known, awareness of quality culture development level differs by role, and appropriate resources are not adequately allocated to employees or facilities. Based on the results, using the index of quality culture development helped to make relative comparisons, and visualize the areas to be addressed for quality culture development. This study established and visualized the index for the degree of quality culture development in domestic generic drug manufacturing companies and hopes this indicator becomes a useful tool for evaluating a company's quality culture development level.


The impact of nTMS mapping on treatment of brain AVMs.
The treatment of brain arteriovenous malformations (BAVMs) is still contrarily discussed. Despite the debatable results of the ARUBA trial, most BAVMs still require treatment depending on the Spetzler-Martin (SM) grading. Since size is measurable and venous drainage is visible, the determination of eloquence is comparably crucial but not fully objective. The present bicentric cohort study aims to examine the influence of preoperative navigated transcranial magnetic stimulation (nTMS) motor and language mapping data on decision-making for or against surgical treatment of BAVMs. The influence of data from nTMS on decision-making for or against treatment of BAVMs was examined by confirming/falsifying presumed motor or language eloquence. The results of nTMS mappings changed the SM grading in nine cases. In six cases, the SM grading changed to a lower grade (= falsified eloquence); in three cases, the SM grading changed to a higher grade due to nTMS mappings (= unexpected eloquence). Out of all 34 cases, indication for surgery was supported by nTMS mappings in 15 cases (7 motors, 8 languages). In six cases, the decision against surgery was made based on nTMS mappings (three motors, three languages). In 21 of 34 cases (62%), nTMS was a supportive argument. We could show that nTMS motor and language data can be used for a more objective decision-making regarding the treatment of BAVMs and for a more detailed SM grading regarding the rating of eloquence.


Safety of intravitreal triamcinolone acetonide: an electrophysiologic and histopathological study in rabbits.
To evaluate the retinal safety of various doses of intravitreal triamcinolone acetonide (TA) in rabbits. Thirty New Zealand albino rabbits were divided into five groups (six animals each). In group 1 (control group), each animal received a single intravitreal injection of 0.1mL phosphate buffered saline. In groups 2, 3, 4 and 5, each rabbit received a single intravitreal injection of 4, 8, 16 and 32mg of TA, respectively. Each dose was contained in 0.1mL phosphate buffered saline. Clinical ocular examinations were performed before the injection and on the 1st, 3rd, 10th and 17th post-injection days. A standard dark adapted electroretinogram (ERG) was obtained before injection and on the 3rd, 10th and 17th post-injection days. After 17d, animals were sacrificed and their eyes prepared for pathological examination. By monitoring ERG as a functional index for the retina, intravitreal injection of 4mg TA showed no significant ERG changes. At doses of 8, 16 and 32, hyper-abnormal responses in a- and b- waves of ERG were detected on the 3rd post-injection day. These changes gradually returned back to normal limits after 17d. Histopathological examination of the retina of all animals showed no pathological changes. High doses of intravitreal TA seemed to have enhancing effects on the retinal function with gradual return to normal limits with no pathological changes detected in examined eyes.


[A case of factitious mourning].
The authors describe the case of a 22-year-old soldier who has experienced two factitious mournings and Ganser's syndrome. Recent literature on these disorders and their diagnostic status are discussed.


Dopamine receptor and adrenoceptor agonists inhibit prolactin release from MMQ cells.
MMQ cells, a prolactin-secreting cell line possessing dopamine receptors, were exposed to the calcium channel activator maitotoxin and dopamine or adrenoceptor agonists or antagonists. Dopamine (500 nM) or the dopamine agonists lisuride (50 nM), terguride (50 nM), and N-0437 (50 nM) decreased maitotoxin-stimulated prolactin release from perifused MMQ cells. In this system, sulpiride (100 nM), a dopamine D2 antagonist, reversed the prolactin inhibition produced by lisuride (20 nM). In static incubations of MMQ cells, lisuride (10-500 nM) inhibited maitotoxin-stimulated prolactin release in a concentration-dependent manner; this inhibition was attenuated in a concentration-related manner by sulpiride (100-500 nM). In addition, sulpiride reversed dopamine (50-500 nM), lisuride (10-500 nM), and terguride (50-500 nM) inhibition of forskolin-stimulated cAMP generation. The alpha 2-adrenergic agonist clonidine inhibited maitotoxin-stimulated prolactin release from perifused MMQ cells; this inhibition was abolished by idazoxan, an alpha 2-adrenergic antagonist. In contrast, serotonin or the serotonin antagonist methysergide had no effect on prolactin release from MMQ cells. These data indicate that activation of dopamine D2 receptors and alpha 2-adrenoceptors by classically defined pharmacological agents inhibits prolactin release and cellular cAMP levels in MMQ cells. Therefore, MMQ cells may provide a valuable model for the development of pharmacological agents and assist in the identification of the mechanisms involved in the dopaminergic inhibition of prolactin release.


Myricetin attenuates hypoxia-induced inflammation in human adipocytes.
Adipose tissue hypoxia plays a crucial role in the development of chronic low-grade systemic inflammation which has been associated with the pathogenesis of obesity-related diseases. Myricetin is a natural compound present in numerous plant-based foods with presumed anti-inflammatory and beneficial health effects. The impact of this flavonoid on hypoxia-induced expression of inflammatory adipokines and hypoxia-regulated pathways is unknown so far and has been addressed in the present study. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured with or without myricetin under normoxic and hypoxic conditions for varying time periods. The effect of hypoxia and myricetin on the expression of the investigated adipokines was measured by real-time RT-PCR. Western blot analysis was used for the detection of transcription factors involved in hypoxia-regulated pathways. Myricetin interfered in the hypoxia-induced regulation of adipokines and the underlying pathways, which are involved in transmitting the inflammatory response. It strongly repressed hypoxia-induced expression of apelin, leptin, chemerin, asprosin, and DPP-4 and HIF-1α accumulation in the nucleus was diminished. Furthermore, the activation of the key regulators in the inflammatory response NF-κB, Akt, and CREB was suppressed by myricetin under hypoxic conditions. Myricetin also decreased hypoxia-induced accumulation of the pro-tumorigenic transcription factors Snail and Slug in the nucleus. Taken together, our results indicated that myricetin regulated hypoxia-induced expression of adipokines and hypoxia-regulated pathways in human adipocytes. Our study therefore provided evidence of the anti-inflammatory effects of myricetin in hypoxia-treated human adipocytes.


[Investigation on plasma homocysteine level and cognition in population at high risk for stroke in Xi'an].
To investigate the relationship between plasma homocysteine (Hcy) and cognitive impairment so as to provide basis for dementia prevention. Subjects at high risk for stroke were selected from the Screening and Prevention Program of Stroke (organized by the Ministry of Health, from August to December, 2012) in Yanta area, Xi'an. Fasting blood was taken from cubital vein to measure Hcy. When Hcy>15 µmol/L was defined as hyperhomocysteinemia, Hcy in the range of 16-30 µ mol/L was considered mild, ≥ 31 µ mol/L as moderate-severe hyperhomocysteinemia. The cognitive function was evaluated by the Mini Mental State Examination (MMSE). MMSE grades under normal value were defined as cognitive impairment. 393 subjects were randomly recruited, including 173 men (44.0%) and 220 women (56.0%). Number of cases with cognitive impairment was 70 (17.8% of the total subjects), with hyperhomocysteinemia was 220 (56.0% of the total subjects). The prevalence of cognitive impairment did not show significant difference with hyperhomocysteinemia or normal Hcy group (16.8% vs. 19.1%, P>0.05), neither with mild and moderate-severe hyperhomocysteinemia group (17.0% vs. 16.3% , P > 0.05). Results from Spearman correlation analysis indicated that there was no correlation between MMSE grades and Hcy (rs = -0.01, P = 0.85). Prevalence of cognitive impairment in the smoking group was higher than that in the non-smoking group (21.3% vs. 7.8%, P < 0.01), but higher in hypertension group than that in the normal blood pressure group (21.7% vs. 8.0%, P < 0.01). In the stroke group, prevalence of cognitive impairment was seen higher than that in the non-stroke group (25.3% vs. 15.4%, P < 0.05). Based on the results from Binary logistic regression, cognitive impairment appeared to be associated with the levels of education (OR = 0.90, 95% CI:0.81-0.98, P = 0.02), histories of hypertension (OR = 1.02, 95%CI:1.01-1.04, P = 0.01) and stroke(OR = 1.86, 95%CI:1.04-3.33, P = 0.04), but there was no correlation seen between Hcy and cognitive impairment (OR = 0.90, 95% CI:0.51-1.58, P = 0.71). Plasma homocysteine did not seem a risk factor for cognitive impairment.


Institutionalizing Clinical Reasoning: A Grounded Theory of the Clinical Reasoning Processes RNs Use to Recognize Delirium.
Delirium is a common disorder among hospitalized older adults often leading to prolonged hospitalization, increased health care costs, and sometimes death. The goal of the current study was to construct a grounded theory that explains the clinical reasoning processes that RNs use to recognize delirium in older adults in acute care settings. Seventeen participants in three hospitals were interviewed. The core category that emerged from the data was institutionalizing clinical reasoning. Findings from the current study can be a starting point for RNs to bring self-awareness to variables that influence their reasoning processes.


Snow conditions may create an invisible barrier for lynx.
The dynamics of Canadian lynx (Lynx canadensis) abundance are geographically structured according to the influence of large-scale climatic regimes. Here we demonstrate that this structuring matches zones of differential snow conditions, in particular surface hardness, as determined by the frequency of winter warm spells. Through a modified functional response curve, we show that various features of the snow may influence lynx interaction with its main prey species, the snowshoe hare (Lepus americanus). This study highlights the importance of snow, and exemplifies how large-scale climatic fluctuations can mechanistically influence population biological patterns.


River chloride trends in snow-affected urban watersheds: increasing concentrations outpace urban growth rate and are common among all seasons.
Chloride concentrations in northern U.S. included in this study have increased substantially over time with average concentrations approximately doubling from 1990 to 2011, outpacing the rate of urbanization in the northern U.S. Historical data were examined for 30 monitoring sites on 19 streams that had chloride concentration and flow records of 18 to 49 years. Chloride concentrations in most studied streams increased in all seasons (13 of 19 in all seasons; 16 of 19 during winter); maximum concentrations occurred during winter. Increasing concentrations during non-deicing periods suggest that chloride was stored in hydrologic reservoirs, such as the shallow groundwater system, during the winter and slowly released in baseflow throughout the year. Streamflow dependency was also observed with chloride concentrations increasing as streamflow decreased, a result of dilution during rainfall- and snowmelt-induced high-flow periods. The influence of chloride on aquatic life increased with time; 29% of sites studied exceeded the concentration for the USEPA chronic water quality criteria of 230 mg/L by an average of more than 100 individual days per year during 2006-2011. The rapid rate of chloride concentration increase in these streams is likely due to a combination of possible increased road salt application rates, increased baseline concentrations, and greater snowfall in the Midwestern U.S. during the latter portion of the study period.


An overview of over the counter drugs in pregnancy and lactation.
Over the counter (OTC) drugs are commonly used by pregnant women. Most OTC drugs are safe in pregnancy but some have unproven safety and may adversely affect the growing foetus. The safety profile of some of the medication may change according to the gestational age of the foetus. Because an estimated 10% or more of the birth defects results from maternal drug exposure, the US Food and Drug Administration (FDA) has assigned a risk category to each drugs. Among the commonly used OTC drugs Acetaminophen, Chlorpheniramine, Kaolin and Pectin preparations and most antacids have a good safety record. The drugs like H2 blockers; Pseudoephedrine and Atropine/Diphenoxylate should be used with caution. The risk and benefit while using OTC drugs in pregnancy has to be assessed.


Synthesis and structural characterization of charybdotoxin, a potent peptidyl inhibitor of the high conductance Ca2(+)-activated K+ channel.
Charybdotoxin (ChTX), a potent inhibitor of the high conductance Ca2(+)-activated K+ channel (PK,Ca) is a highly basic peptide isolated from venom of the scorpion Leiurus quinquestriatus hebraeus, whose primary structure has been determined (Gimenez-Gallego, G., Navia, M. A., Reuben, J. P., Katz, G. M., Kaczorowski, G. J., and Garcia, M. L. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 3329-3333). The synthesis of this peptide using continuous flow solid phase fluorenylmethyloxycarbonyl-pentafluorophenyl ester methodology has now been achieved. The 1-37-amino acid hexasulfhydryl peptide oxidizes readily to give the tricyclic disulfide structure in good yield. This folded synthetic material is identical to native toxin based on three criteria: co-migration with ChTX on reversed phase high performance liquid chromatography (HPLC); competitive inhibition of 125I-labeled monoiodotyrosine charybdotoxin binding to bovine aortic sarcolemmal membrane vesicles with a Ki (10 pM) identical to that of native toxin; blockade of PK,Ca activity in excised outside-out patches from bovine aortic smooth muscle with the potency and inhibitory properties characteristic of ChTX (i.e. appearance of silent periods interdispersed with normal bursts of channel activity in single channel recordings). Selective enzymatic digestion of native or synthetic ChTX by simultaneous exposure to chymotrypsin and trypsin yields identical reversed phase HPLC profiles. Analysis of the sequence and amino acid composition of the resulting fragments defines a disulfide bond arrangement (Cys7-Cys28, Cys13-Cys33, Cys17-Cys35) which differs from that previously suggested. This configuration predicts a highly folded tertiary structure for ChTX which, together with observations from electrophysiological and binding experiments, suggests a possible mechanism by which ChTX interacts with PK,Ca to block channel function.


Pulsed Electric Fields in Oncology: A Snapshot of Current Clinical Practices and Research Directions from the 4th World Congress of Electroporation.
The 4th World Congress of Electroporation (Copenhagen, 9-13 October 2022) provided a unique opportunity to convene leading experts in pulsed electric fields (PEF). PEF-based therapies harness electric fields to produce therapeutically useful effects on cancers and represent a valuable option for a variety of patients. As such, irreversible electroporation (IRE), gene electrotransfer (GET), electrochemotherapy (ECT), calcium electroporation (Ca-EP), and tumour-treating fields (TTF) are on the rise. Still, their full therapeutic potential remains underappreciated, and the field faces fragmentation, as shown by parallel maturation and differences in the stages of development and regulatory approval worldwide. This narrative review provides a glimpse of PEF-based techniques, including key mechanisms, clinical indications, and advances in therapy; finally, it offers insights into current research directions. By highlighting a common ground, the authors aim to break silos, strengthen cross-functional collaboration, and pave the way to novel possibilities for intervention. Intriguingly, beyond their peculiar mechanism of action, PEF-based therapies share technical interconnections and multifaceted biological effects (e.g., vascular, immunological) worth exploiting in combinatorial strategies.


Oncologic outcomes of patients with incidental prostate cancer who underwent RARC: a comparison between nerve sparing and non-nerve sparing approach.
Incidental Prostate cancer (iPCa) is a relatively common finding during histopathological evaluation of radical cystectomy (RC) specimens. To reduce the high impact of RC on erectile function, several sexual-preserving techniques have been proposed. The aim of this study was to evaluate and compare the oncologic outcomes of patients with iPCa who underwent nerve spring and no-nerve sparing robot-assisted radical cystectomy (RARC). The clinicopathologic data of male patients who underwent RARC at our institution between 2006 and 2016 were retrospectively analysed. Patients with iPCa at definitive pathological examinations were stratified in two groups, according to the preservation of the neurovascular bundles (nerve sparing vs no nerve sparing). Significant PCa was defined as any Gleason score ≥ 3 + 4. Biochemical recurrence (BR) was defined as a sustained PSA level > 0.2 ng/mL on two or more consecutive appraisals. BR rate was assessed only in patients with incidental prostate cancer and at least 2 years of follow-up. Differences in categorical and continuous variables were analysed using the chi-squared test and the Mann-Withney U test, respectively. Biochemical recurrence curves were generated using the Kaplan-Meier method and compared with the Log-rank test. Overall, 343 male patients underwent RARC for bladder cancer within the study period. Nerve-sparing surgery was performed in 143 patients (41%), of these 110 had at least 2 years of follow up after surgery. Patients who underwent nerve-sparing surgery were significantly younger (p < 0.001). Clinically significant PCa was found in 24% of patients. No significant differences regarding preoperative PSA value (p = 0.3), PCa pathological stage (p = 0.5), Gleason score (p = 0.3) and positive surgical margin rates (p = 0.3) were found between the two groups. After a median follow-up of 51 months only one patient, in the no-nerve-sparing group had developed a biochemical recurrence (p = 0.4). In our series most of the iPca detected in RC specimens can be considered as insignificant with a low rate of BR (0.9%). Nerve-sparing RARC is a safe procedure which did not affect oncological outcomes of patients with iPCa.


Brachytherapy for cancer of the female urethra.
Carcinoma of the female urethra is uncommon. The review of literature and our own experience indicates that early distal urethral cancers (squamous and adenocarcinoma) can be treated either with surgery (70-80% 5-year survival) or with radiotherapy (brachytherapy) with excellent results (75% 5-year survival). Early proximal or entire urethral cancers (squamous and adenocarcinoma), if treated surgically, will require exenterative procedures. Alternatively, these cancers can be treated with a combination of external beam and brachytherapy with or without chemotherapy with good results and preservation of organs. Surgery can be used for failures or persistent tumors. Advanced cancers require a multimodality approach, and a combination of radiation and chemotherapy appears to be the optimal way to treat these patients-with surgery to be used for biopsy-proven persistent tumors or recurrences.


Synthesis of a C-linked glycosylated thymine-based PNA monomer and its incorporation into a PNA oligomer.
Backbone modification of peptide nucleic acids (PNAs) by glycosylation has been shown to enhance selective biodistribution and cellular targeting of PNA oligomers based on sugar and cell surface lectin interactions. Here we report the synthesis of a new backbone-glycosylated thymine-based PNA monomer (T(gal)). The sugar residue was attached to the backbone of PNA via a stable carbon-carbon linkage between the sugar and the PNA monomers. Also, incorporation of the modified monomer into a PNA decamer (H-Ala(gal)-G-G-G-T(gal)-C-A-G-C-T(gal)-T-Lys-NH2) was successfully performed. Melting temperature (UV-Tm) of the modified PNA against the complementary DNA was only slightly lower than unmodified PNA.


The magnitude and durability of functional improvement after total shoulder arthroplasty for degenerative joint disease.
So that patients with degenerative glenohumeral joint disease who wish to consider total shoulder arthroplasty will be better informed, we sought to document the magnitude and durability of the improvement in shoulder function after this procedure. The function of 124 shoulders with primary degenerative joint disease was documented by patient self-assessment with the Simple Shoulder Test before and sequentially after total shoulder arthroplasty performed with a standardized technique. Patients reported that they could perform 3.8 +/- 0.3 (SEM) of the 12 Simple Shoulder Test functions before surgery. The total number of performable functions was consistent at different follow-up intervals: 8.0 +/- 0.4 at 6 months, 9.5 +/- 0.4 at 1 year, 10.0 +/- 0.3 at 2 years, 9.2 +/- 0.4 at 3 years, 9.6 +/- 0.4 at 4 years, and 10.0 +/- 0.4 at 5 years. We conclude that total shoulder arthroplasty can provide substantial and durable improvement in shoulder function.


Argatroban Attenuates Diabetic Cardiomyopathy in Rats by Reducing Fibrosis, Inflammation, Apoptosis, and Protease-Activated Receptor Expression.
Chronic diabetes is associated with cardiovascular dysfunctions. Diabetic cardiomyopathy (DCM) is one of the serious cardiovascular complications associated with diabetes. Despite significant efforts in understanding the pathophysiology of DCM, management of DCM is not adequate due to its complex pathophysiology. Recently, involvement of protease-activated receptors (PARs) has been postulated in cardiovascular diseases. These receptors are activated by thrombin, trypsin, or other serine proteases. Expression of PAR has been shown to be increased in cardiac diseases such as myocardial infarction, viral myocarditis, and pulmonary arterial hypertension. However, the role of PAR in DCM has not been elucidated yet. Therefore, in the present study, we have investigated the role of PAR in the condition of DCM using a pharmacological approach. We used argatroban, a direct thrombin inhibitor for targeting PAR. Type-2 diabetes mellitus (T2DM) was induced by high-fat feeding along with low dose streptozotocin (STZ 35 mg/kg, i.p. single dose) in male Sprague-Dawley rats. After 16 weeks of diabetes induction, animals were treated with argatroban at 0.3 and 1 mg/kg dose daily for 4 weeks. After 20 weeks, ventricular functions were measured using ventricular catheterization. Cardiac histology, TUNEL staining, and immunoblotting were performed to evaluate cardiac fibrosis, DNA fragmentation, and expression level of different proteins, respectively. T2DM was associated with cardiac structural and functional disturbances as evidenced from impaired cardiac functional parameters and increased fibrosis. There was a significant increase in PAR expression after 20 weeks of diabetes induction. Four weeks argatroban treatment ameliorated metabolic alterations (reduced plasma glucose and cholesterol), ventricular dysfunctions (improved systolic and diastolic functions), cardiac fibrosis (reduced percentage area of collagen in picro-sirius red staining), and apoptosis (reduced TUNEL positive nuclei). Reduced expression of PAR1 and PAR4 in the argatroban-treated group indicates a response towards inhibition of thrombin. In addition, AKT (Ser-473), GSK-3β (Ser-9), p-65 NFĸB phosphorylation, TGF-β, COX-2, and caspase-3 expression were reduced significantly along with an increase in SERCA expression in argatroban-treated diabetic rats which indicated the anti-fibrotic, anti-inflammatory, and anti-apoptotic potential of argatroban in DCM. This study suggests the ameliorative effects of argatroban in diabetic cardiomyopathy by improving ventricular functions and reducing fibrosis, inflammation, apoptosis, and PAR expression.


Making sense of age-related distractibility: the critical role of sensory modality.
Older adults are known to have reduced inhibitory control and therefore to be more distractible than young adults. Recently, we have proposed that sensory modality plays a crucial role in age-related distractibility. In this study, we examined age differences in vulnerability to unimodal and cross-modal visual and auditory distraction. A group of 24 younger (mean age=21.7 years) and 22 older adults (mean age=65.4 years) performed visual and auditory n-back tasks while ignoring visual and auditory distraction. Whereas reaction time data indicated that both young and older adults are particularly affected by unimodal distraction, accuracy data revealed that older adults, but not younger adults, are vulnerable to cross-modal visual distraction. These results support the notion that age-related distractibility is modality dependent.


An Ultrasonication-Assisted Cobalt Hydroxide Composite with Enhanced Electrocatalytic Activity toward Oxygen Evolution Reaction.
A catalyst toward oxygen evolution reaction (OER) was synthesized by depositing cobalt hydroxide on carbon black. Ultrasonication was applied during precipitation to improve the performance of the catalyst. The ultrasonic-assisted process resulted in the refinement of the cobalt hydroxide particles from 400 nm to 50 nm, and the thorough incorporation of these particles with carbon black substrate. The resulting product exhibited enhanced OER catalytic activity with an onset potential of 1.54 V (vs. reversible hydrogen electrode), a Tafel slope of 18.18 mV/dec, and a stable OER potential at a current density of 10 mA cm-2, because of the reduced resistance of the catalyst and the electron transfer resistance.


Parasites, democratization, and the liberalization of values across contemporary countries.
The countries of the world vary in their position along the autocracy-democracy continuum of values. Traditionally, scholars explain this variation as based on resource distribution and disparity among nations. We provide a different framework for understanding the autocracy-democracy dimension and related value dimensions, one that is complementary (not alternative) to the research tradition, but more encompassing, involving both evolutionary (ultimate) and proximate causation of the values. We hypothesize that the variation in values pertaining to autocracy-democracy arises fundamentally out of human (Homo sapiens) species-typical psychological adaptation that manifests contingently, producing values and associated behaviours that functioned adaptively in human evolutionary history to cope with local levels of infectious diseases. We test this parasite hypothesis of democratization using publicly available data measuring democratization, collectivism-individualism, gender egalitarianism, property rights, sexual restrictiveness, and parasite prevalence across many countries of the world. Parasite prevalence across countries is based on a validated index of the severity of 22 important human diseases. We show that, as the hypothesis predicts, collectivism (hence, conservatism), autocracy, women's subordination relative to men's status, and women's sexual restrictiveness are values that positively covary, and that correspond with high prevalence of infectious disease. Apparently, the psychology of xenophobia and ethnocentrism links these values to avoidance and management of parasites. Also as predicted, we show that the antipoles of each of the above values--individualism (hence, liberalism), democracy, and women's rights, freedom and increased participation in casual sex--are a positively covarying set of values in countries with relatively low parasite stress. Beyond the cross-national support for the parasite hypothesis of democratization, it is consistent with the geographic location at high latitudes (and hence reduced parasite stress) of the early democratic transitions in Britain, France and the U.S.A. It, too, is consistent with the marked increase in the liberalization of social values in the West in the 1950s and 1960s (in part, the sexual revolution), regions that, a generation or two earlier, experienced dramatically reduced infectious diseases as a result of antibiotics, vaccinations, food- and water-safety practices, and increased sanitation. Moreover, we hypothesize that the generation and diffusion of innovations (in thought, action and technology) within and among regions, which is associated positively with democratization, is causally related to parasite stress. Finally, we hypothesize that past selection in the context of morbidity and mortality resulting from parasitic disease crafted many of the aspects of social psychology unique to humans.