Medium-range atomic correlation in simple liquids. II. Theory of temperature dependence.
The spatial atomic correlations in liquids and glasses extend often significantly beyond the nearest neighbors. Such correlations, called the medium-range order (MRO), affect many physical properties, but their nature is not well understood. In this article the variation of the MRO with temperature is calculated based upon the concept of the atomic-level pressure, focusing on simple liquids, such as metallic liquids. It is shown that the structural coherence length that characterizes MRO follows the Curie-Weiss law with a negative Curie temperature as observed by experiment and simulation. It is also shown that the glass transition is induced by freezing of the MRO, rather than the freezing of the nearest-neighbor shell. The implications of these results are discussed.


Therapeutic targeting of c-Myc in T-cell acute lymphoblastic leukemia, T-ALL.
T-ALL patients treated with intensive chemotherapy achieve high rates of remission. However, frequent long-term toxicities and relapses into chemotherapy-refractory tumors constitute major clinical challenges which could be met by targeted therapies. c-MYC is a central oncogene in T-ALL, prompting the exploration of the efficacy of MYC inhibitors such as JQ1 (BET-bromodomain inhibitor), and SAHA (HDAC inhibitor). Using a standardized ex vivo drug screening assay, we show here that JQ1 and SAHA show competitive efficiency compared to inhibitors of proteasome, PI3K/AKT/mTOR and NOTCH pathways, and synergize in combination with Vincristine. We also compared for the first time the in vivo relevance of such associations in mice xenografted with human primary T-ALLs. Our data indicate that although treatments combining JQ1 or SAHA with chemotherapeutic regimens might represent promising developments in T-ALL, combinations will need to be tailored to specific subgroups of responsive patients, the profiles of which still remain to be precisely defined.


Associations between Demographic Characteristics, Lifestyle Factors and School-Related Conditions and Symptoms of Mental Health Problems in Norwegian Upper Secondary School Students.
Background: The purpose of this study was to evaluate the associations between demographic characteristics, lifestyle factors and school-related conditions, and symptoms of mental health problems in Norwegian upper secondary school students following the COVID-19 pandemic. Methods: In this cross-sectional study design we used a binary logistic regression model to evaluate potential associations between the predictors and dependent variable. Results: The following six predictors had a statistically significant impact on symptoms of mental health problems; gender effect of being a girl (p < 0.001), self-perceived body image (p < 0.001), sleep problems (p < 0.001), dietary habits (p = 0.033), school satisfaction (p = 0.013), and satisfaction with physical education (PE) class participation (p = 0.025). Conclusions: Being a girl was associated with a 315% higher probability of reporting symptoms of mental health problems than boys, whereas one unit increase in sleep problems showed a 192% higher probability of symptoms of mental health problems. Furthermore, a one unit increase on the respective beneficial predictors' scales was associated with the following percentage having a lower probability of reporting symptoms of mental health problems; self-perceived body image (59%), dietary habits (58%), school satisfaction (82%), and satisfaction with PE class participation (68%).


Modes of resonators with mirror reflectivity modulated by absorbing masks.
The modes of a stable laser resonator containing, near one mirror, an absorbing mask with two apertures have been calculated on the basis of scalar diffraction theory and experimentally observed in a pulsed Nd:YAG laser. The mode structure has been investigated as a function of the mask geometry, and an interpretation in terms of supermodes is provided.


Identification and analysis of candidate fungal tRNA 3'-end processing endonucleases tRNase Zs, homologs of the putative prostate cancer susceptibility protein ELAC2.
tRNase Z is the endonuclease that is responsible for the 3'-end processing of tRNA precursors, a process essential for tRNA 3'-CCA addition and subsequent tRNA aminoacylation. Based on their sizes, tRNase Zs can be divided into the long (tRNase ZL) and short (tRNase ZS) forms. tRNase ZL is thought to have arisen from a tandem gene duplication of tRNase ZS with further sequence divergence. The species distribution of tRNase Z is complex. Fungi represent an evolutionarily diverse group of eukaryotes. The recent proliferation of fungal genome sequences provides an opportunity to explore the structural and functional diversity of eukaryotic tRNase Zs. We report a survey and analysis of candidate tRNase Zs in 84 completed fungal genomes, spanning a broad diversity of fungi. We find that tRNase ZL is present in all fungi we have examined, whereas tRNase ZS exists only in the fungal phyla Basidiomycota, Chytridiomycota and Zygomycota. Furthermore, we find that unlike the Pezizomycotina and Saccharomycotina, which contain a single tRNase ZL, Schizosaccharomyces fission yeasts (Taphrinomycotina) contain two tRNase ZLs encoded by two different tRNase ZL genes. These two tRNase ZLs are most likely localized to the nucleus and mitochondria, respectively, suggesting partitioning of tRNase Z function between two different tRNase ZLs in fission yeasts. The fungal tRNase Z phylogeny suggests that tRNase ZSs are ancestral to tRNase ZLs. Additionally, the evolutionary relationship of fungal tRNase ZLs is generally consistent with known phylogenetic relationships among the fungal species and supports tRNase ZL gene duplication in certain fungal taxa, including Schizosaccharomyces fission yeasts. Analysis of tRNase Z protein sequences reveals putative atypical substrate binding domains in most fungal tRNase ZSs and in a subset of fungal tRNase ZLs. Finally, we demonstrate the presence of pseudo-substrate recognition and catalytic motifs at the N-terminal halves of tRNase ZLs. This study describes the first comprehensive identification and sequence analysis of candidate fungal tRNase Zs. Our results support the proposal that tRNase ZL has evolved as a result of duplication and diversification of the tRNase ZS gene.


Using machine learning to identify health outcomes from electronic health record data.
Electronic health records (EHRs) contain valuable data for identifying health outcomes, but these data also present numerous challenges when creating computable phenotyping algorithms. Machine learning methods could help with some of these challenges. In this review, we discuss four common scenarios that researchers may find helpful for thinking critically about when and for what tasks machine learning may be used to identify health outcomes from EHR data. We first consider the conditions in which machine learning may be especially useful with respect to two dimensions of a health outcome: 1) the characteristics of its diagnostic criteria, and 2) the format in which its diagnostic data are usually stored within EHR systems. In the first dimension, we propose that for health outcomes with diagnostic criteria involving many clinical factors, vague definitions, or subjective interpretations, machine learning may be useful for modeling the complex diagnostic decision-making process from a vector of clinical inputs to identify individuals with the health outcome. In the second dimension, we propose that for health outcomes where diagnostic information is largely stored in unstructured formats such as free text or images, machine learning may be useful for extracting and structuring this information as part of a natural language processing system or an image recognition task. We then consider these two dimensions jointly to define four common scenarios of health outcomes. For each scenario, we discuss the potential uses for machine learning - first assuming accurate and complete EHR data and then relaxing these assumptions to accommodate the limitations of real-world EHR systems. We illustrate these four scenarios using concrete examples and describe how recent studies have used machine learning to identify these health outcomes from EHR data. Machine learning has great potential to improve the accuracy and efficiency of health outcome identification from EHR systems, especially under certain conditions. To promote the use of machine learning in EHR-based phenotyping tasks, future work should prioritize efforts to increase the transportability of machine learning algorithms for use in multi-site settings.


Serotype-specific and serotype-independent strategies for preharvest control of food-borne Salmonella in poultry.
Of more than 2500 identified Salmonella serotypes, only a small proportion are common in poultry flocks. However, there is an epidemiologically important connection between poultry products and human infections because many of the serotypes that are most prevalent in humans (such as Salmonella Typhimurium and Salmonella Enteritidis) are similarly common in poultry. The scope of food safety efforts for poultry products has been broadened in recent years to include more attention to animal production (or preharvest) issues. The goal of preharvest poultry food safety is to minimize opportunities for the introduction, persistence, and transmission of flock infections with Salmonella and other human pathogens. This objective can be pursued either by general strategies directed against all Salmonella serotypes (and in some instances against other pathogenic microorganisms as well) or by more specific strategies that are designed to act with precision against particular Salmonella serotypes with distinctive public health or economic significance. Risk assessment studies have recommended intervention at multiple steps in the farm-to-table continuum as the most productive overall approach. A comprehensive quality assurance strategy, encompassing both broadly based risk-reduction practices and targeted testing to detect pathogens of concern, has been associated with a lower incidence of Salmonella Enteritidis infections in both egg-laying flocks and humans in a number of countries. Although the emphasis in these types of programs is primarily on risk reduction, testing provides essential verification of the efficacy and cost-effectiveness of risk-reduction practices (and identifies flocks infected with uniquely problematic serotypes). Vaccination can enhance the short-term responsiveness of control programs to address problems involving specific serotypes of elevated significance.


Recurrence of Hepatitis D Virus in Liver Transplant Recipients With Hepatitis B and D Virus-Related Chronic Liver Disease.
Data on recurrence of hepatitis D virus (HDV) and its long-term impact on liver transplant (LT) are limited. In this study, we investigated the incidence of hepatitis B virus (HBV) and the long-term effect of postoperative HDV recurrence HDV coinfection in our liver transplant patients. Between 2004 and 2018, all patients with LT because of HBV (n = 361; 37.3%) were reviewed, and those with HBV and HDV coinfection (n = 104; 30% of all HBV patients) were enrolled in our study. All patients received post-transplant combination therapy with nucleos(t)ide analogue and antihepatitis B immunoglobulins. Breakthrough infection was defined as reemergence of HBV DNA or hepatitis B surface antigen during postoperative treatment. In case of recurrence, another oral nucleos(t)ide analogue was added and antihepatitis B immunoglobulins were stopped. During the study period, the frequency of HDV (+) was decreased (41% to 14%). Median follow-up time was 82 months (range, 1-274 months). Post LT survival and HBV recurrence were 97% (n = 15) and 13.4%, respectively. Only 15 patients (14%) developed breakthrough infection. There was no predictive factor for recurrent HDV infection, including demographics data and concomitant hepatocellular carcinoma (P = .73). Mortality was similar between patients with and without recurrence (2.2% vs 7.1%, P = .35) CONCLUSIONS: Patients who received transplants for hepatitis B and D virus cirrhosis had favorable prognosis and good long-term results despite recurrent infection. Close follow-up of patients and effective postoperative viral suppression with appropriate medications seems to be favorable for both prevention and management of recurrence and provides comparable outcome with patients without recurrence.


Mitoproteomics: Tackling Mitochondrial Dysfunction in Human Disease.
Mitochondria are highly dynamic and regulated organelles that historically have been defined based on their crucial role in cell metabolism. However, they are implicated in a variety of other important functions, making mitochondrial dysfunction an important axis in several pathological contexts. Despite that conventional biochemical and molecular biology approaches have provided significant insight into mitochondrial functionality, innovative techniques that provide a global view of the mitochondrion are still necessary. Proteomics fulfils this need by enabling accurate, systems-wide quantitative analysis of protein abundance. More importantly, redox proteomics approaches offer unique opportunities to tackle oxidative stress, a phenomenon that is intimately linked to aging, cardiovascular disease, and cancer. In addition, cutting-edge proteomics approaches reveal how proteins exert their functions in complex interaction networks where even subtle alterations stemming from early pathological states can be monitored. Here, we describe the proteomics approaches that will help to deepen the role of mitochondria in health and disease by assessing not only changes to mitochondrial protein composition but also alterations to their redox state and how protein interaction networks regulate mitochondrial function and dynamics. This review is aimed at showing the reader how the application of proteomics approaches during the last 20 years has revealed crucial mitochondrial roles in the context of aging, neurodegenerative disorders, metabolic disease, and cancer.


Deep Learning for Automated Diabetic Retinopathy Screening Fused With Heterogeneous Data From EHRs Can Lead to Earlier Referral Decisions.
Fundus images are typically used as the sole training input for automated diabetic retinopathy (DR) classification. In this study, we considered several well-known DR risk factors and attempted to improve the accuracy of DR screening. Fusing nonimage data (e.g., age, gender, smoking status, International Classification of Disease code, and laboratory tests) with data from fundus images can enable an end-to-end deep learning architecture for DR screening. We propose a neural network that simultaneously trains heterogeneous data and increases the performance of DR classification in terms of sensitivity and specificity. In the current retrospective study, 13,410 fundus images and their corresponding nonimage data were collected from the Chung Shan Medical University Hospital in Taiwan. The images were classified as either nonreferable or referable for DR by a panel of ophthalmologists. Cross-validation was used for the training models and to evaluate the classification performance. The proposed fusion model achieved 97.96% area under the curve with 96.84% sensitivity and 89.44% specificity for determining referable DR from multimodal data, and significantly outperformed the models that used image or nonimage information separately. The fusion model with heterogeneous data has the potential to improve referable DR screening performance for earlier referral decisions. Artificial intelligence fused with heterogeneous data from electronic health records could provide earlier referral decisions from DR screening.


Investigating the role of site specific synonymous variation in disease association studies.
Synonymous codon changes may not always be neutral indicating their significance in disease association studies, which is almost always overlooked. Synonymous substitutions may affect protein-folding rates leading to protein misfolding and aggregation. Genome wide analysis of 2301 mitochondrial genomes is performed to evaluate the significance of synonymous codons in disease association studies. The analysis revealed usage of rare codons at several sites in mitochondrial genes with rare codon usage higher for hydrophobic amino acids. The analysis suggests that variation data in association studies should be analyzed using site-specific codon usage values to infer the potential phenotypic impact of synonymous changes.


Pathology and pathogenesis of fatal Bordetella pertussis infection in infants.
Each year, Bordetella pertussis infection causes an estimated 294,000 deaths worldwide, primarily among young, nonvaccinated children. Approximately 90% of all deaths due to pertussis in the Unites States occur in young infants. These children often develop intractable pulmonary hypertension; however, the pathophysiologic mechanism responsible for this complication has not been well characterized, and there have been no detailed descriptions of the pathology of this disease since the 1940s. Respiratory tissue samples obtained at autopsy from 15 infants aged <or=4 months who had polymerase chain reaction- or culture-confirmed B. pertussis pneumonia were evaluated by multiple histochemical stains, immunohistochemical evaluation, and electron microscopic examination. The pulmonary histopathologic examination of the samples revealed a descending infection dominated by necrotizing bronchiolitis, intra-alveolar hemorrhage, and fibrinous edema. All samples had marked leukocytosis, and most showed luminal aggregates of abundant leukocytes in small pulmonary arteries, veins, and lymphatics. A novel immunohistochemical stain for B. pertussis revealed abundant extracellular bordetellae in cilia of the trachea, bronchi, and bronchioles, as well as intracellular bacteria and antigens in alveolar macrophages and ciliated epithelium. Pertussis should be suspected in any infant death associated with marked leukocytosis, bronchopneumonia, or refractory pulmonary hypertension, particularly in children aged <or=4 months. The pathologic findings identified in the respiratory tracts of these children, in addition to recognized physiologic responses of the infant lung to hypoxia, suggest that B. pertussis pneumonia triggers a cascade of events that includes acute pulmonary vasoconstriction and pertussis toxin-mediated increases in circulating leukocyte mass. These responses ultimately compromise pulmonary blood flow, exacerbate hypoxemia, and create a vicious cycle of refractory pulmonary hypertension.


Reinventing R&D in an open innovation ecosystem.
Today, the idea that random collisions and interactions offer solutions and business opportunities is no longer acceptable. Instead, partnerships and alignments, both downstream and upstream, are paramount for cross-fertilization and synergy. To survive, and thrive, in today's world of global innovation, alliances based on compatible differences must be sought. Innovation Partnerships and the Sharing-is-Winning model represent a paradigm shift toward accelerating co-development of sustainable innovation, with alignment of the entire value chain with consumer-centric innovations being one of its main pillars. It includes 3 levels of typical joint development: universities, research institutes, and centers; start-ups and individual inventors; a select number of key strategic suppliers. Reinventing R&D in an open innovation ecosystem and increasing success rates in an increasingly competitive marketplace require implementing significant steps--both perceived and tangible. Specific recommendations are provided for 10 major identified topics: leadership, strategy, the consumer, the value chain, internal experts and championship, metrics, IP, culture, academia, and passion. The Sharing-is-Winning model extends the scope of open innovation to sustainable and enhanced processes of co-innovation.


Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults.
A randomized clinical trial was performed in 160 children and 223 adults with acute immune thrombocytopenic purpura (ITP). The role of corticoids at this phase of the disease is still controversial. Therefore, patients were randomized to receive either conventional doses (1 mg/kg/day) of corticotherapy or low doses (0.25 mg/kg/day) for 3 weeks. The remission, defined by platelet count superior to 100,000/microliter was studied for adults and children after 6 months and 12 months, respectively. The statistical analysis showed no significant difference between the two corticotherapy regimens neither in children nor in adults. Overall, 74% of children and 41% of adults were in remission. For the first time in acute ITP, a randomized prospective trial showed that both in children and adults low dose corticotherapy (0.25 mg/kg/day) proves to have the same efficacy as conventional doses (1 mg/kg/day).


Epidemiology and Prognosis of Invasive Fungal Disease in Chinese Lung Transplant Recipients.
This study explored the epidemiology, risk factors, and prognosis of invasive fungal disease (IFD) in Chinese lung transplant recipients (LTRs). This retrospective cohort study included patients who received lung transplants at four hospitals in South China between January 2015 and June 2019. The participants were divided into IFD and non-IFD (NIFD) groups. The final analysis included 226 LTRs (83.2% males) aged 55.0 ± 14.2 years old. Eighty-two LTRs (36.3%) developed IFD (proven or probable diagnosis). The most common pathogens were Aspergillus (57.3%), Candida (19.5%), and Pneumocystis jiroveci (13.4%). Multivariate logistic regression revealed that anastomotic disease [odds ratio (OR): 11.86; 95% confidence interval (95%CI): 4.76-29.54; P < 0.001], cytomegalovirus (CMV) pneumonia (OR: 3.85; 95%CI: 1.88-7.91; P = 0.018), and pre-transplantation IFD (OR: 7.65; 95%CI: 2.55-22.96; P < 0.001) were associated with higher odds of IFD, while double-lung transplantation (OR: 0.40; 95%CI: 0.19-0.79; P = 0.009) was associated with lower odds of IFD. Logistic regression analysis showed that anastomotic disease was associated with higher odds of death (OR: 5.01; 95%CI: 1.24-20.20; P = 0.02) and that PJP prophylaxis was associated with lower odds of death (OR: 0.01; 95%CI: 0.001-0.11; P < 0.001). Invasive fungal disease is prevalent among LTRs in southern China, with Aspergillus the most common pathogen. Prophylaxis should be optimized based on likely pathogens.


Angiotensin II-induced constrictions are masked by bovine retinal vessels.
To unmask the vasoconstricting effect of angiotensin II (Ang II) on retinal smooth muscle by studying its interaction with endothelium-derived paracrine substances. This study focused specifically on determining the changes in vascular diameter and the release of endothelial-derived vasodilators, nitric oxide (NO) and prostaglandin (PG) I2, from isolated retinal microvessels. Bovine retinal central artery and vein were cannulated, and arterioles and venules were perfused with oxygenated/heparinized physiological salt solution at 37 degrees C. This ex vivo perfused retinal microcirculation model was used to observe the contractile effects of Ang II on arterioles and venules of different diameters. The NO and PGI2 synthase inhibitors, 1-NOARG and flurbiprofen, respectively, were used to unmask Ang II vasoconstriction; the changes in vascular diameters were then measured. Enzyme immunoassays were used to measure the release of cGMP (an index of NO release) and 6-keto-PG-F1alpha (a stable metabolite of PGI2) from isolated bovine retinal vessels. Topically applied Ang II (10(-10) M to 10(-4) M) caused significant (P < 0.05) arteriolar and venular constrictions in a dose-dependent manner, with the smallest retinal arterioles (7+/-0.2 microm luminal diameter) and venules (12+/-2 microm luminal diameter) significantly more sensitive than larger vessels. After the inhibition of endogenous NO and PGI2 synthesis by 1-NOARG and flurbiprofen, respectively, the vasoconstriction effects of Ang II became more pronounced. Again, the smallest vessels tested were significantly more sensitive, and synthesis of endothelial-derived relaxing factor (EDRF), therefore, may be most important in these vessels. Vasoactive doses of Ang II (10(-10) M to 10(-4) M) caused a dose-dependent increase in the release of NO and PGI2 from isolated bovine retinal vessels, indicating that the increase in EDRF may nullify direct Ang II-induced vasoconstriction. Interestingly, intraluminal administration of Ang II caused only vasodilation. This study demonstrates that the retinal vascular endothelium acts as a buffer against the vasoconstricting agent Ang II via release of vasodilators NO and PGI2, and the vasoconstriction effects due to Ang II are most prominent in the smallest diameter vessels.


PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival.
Mutations in PIK3CA are present in 10 to 15% of colorectal carcinomas. We aimed to examine how PIK3CA mutations relate to other molecular alterations in colorectal carcinoma, to pathologic phenotype and survival. PIK3CA mutation testing was carried out using direct sequencing on 757 incident tumors from the Melbourne Collaborative Cohort Study. The status of O-6-methylguanine-DNA methyltransferase (MGMT) was assessed using both immunohistochemistry and methyLight techniques. Microsatellite instability, CpG island phenotype (CIMP), KRAS and BRAF V600E mutation status, and pathology review features were derived from previous reports. PIK3CA mutation was observed in 105 of 757 (14%) of carcinomas, characterized by location in the proximal colon (54% vs. 34%; P<0.001) and an increased frequency of KRAS mutation (48% vs. 25%; P<0.001). High-levels of CIMP were more frequently found in PIK3CA-mutated tumors compared with PIK3CA wild-type tumors (22% vs. 11%; P = 0.004). There was no difference in the prevalence of BRAF V600E mutation between these two tumor groups. PIK3CA-mutated tumors were associated with loss of MGMT expression (35% vs. 20%; P = 0.001) and the presence of tumor mucinous differentiation (54% vs. 32%; P<0.001). In patients with wild-type BRAF tumors, PIK3CA mutation was associated with poor survival (HR 1.51 95% CI 1.04-2.19, P = 0.03). In summary, PIK3CA-mutated colorectal carcinomas are more likely to develop in the proximal colon, to demonstrate high levels of CIMP, KRAS mutation and loss of MGMT expression. PIK3CA mutation also contributes to significantly decreased survival for patients with wild-type BRAF tumors.


Alternative approaches to modeling heterogeneity to analyze injury severity sustained by motorcyclists in two-vehicle crashes.
The presence of unobserved factors in the motorcycle involved two-vehicle crashes (MV) data could lead to heterogenous associations between observed factors and injury severity sustained by motorcyclists. Capturing such heterogeneities necessitates distinct methodological approaches, of which random and scale heterogeneity models are paramount. Herein, we undertake an empirical evaluation of random and scale heterogeneity models, exploring their efficacy in delineating the influence of external determinants on the degree of injury severity in crashes. Within the effects of scale heterogeneity, this study delves into two dominant models: the scaled multinomial logit model (S-MNL) and its generalized counterpart, the G-MNL, which encompasses both the S-MNL and the random parameters multinomial logit model (RPL). While the random heterogeneity domain is represented by the random parameters multinomial logit and an upgraded variant - the random parameters multinomial logit model with heterogeneity in means and variances (RPLHMV). Motorcycle involved two-vehicle crashes data were extracted from the UK STATS19 dataset from 2016 to 2020. Likelihood ratio tests are computed to assess the temporal variability of the significant factors. The test result demonstrates the temporal variations over a five-year study period. Some very important differences started to show up across the years based on the model estimation results: that the RPLHMV model statistically outperforms the G-MNL model in the 2016, 2018, and 2019 models, while the S-MNL model is statistically superior in the 2017 and 2020 years. These important findings suggest that the origin of heterogeneity in explaining factor weights can be captured by scale effects, not just random heterogeneity. In addition, the model results further show that motorcyclists' injury severities are significantly affected by motorcycle-related characteristics; there is the added factor of external influences, such as non-motorcycle drivers (males, young drivers, and elderly drivers) and vehicles (the moving status, age, and types of vehicles) that collide with motorcycles. The results of this paper are anticipated to help policymakers develop effective strategies to mitigate motorcycle involved two-vehicle crashes by implementing appropriate measures.


Molecular and Functional Characterization of Pheromone Binding Protein 2 from Cyrtotrachelus buqueti (Coleoptera: Curculionidae).
Pheromone-binding proteins (PBPs) play important roles in binding and transporting sex pheromones. However, the PBP genes identified in coleopteran insects and their information sensing mechanism are largely unknown. Cyrtotrachelus buqueti (Coleoptera: Curculionidae) is a major insect pest of bamboo plantations. In this study, a novel PBP gene, CbuqPBP2, from C. buqueti was functionally characterized. CbuqPBP2 was more abundantly expressed in the antennae of both sexes than other body parts, and its expression level was significantly male-biased. Fluorescence competitive binding assays showed that CbuqPBP2 exhibited the strongest binding affinity to dibutyl phthalate (Ki = 6.32 μM), followed by styrene (Ki = 11.37 μM), among twelve C. buqueti volatiles. CbuqPBP2, on the other hand, showed high binding affinity to linalool (Ki = 10.55), the main volatile of host plant Neosinocalamus affinis. Furthermore, molecular docking also demonstrated the strong binding ability of CbuqPBP2 to dibutyl phthalate, styrene, and linalool, with binding energy values of -5.7, -6.6, and -6.0 kcal/mol, respectively, and hydrophobic interactions were the prevailing forces. The knockdown of CbuqPBP2 expression via RNA interference significantly reduced the electroantennography (EAG) responses of male adults to dibutyl phthalate and styrene. In conclusion, these results will be conducive to understanding the olfactory mechanisms of C. buqueti and promoting the development of novel strategies for controlling this insect pest.


Constitutive equations of symmetrical triple layer piezoelectric benders.
Piezoelectric triple layer benders, with a structure of two piezoelectric top and bottom layers sandwiched by a non-piezoelectric elastic central layer, are one of the most commonly used piezoelectric devices. In this paper, we present the derivation of the constitutive equations of a symmetrical triple layer piezoelectric bender under different excitation conditions. The constitutive equations are presented by a 4x4 matrix with an external moment M, an external tip force F, a uniform load p, and an applied electric voltage V as the extensive parameters, with the generated tip angular deflection (slope) alpha, tip deflection delta, volume displacement v, and electric charge Q as the internal parameters. Further analysis on the electromechanical behavior of the triple layer piezoelectric bender can be made on the constitutive equations.


Clinical characteristics of Buerger's disease in Iran.
To determine the clinical course of Buerger's disease as observed in two vascular surgery centers located in the capital of Iran. Case series. Sina and Imam Hospitals, Tehran, Iran, during the years 1997 to 2002. The records of all the patients admitted with Buerger's disease diagnosed on the basis of Shionoya's clinical criteria were studied. Their clinical characteristics, treatment offered and short-term follow-up results are described as frequencies and percentages. A total of 116 patients, aged 41.1+/-11.3 years, were enrolled. All patients were males; 99% of them were smokers with an average of 22.9 pack-years of tobacco use. Lower-extremity was affected in 102 (87.9%) patients, upper-extremity in 3 (2.6%) patients and both in 11 (9.5%). The most frequent reasons for being referred to hospital were ischemic ulcers (90.5%), claudication (87.9%), paresthesia (75.9%), rest pain (66.4%), gangrene (60.3%), Raynaud's phenomenon (23.3%) and thrombophlebitis (9.5%). Diagnostic arteriography, vascular bypass surgery and sympathectomy were performed in 60%, 24% and 83% of the patients, respectively. Sixty-eight patients (58.6%) had one of the following amputations: toe 36 (52.9%), transmetatarsal 3 (4.4%), below knee 25 (36.8%), finger 3 (4.4%) and above knee one (1.5%) patient. Since the studied hospitals are the referral centers for vascular surgery in Iran admitting patients with severe symptoms; therefore, a higher number of complications and amputations was found in the present study. Upper extremity involvement as well as the occurrence of thrombophlebitis and Raynaud's phenomenon was rather infrequent among the studied cases.


Linoleic acid-induced VCAM-1 expression in human microvascular endothelial cells is mediated by the NF-kappa B-dependent pathway.
Vascular cell adhesion molecule-1 (VCAM-1) has been reported to play an important role in cancer metastasis via the adhesive interaction between tumor cells and endothelial cells. In this study, we examined the effects of linoleic acid on VCAM-1 expression and its transcriptional regulatory mechanism in human microvascular endothelial cells (HMEC-1). Time- and dose-dependent increases of VCAM-1 mRNA levels were observed in linoleic acid-treated HMEC-1 as detected by reverse transcriptase-polymerase chain reaction. Flow cytometry analysis showed a significant and dose-dependent upregulation of VCAM-1 expression in HMEC-1 stimulated with linoleic acid compared with controls. To clarify the transcriptional regulatory pathway, we investigated the role of nuclear factor-kappa B (NF-kappa B) in the expression of VCAM-1 by linoleic acid in HMEC-1. Nuclear extracts from HMEC-1 stimulated with linoleic acid showed a dose-dependent increase in binding activity to the NF-kappa B consensus sequences. These effects were preventable by cotreatment with inhibitors of NF-kappa B activity, such as sodium salicylate, aspirin, or pyrrolidine dithiocarbamate. In addition, pretreatment with NF-kappa B inhibitors markedly suppressed the ability of linoleic acid to induce VCAM-1 gene expression. The role of NF-kappa B in linoleic acid-induced VCAM-1 expression was confirmed by functional promoter studies in HMEC-1 transfected with reporter constructs of the VCAM-1 promoter with or without mutated NF-kappa B binding site. These results indicate that linoleic acid upregulates VCAM-1 expression in HMEC-1 through the NF-kappa B-dependent pathway.


Biliary complications in 108 consecutive recipients with duct-to-duct biliary reconstruction in living-donor liver transplantation.
Biliary complications remain the leading cause of postoperative complications after living-donor liver transplantation (LDLT) in patients undergoing duct-to-duct choledochocholedochostomy. The aim of this study was to analyze the causes of these complications. One hundred eight patients who underwent LDLT with duct-to-duct biliary reconstruction at Mie University Hospital were enrolled in this study. The mean follow-up time was 58.4 months (range, 3-132). The most recent 18 donors underwent indocyanine green (ICG) fluorescence cholangiography for donor hepatectomy. The development of biliary complications was retrospectively analyzed. Biliary complications were defined as needing endoscopic or radiologic treatment. Biliary leakages and strictures occurred in 6 (5.6%) and 15 (13.9%) of the recipients, respectively, and 3 donors (2.7%) experienced biliary leakage. However, since the introduction of ICG fluorescence cholangiography, we have not encountered any biliary complications in either donors or recipients. Biliary leakage was an independent risk factor for the development of biliary stricture (P = .013). Twelve (80%) of the 15 recipients with biliary stricture had successful nonoperative endoscopic or radiologic management, and 3 patients underwent surgical repair with hepaticojejunosotomy. Biliary leakage was an independent factor for biliary stricture. ICG fluorescence cholangiography might be helpful to reduce biliary complications after LDLT in both donors and recipients.


HHF35, a muscle-actin-specific monoclonal antibody. I. Immunocytochemical and biochemical characterization.
A monoclonal antibody to muscle cell actin isotypes was produced and characterized. Immunocytochemical analysis of methanol-Carnoy's-fixed, paraffin-embedded human tissue revealed that this antibody, termed HHF35, reacts with skeletal muscle cells, cardiac muscle cells, smooth muscle cells, pericytes, and myoepithelial cells, but is nonreactive with endothelial, epithelial, neural, or connective tissue cells. When assayed by indirect immunofluorescence, HHF35 reacts with microfilament bundles from various cultured mammalian smooth muscle cells, but does not react with cultured human dermal fibroblasts or various epithelial tumor cell lines. In one-dimensional gel electrophoresis immunoblot experiments this antibody detects a 42-kd polypeptide from tissue extracts of uterus, ileum, aorta, diaphragm, and heart and extract from smooth muscle cells. The antibody also reacts with a comigrating 42-kd band of highly purified rabbit skeletal muscle actin. HHF35 is nonreactive on immunoblots of extracts from all tested nonmuscle cell extracts. Immunoelectrophoresis followed by immunoblotting performed in the presence of urea and reducing agents reveals recognition of the alpha isoelectrophoretic variant of actin from skeletal, cardiac, and smooth muscle sources and of the gamma variant from smooth muscle sources. Because HHF35 reacts with virtually all muscle cells, it will be useful as a marker for muscle and muscle-derived cells.


Deficiency of telomerase activity aggravates the blood-brain barrier disruption and neuroinflammatory responses in a model of experimental stroke.
Epidemiology and genetic studies indicate that patients with telomere length shorter than average are at higher risk of dying from heart disease or stroke. Telomeres are located at the ends of eukaryotic chromosomes, which demonstrate progressive length reduction in most somatic cells during aging. The enzyme telomerase can compensate for telomere loss during cell replication. The present study sought to investigate the contribution of telomerase to stroke and blood-brain barrier (BBB) dysfunction. Telomerase reverse transcriptase knockout (TERT(-/-)) mice and littermate controls with normal TERT expression were subjected to a 24-hr permanent middle cerebral artery occlusion (pMCAO). The stroke outcomes were assessed in terms of neurological scores and infarct volumes. In addition, we evaluated oxidative stress, permeability across the BBB, and integrity of tight junctions in brain microvessels. Neurological testing revealed that TERT(-/-) mice showed enhanced deficits compared with controls. These changes were associated with a greater infarct volume. The expression of tight junction protein ZO-1 decreased markedly in ischemic hemispheres of TERT(-/-) mice. The brain microvessels of TERT(-/-) mice also were more susceptible to oxidative stress, revealing higher superoxide and lower glutathione levels compared with mice with normal TERT expression. Importantly, TERT deficiency potentiated the production of inflammatory mediators, such as tumor necrosis factor-alpha, interleukin-1 beta, and intercellular adhesion molecule-1, in the ischemic hemispheres of mice with pMCAO. Our study suggests that TERT deficiency can predispose to the development of stroke in an experimental model of this disease.


Long term treatment of a thyrotropin-secreting microadenoma with somatostatin analogues.
Thyrotropin (TSH) secreting pituitary adenomas (TSH-omas) account for < 1% of all pituitary adenomas and are a rare cause of hyperthyroidism. The diagnosis is often made at the stage of macroadenoma because of the aggressive nature of the tumor and due to the fact that patients are mistakenly treated for more common primary hyperthyroidism for a long time. First line therapy is transsphenoidal resection of the tumor, which can cure one-third of the patients completely. However, if surgery is not possible or curative, pituitary radiotherapy and/or somatostatin analogs (SSA) can be useful. We report the case of a 54-year-old woman treated 20 years earlier for a mistakenly suspected primary hyperthyroidism. Given the persistence of symptoms she was studied further and was diagnosed with a thyrotropinoma. Despite the delay in diagnosis and prior thyroid ablation, a microadenoma was found. As transsphenoidal surgery was not considered effective, medical therapy with a somatostatin analogue was initiated. Currently, at four years of follow-up, the patient continues on this treatment and remains euthyroid and asymptomatic. We report a case of successful long-term treatment with SSA, after unsuccessful surgery.


Post-discharge compliance to venous thromboembolism prophylaxis in high-risk orthopaedic surgery: results from the ETHOS registry.
Venous thromboembolism (VTE) risk persists for several weeks following high-risk orthopaedic surgery (HROS). The ETHOS registry evaluated post-operative VTE prophylaxis prescribed, and actual VTE prophylaxis received, compared with the 2004 American College of Chest Physicians (ACCP) guidelines in HROS patients. We performed a subanalysis of ETHOS to assess patient compliance with ACCP-adherent prophylaxis after discharge and the factors predicting poor compliance. Consecutive patients undergoing hip fracture surgery, total hip arthroplasty, or knee arthroplasty were enrolled at discharge from 161 centres in 17 European countries if they had received adequate in-hospital VTE prophylaxis. Data on prescribed and actual prophylaxis received were obtained from hospital charts and patient post-discharge diaries. Good compliance was defined as percentage treatment intake ≥80% with no more than two consecutive days without treatment. A total of 3,484 patients (79.4%) received ACCP-adherent anticoagulant prescription at discharge and 2,999 (86.0%) had an evaluable patient diary. In total, 87.7% of evaluable patients were compliant with prescribed treatment after discharge. The most common reason for non-compliance (33.4%) was "drug was not bought". Injection of treatment was not a barrier to good compliance. Main factors affecting compliance related to purchase of and access to treatment, patient education, the person responsible for administering injections, country, and type of hospital ward at discharge. Within our study population, patient compliance with ACCP-adherent thromboprophylaxis prescribed at discharge was good. Improvements in patient education and prescribing practices at discharge may be important in further raising compliance levels in high-risk orthopaedic surgery patients.


Aberrant interhemispheric functional connectivity within default mode network and its relationships with neurocognitive features in cognitively normal APOE ε 4 elderly carriers.
Default mode network (DMN) is vulnerable to the effects of APOE genotype. Given the reduced brain volumes and APOE ε 4-related brain changes in elderly carriers, it is less known that whether these changes would influence the functional connectivity and to what extent. This study aimed to examine the functional connectivity within DMN, and its diagnostic value with age-related morphometric alterations considered. Whole brain and seed-based resting-state functional connectivity (RSFC) analysis were conducted in cognitively normal APOE ε 4 carriers and matched non-carriers (N=38). The absolute values of mean correlation coefficients (z-values) were used as a measure of functional connectivity strength (FCS) between DMN subregions, which were also used to estimate their diagnostic value by receiver-operating characteristic (ROC) curves. APOE ε 4 carriers demonstrated decreased interhemispheric FCS, particularly between right hippocampal formation (R.HF) and left inferior parietal lobular (L.IPL) (t=3.487, p<0.001). ROC analysis showed that the FCS of R.HF and L.IPL could differentiate APOE ε 4 carriers from healthy counterparts (AUC value=0.734, p=0.025). Moreover, after adjusting the impact of morphometry, the differentiated value of FCS of R.HF and L.IPL was markedly improved (AUC value=0.828, p=0.002). Our findings suggest that APOE ε 4 allele affects the functional connectivity within posterior DMN, particularly the atrophy-corrected interhemispheric FCS before the clinical expression of neurodegenerative disease.


Border disease virus isolation from postpartum ewes.
The prevalence of border disease virus in a flock of Targhee sheep in southern Idaho was determined by serologic and virologic techniques. Of 249 ewes, 73 (29%) were seropositive to the antigenically related togavirus, bovine seropositive to the antigenically related togavirus, bovine viral diarrhea virus (BVDV). Concurrent testing of sera from 337 neonatal lambs indicated that 172 (51%) were seropositive for BVDV. It was observed that a high percentage (35%) of the BVDV-seropositive lambs were derived from seronegative ewes. Immunotolerance of the ewe was considered as the explanation for the lack of serologic relationship between seropositive lambs and their seronegative dams. Eleven cytopathogenic viruses were isolated from nasal and vaginal specimens obtained from 80 clinically healthy ewes within 24 hours of parturition. The viral isolates were demonstrated to be antigenically related to BVDV by direct immunofluorescence. Six of the 11 isolates were obtained from BVDV-seronegative ewes.


Optimization of anesthesia antiemetic measures versus combination therapy using dexamethasone or ondansetron for the prevention of postoperative nausea and vomiting.
More than half of the patients undergoing laparoscopic cholecystectomy experience postoperative nausea and vomiting (PONV). This condition is related to the surgical, anesthetic, and patient factors. Volatile anesthetics, nitrous oxide, and opioids are known anesthetic risk factors for PONV, and thus preventive measures are justified. Propofol-based total intravenous anesthesia (TIVA), ondansetron, and dexamethasone each are reported to reduce PONV by approximately 30%. Avoiding or reducing perioperative narcotic analgesics, use of an 80% oxygen concentration, and proper intravenous fluid administration also reduce PONV. The anesthetic antiemetic measures have been studied separately. This study aimed to test the efficacy of these anesthetic antiemetic measures collectively with or without ondansetron or dexamethasone in preventing PONV among patients undergoing laparoscopic cholecystectomy. For this study, 160 patients undergoing laparoscopic cholycestectomy (33 males and 147 females) were randomized into one of three groups. Group O received 4 mg of ondansetron; group D received 8 mg of dexamethasone; and group P received normal saline immediately after induction of anesthesia. All the patients received propofol-based TIVA, 80% oxygen concentration, 20 ml/kg of Hartman's solution, and 1.5 mg/kg of tramadol. Opioids, nitrous oxide, and volatile anesthetics were not used for any patient. Episodes of PONV were recorded at 0- to 4-h and 4- to 24-h intervals. The incidences of PONV were 32% in the ondansetron group, 30% in the dexamethasone group, and 33% in the saline group. There were no significant differences among the groups (p > 0.05). Ondansetron or dexamethasone added to collective anesthetic antiemetic measures does not further decrease the incidence of PONV after laparoscopic cholycestectomy.


Foraminal encroachment syndrome in true lumbosacral spondylolisthesis: a preliminary report.
The source of pain in isthmic spondylolisthesis is uncertain. Some authors believe that spondylolysis and/or spondylolisthesis is not a predisposing factor to low back pain and that the mere presence of isthmic spondylolisthesis may, indeed, not be the cause of low back pain in the patient. This study explores a possible source of biomechanical dysfunction as an origin of pain in isthmic spondylolisthesis. One hundred and twenty lumbar intervertebral disc angles were measured, 60 of which had spondylolisthesis and the remaining 60 without spondylolisthesis for comparison of the effect that spondylolisthesis has on intervertebral disc angulation of the lumbar spine. The results reveal that the L4-L5 joint has the greatest biomechanical stress placed upon it by virtue that it had the highest intervertebral disc angulation when the component of spondylolisthesis was a factor at L5-S1. Therefore, due to increased intervertebral disc angles at L4-L5, a biomechanical stressing and resulting hyperextension of the facet articulation at L4-L5 may represent a source of symptomatology in isthmic spondylolisthesis of L5-S1.


Data mining methods for classification of Medium-Chain Acyl-CoA dehydrogenase deficiency (MCADD) using non-derivatized tandem MS neonatal screening data.
Newborn screening programs for severe metabolic disorders using tandem mass spectrometry are widely used. Medium-Chain Acyl-CoA dehydrogenase deficiency (MCADD) is the most prevalent mitochondrial fatty acid oxidation defect (1:15,000 newborns) and it has been proven that early detection of this metabolic disease decreases mortality and improves the outcome. In previous studies, data mining methods on derivatized tandem MS datasets have shown high classification accuracies. However, no machine learning methods currently have been applied to datasets based on non-derivatized screening methods. A dataset with 44,159 blood samples was collected using a non-derivatized screening method as part of a systematic newborn screening by the PCMA screening center (Belgium). Twelve MCADD cases were present in this partially MCADD-enriched dataset. We extended three data mining methods, namely C4.5 decision trees, logistic regression and ridge logistic regression, with a parameter and threshold optimization method and evaluated their applicability as a diagnostic support tool. Within a stratified cross-validation setting, a grid search was performed for each model for a wide range of model parameters, included variables and classification thresholds. The best performing model used ridge logistic regression and achieved a sensitivity of 100%, a specificity of 99.987% and a positive predictive value of 32% (recalibrated for a real population), obtained in a stratified cross-validation setting. These results were further validated on an independent test set. Using a method that combines ridge logistic regression with variable selection and threshold optimization, a significantly improved performance was achieved compared to the current state-of-the-art for derivatized data, while retaining more interpretability and requiring less variables. The results indicate the potential value of data mining methods as a diagnostic support tool.


A tsunami deposit at the cretaceous-tertiary boundary in Texas.
At sites near the Brazos River, Texas, an iridium anomaly and the paleontologic Cretaceous-Tertiary boundary directly overlie a sandstone bed in which coarse-grained sandstone with large clasts of mudstone and reworked carbonate nodules grades upward to wave ripple-laminated, very fine grained sandstone. This bed is the only sandstone bed in a sequence of uppermost Cretaceous to lowermost Paleocene mudstone that records about 1 million years of quiet water deposition in midshelf to outer shelf depths. Conditions for depositing such a sandstone layer at these depths are most consistent with the occurrence of a tsunami about 50 to 100 meters high. The most likely source for such a tsunami at the Cretaceous-Tertiary boundary is a bolidewater impact.


Fecal Microbiota Transplantation for the Critically Ill Patient.
The gut microbiome has been implicated in a diversity of diseases, such as irritable bowel syndrome, inflammatory bowel disease, hepatic steatosis, metabolic syndrome, obesity, and anxiety. Current research also suggests the presence of a bidirectional relationship between the composition of the gut microbiome and critical illness. In the critical care setting, multiple factors (eg, use of antibiotics, aberrant nutrition, bloodstream infections, bowel ischemia, and abnormal bowel motility) strongly contribute to intestinal dysbiosis. Conversely, early studies have associated intestinal dysbiosis with worse clinical outcomes in the intensive care unit (ICU), such as infection, organ failure, and mortality. The possibility of intestinal dysbiosis influencing these clinical outcomes has prompted the question of whether microbiome manipulation strategies, such as fecal microbiota transplantation (FMT), may have a role in the management of critical illness. After a literature search of FMT used in the ICU for indications other than Clostridium difficile infections, we found 4 case reports that describe the use of FMT in 5 critically ill patients with systemic inflammatory responses and no clear source of infection. This review discusses the relationship between the gut microbiome and critical illness, early data on the use of FMT in critical care, and safety considerations of FMT in the critically ill and immunocompromised populations.


Energy-Reduced Arrhythmia Termination Using Global Photostimulation in Optogenetic Murine Hearts.
Complex spatiotemporal non-linearity as observed during cardiac arrhythmia strongly correlates with vortex-like excitation wavelengths and tissue characteristics. Therefore, the control of arrhythmic patterns requires fundamental understanding of dependencies between onset and perpetuation of arrhythmia and substrate instabilities. Available treatments, such as drug application or high-energy electrical shocks, are discussed for potential side effects resulting in prognosis worsening due to the lack of specificity and spatiotemporal precision. In contrast, cardiac optogenetics relies on light sensitive ion channels stimulated to trigger excitation of cardiomyocytes solely making use of the inner cell mechanisms. This enables low-energy, non-damaging optical control of cardiac excitation with high resolution. Recently, the capability of optogenetic cardioversion was shown in Channelrhodopsin-2 (ChR2) transgenic mice. But these studies used mainly structured and local illumination for cardiac stimulation. In addition, since optogenetic and electrical stimulus work on different principles to control the electrical activity of cardiac tissue, a better understanding of the phenomena behind optogenetic cardioversion is still needed. The present study aims to investigate global illumination with regard to parameter characterization and its potential for cardioversion. Our results show that by tuning the light intensity without exceeding 1.10 mW mm-2, a single pulse in the range of 10-1,000 ms is sufficient to reliably reset the heart into sinus rhythm. The combination of our panoramic low-intensity photostimulation with optical mapping techniques visualized wave collision resulting in annihilation as well as propagation perturbations as mechanisms leading to optogenetic cardioversion, which seem to base on other processes than electrical defibrillation. This study contributes to the understanding of the roles played by epicardial illumination, pulse duration and light intensity in optogenetic cardioversion, which are the main variables influencing cardiac optogenetic control, highlighting the advantages and insights of global stimulation. Therefore, the presented results can be modules in the design of novel illumination technologies with specific energy requirements on the way toward tissue-protective defibrillation techniques.


Filaments assembly of ectopically expressed Caenorhabditis elegans lamin within Xenopus oocytes.
Lamins are the major components of the nuclear lamina, a filamentous layer underlying the inner nuclear membrane and attached to the peripheral chromatin. Lamins are required for maintaining nuclear shape and are involved in most nuclear activities. Here, we studied the 3D organization of the nuclear lamina formed upon the expression of Caenorhabditis elegans lamin (Ce-lamin) within the nucleus of a Xenopus laevis oocyte. We show that Ce-lamin forms an intricate 3D meshwork of 5-6 nm lamin protofilaments. The diverse protofilament interactions and organization may shed light upon the unique mechano-elastic properties of the nuclear lamina scaffold supporting the nuclear envelope. The Q159K Hutchinson-Gilford Progeria Syndrome-linked mutation alters interactions between protofilaments within the lamina, leading to the formation of more bundled arrays of less isotropically-oriented protofilaments. Using this system, we show for the first time the organization of lamin proteins that were translated and assembled within the environment of a living cell.


Exploration of Potential Biomarkers for Type 2 Diabetes by UPLC-QTOF-MS and WGCNA of Skin Surface Lipids.
Diabetes has become popular and has become one of the most important global health care challenges. Patients with diabetes have a high incidence of skin diseases. Cell and animal models are often used to study the skin conditions of people with diabetes. In this study, a volunteer questionnaire survey, skin lipomics analysis based on ultra-high performance liquid chromatography-quadrupole tandem time-of-flight mass spectrometry (UPLC-QTOF-MS), and weighted gene co-expression network analysis (WGCNA) were used to study the differences in skin conditions and skin lipids of participants with type 2 diabetes mellitus (Group D) versus healthy individuals (Group H) and the correlation between these groups. The questionnaire was used to investigate personal basic, diabetes, and facial skin status information of 77 female volunteers aged 55-65 years old from the Peking University Shougang Hospital. The facial skin lipids of all volunteers were analysed by UPLC-QTOF-MS technique; the differential lipids between groups D and H were analysed by partial least-squared discriminant and univariate analysis. In total, 23 kinds of differential lipids were identified, all of which belonged to sphingolipids. The use of WGCNA combined clinical information with lipid analysis to study the relationship between glycosylated haemoglobin, skin pigmentation/non-pigmentation, and skin lipids. Two types of lipids were identified to distinguish between hub lipids of high and low glycosylated haemoglobin; 12 types of lipids were identified that could distinguish between the hub lipids of pigmented and non-pigmented participants (PLS-DA). The experimental results not only provide a reference for the diagnosis and classification of diabetes via analysing the skin lipids of patients, but also provides a theoretical basis for further study on the effects of diabetes on the skin of patients.


Treatment trends for muscle-invasive bladder cancer in Germany from 2006 to 2019.
To examine national treatment trends of muscle-invasive bladder cancer (MIBC) in Germany with a special focus on radical cystectomy (RC). Population-based data were derived from the nationwide hospital billing database of the German Federal Statistical Office and institution-related information from the reimbursement.INFO tool based on hospitals' quality reports from 2006 to 2019. Additionally, we used the German National Center for Cancer Registry data to analyze all cases of bladder cancer with stage ≥ T2 who received RC, chemotherapy, radiation therapy or a combination from 2006 to 2017. The annual number of RC cases in Germany increased by 28% from 5627 cases in 2006 to 7292 cases in 2019 (p = 0.001). The proportion of patients undergoing RC remained constant at about 75% in all age groups between 2006 and 2017 (p = 0.3). Relative to all performed RC, the proportion of patients > 75 years increased from 25% in 2006 to 38% in 2019 (p = 0.03). The proportion of patients receiving a combination of RC and chemotherapy increased from 9% in 2006 to 13% in 2017 (p = 0.005). In 2006, 8 of 299 urology departments (2.7%) performed more than 50 RCs per year, which increased to 17 of 360 (4.7%) in 2019. In 2019, 107 departments (29%) performed 25-49 RCs and 236 (66%) departments performed < 25 RCs. In Germany, three out of four patients with MIBC receive RC and the proportion of patients > 75 years is increasing. The combination of surgery and chemotherapy is increasingly used. With overall increasing case numbers, there is a slight tendency towards centralization.


In vitro activity of ferroquine against artemisinin-based combination therapy (ACT)-resistant Plasmodium falciparum isolates from Cambodia.
Cambodia is the epicentre of resistance emergence for virtually all antimalarial drugs. Selection and spread of parasites resistant to artemisinin-based combination therapy (ACT) is a major threat for malaria elimination, hence the need to renew the pool of effective treatments. To determine whether ACT resistance haplotypes could have an effect on ferroquine in vitro antimalarial activity. In vitro susceptibility to ferroquine was measured for 80 isolates from Cambodia characterized for their molecular resistance profile to artemisinin, piperaquine and mefloquine. Among the 80 isolates tested, the overall median (IQR) IC50 of ferroquine was 10.9 nM (8.7-18.3). The ferroquine median (IQR) IC50 was 8.9 nM (8.1-11.8) for Pfk13 WT parasites and was 12.9 nM (9.5-20.0) for Pfk13 C580Y parasites with no amplification of Pfpm2 and Pfmdr1 genes. The median (IQR) IC50 of ferroquine for Pfk13 C580Y parasites with amplification of the Pfpm2 gene was 17.2 nM (14.5-20.5) versus 9.1 nM (7.9-10.7) for Pfk13 C580Y parasites with amplification of the Pfmdr1 gene. Ferroquine exerts promising efficacy against ACT-resistant isolates. Whereas Pfpm2 amplification was associated with the highest parasite tolerance to ferroquine, the susceptibility range observed was in accordance with those measured in ACT resistance-free areas. This enables consideration of ferroquine as a relevant therapeutic option against ACT-resistant malaria.


Endovenous laser: a new minimally invasive method of treatment for varicose veins--preliminary observations using an 810 nm diode laser.
Long-term success in the treatment of truncal and significant branch leg varicosities, when the saphenofemoral junction (SFJ) and the greater saphenous vein (GSV) are involved, depends on the elimination of the highest point of reflux and the incompetent venous segment, and is best achieved by surgical ligation and stripping. Minimally invasive alternatives in the treatment of varicose veins with SFJ and GSV incompetence have been tried over the years to increase patient comfort, reduce cost and risk, and allow implementation by a wide variety of practitioners resulting in varying degrees of success depending on the fulfillment of the above two premises and the effectiveness of the method used. To demonstrate a novel way to use laser energy through an endoluminal laser fiber for the minimally invasive treatment of truncal varicosities that eliminates the highest point of reflux and the incompetent segment. Patients were treated with 810 nm diode laser energy administered endovenously through a bare-tipped laser fiber (400-750 microm). Vein access for endoluminal placement of the fiber through a catheter was achieved by means of percutaneous or stab wound incision under ultrasound guidance and local anesthesia. Exact placement of the fiber was determined by direct observation of the aiming beam through the skin and by ultrasound confirmation. Preliminary short-term postprocedure results (up to 1 year, 2 months after treatment) in the endovenous laser treatment of 40 greater saphenous veins in 33 patients indicate a 100% rate of closure with no significant complications. In addition, a 2-year experience of 80 cases of isolated branch varicosities (Giacomini, anterolateral branch, etc.) also shows a 100% rate of closure. Early results of our endoluminal laser methodology indicate a very effective and safe way to eliminate SFJ incompetence and close the GSV. With proper patient selection, the ease of methodology and the reduced risk and cost associated with endovenous laser treatment may make it a successful minimally invasive alternative for a wide group of patients that previously would have required ligation and stripping.


A novel liquid template corrosion approach for layered silica with various morphologies and different nanolayer thicknesses.
A novel liquid template corrosion (LTC) method has been developed for the synthesis of layered silica materials with a variety of morphologies, including hollow nanospheres, trilobite-like nanoparticles, spherical particles and a film resembling the van Gogh painting 'Starry Night'. Lamellar micelles and microemulsion droplets are first formed in an oil-water (O/W) mixture of ethyl acetate (EA), cetyltrimethylammonium bromide (CTAB) and water. After adding aqueous ammonia the EA becomes hydrolyzed, which results in corrosion of microemulsion droplets. These droplets subsequently act as templates for the synthesis of silica formed by hydrolysis of tetraethyl orthosilicate. The morphological evolution of silica can be tuned by varying the concentration of aqueous ammonia which controls the degree of corrosion of the microemulsion droplet templates. A possible mechanism is proposed to explain why the LTC approach affords layered silica nanostructured materials with various morphologies and nanolayer thickness (2.6-4.5 nm), rather than the usual ordered mesostructures formed in the absence of EA. Our method provides a simple way to fabricate a variety of building blocks for assembling nanomaterials with novel structures and functionality, which are not available using conventional template methods.


[Analysis of Imaging Performance Standards of CBCT X-IGRT System Used in Radiotherapy].
This article briefly describes the imaging performance standards of the kilovolt X-ray image guidance system used in radiotherapy, analyzes the main aspects that should be considered in the image quality of X-IGRT system, and focuses on parameters that should be considered in the imaging performance evaluation criteria of the CBCT X-IGRT. The purpose is to sort out the imaging performance evaluation standards of kilovolt X-IGRT system, clarify the image quality requirements of X-IGRT equipment, and reach a consensus when evaluating the imaging performance of X-IGRT system.


Retinal GFAP and bFGF expression after multiple argon laser photocoagulation injuries assessed by both immunoreactivity and mRNA levels.
The expression of GFAP and bFGF after retinal photocoagulation injury in the rat was assessed by immunocytochemistry and reverse transcriptase PCR. Beta-actin mRNA expression was unaltered after injury and was therefore a good control for the quality of the RNA samples and the PCR reaction. GFAP mRNA increased from undetectable levels in normal retina to relatively high levels at 24 and 48 hr after injury, returning to barely detectable levels at 3 and 7 days. Müller cell GFAP immunoreactivity was elevated by 24 hr, stronger by 48 hr and persisted for 30-45 days. Thus, the expression of GFAP immunoreactivity after photocoagulation was due to new protein synthesis but the mRNA, and therefore the stimulus, was only present for a few days. This indicates that the GFAP protein in Müller cells has a long lifetime similar to that of astrocytes despite different gene control elements. bFGF is a possible stimulus for Müller GFAP expression because Müller cells have bFGF receptors. bFGF mRNA was detectable in normal, 24 and 48 hr retinas but decreased to undetectable levels (even after 35 cycles of PCR) at three days after injury and had only partly recovered by 7 days. Immunocytochemistry demonstrated a rapid change in localization of bFGF at the lesion sites early after lesion. At 2-3 days bFGF in blood vessels was markedly increased while at 7 days there was an increase around the photoreceptors flanking each lesion. These shifts in bFGF localization were too late to be a stimulus for the widespread upregulation of GFAP expression by Müller cells. The reduction in bFGF mRNA at three days was unexpected as studies of brain injury generally show a longer lasting elevation of bFGF expression. Therefore it is likely that bFGF expression is controlled by different mechanisms in the retina compared to the brain. However, a reduction in bFGF synthesis after photocoagulation is consistent with the anti-angiogenic effect of laser photocoagulation in diabetic retinopathy.


Identification of PFKFB2 as a key gene for the transition from acute to old myocardial infarction in peripheral blood.
This study aims to analyze the gene expression profile of peripheral blood in different stages of myocardial infarction (MI) by transcriptome sequencing, and to study the gene expression characteristics of peripheral blood after MI. Differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) were used to identify genes and modules associated with old myocardial infarction (OMI). Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation were applied to analyze the potential functions of genes. Hub genes were identified by Random Forest Classifier. CIBERSORT was used to provide an estimate of the abundance of 22 immune cells in peripheral blood. Quantitative polymerase chain reaction (qPCR) was used to detect gene expression levels in clinical samples. The cellular components (CC) of peripheral blood were counted by an automatic hematology analyzer. Through differential gene analysis and co-expression network analysis, 11 candidate genes were obtained. A random forest classifier identified 10 hub genes. Immune cell distribution of peripheral blood was found that T cell CD4 memory resting, NK cells resting, Dendritic cells activated, Mast cells resting, Monocytes and Neutrophils were correlated with OMI. Spearman correlation analysis found that PFKFB2 is related to the above immune cells. Low expression of PFKFB2 in peripheral blood of OMI was detected in clinical samples, and the relationship between PFKFB2 and peripheral blood immune cell counts was analyzed, which showed monocytes were associated with PFKFB2 in our study. PFKFB2 was low expressed in OMI, and related to the distribution of immune cells. PFKFB2 may play a key role in reflecting the transition from AMI to OMI, and predicting the distribution of immune cells, which provided a new perspective for improving myocardial fibrosis and adverse remodeling.


Differential stability of 28s and 18s rat liver ribosomal ribonucleic acids.
Rat liver ribosomal RNA (rRNA) free from nuclease contaminants was isolated by a modification of the phenol technique. The 28s and 18s rRNA species were separated by preparative agar-gel electrophoresis. The two rRNA species were heated at different temperatures under various conditions and the amount of undegraded rRNA was determined by analytical agar-gel electrophoresis. The 18s rRNA remained unaltered after heating for up to 10min. at 90 degrees in water, acetate buffer, pH5.0, or phosphate buffer, pH7.0. Under similar or milder conditions 28s rRNA was partially degraded, giving rise to a well-delimited 6s peak and a heterogeneous material located in the zone between 28s and 6s. The dependence of degradation of 28s rRNA on the temperature and the ionic strength of the medium was studied. The greatest extent of degradation of 28s rRNA was observed on heating at 90 degrees in water. It is suggested that the instability of rat liver 28s rRNA is due to two factors: the presence of hidden breaks in the polymer chain and a higher susceptibility of some phosphodiester bonds to thermal hydrolysis.


Automatic identification of fluorescently labeled brain cells for rapid functional imaging.
The on-line identification of labeled cells and vessels is a rate-limiting step in scanning microscopy. We use supervised learning to formulate an algorithm that rapidly and automatically tags fluorescently labeled somata in full-field images of cortex and constructs an optimized scan path through these cells. A single classifier works across multiple subjects, regions of the cortex of similar depth, and different magnification and contrast levels without the need to retrain the algorithm. Retraining only has to be performed when the morphological properties of the cells change significantly. In conjunction with two-photon laser scanning microscopy and bulk-labeling of cells in layers 2/3 of rat parietal cortex with a calcium indicator, we can automatically identify ∼ 50 cells within 1 min and sample them at ∼ 100 Hz with a signal-to-noise ratio of ∼ 10.


Diffusion kurtosis imaging of white matter in bipolar disorder.
White matter pathology likely contributes to the pathogenesis of bipolar disorder (BD). Most studies of white matter in BD have used diffusion tensor imaging (DTI), but the advent of more advanced multi-shell diffusion MRI imaging offers the possibility to investigate other aspects of white matter microstructure. Diffusion kurtosis imaging (DKI) extends the DTI model and provides additional measures related to diffusion restriction. Here, we investigated white matter in BD by applying whole-brain voxel-based analysis (VBA) and a network-based connectivity approach using constrained spherical deconvolution tractography to assess differences in DKI and DTI metrics between BD (n = 25) and controls (n = 24). The VBA showed lower mean kurtosis in the corona radiata and posterior association fibers in BD. Regional differences in connectivity were indicated by lower mean kurtosis and kurtosis anisotropy in streamlines traversing the temporal and occipital lobes, and lower mean axial kurtosis in the right cerebellar, thalamo-subcortical pathways in BD. Significant differences were not seen in DTI metrics following FDR-correction. The DKI findings indicate altered connectivity across cortical, subcortical and cerebellar areas in BD. DKI is sensitive to different microstructural properties and is a useful complementary technique to DTI to more fully investigate white matter in BD.


Clinical significance of duodenal lymphangiectasia incidentally found during routine upper gastrointestinal endoscopy.
Although duodenal lymphangiectasia in individuals without clinical evidence of malabsorption has been reported, the prevalence and clinical significance in this situation are not yet known. The aim of this study was to evaluate the prevalence and clinical significance of incidentally found duodenal lymphangiectasia. A retrospective review of medical records was undertaken for consecutive patients who had undergone diagnostic upper endoscopy between January 2005 and June 2006. A prospective study was then performed in consecutive individuals undergoing routine upper endoscopy for health examination between July 2006 to October 2006. Endoscopic features of duodenal lymphangiectasia were classified into three types: (1) multiple scattered pinpoint white spots; (2) diffuse prominent villi with whitish-discolored tips; and (3) focal small whitish macule or nodule. The histologic grade of duodenal lymphangiectasia was classified according to the depth and severity of lymphatic duct dilatations. Prevalence and clinical data of incidentally found duodenal lymphangiectasia were evaluated in the retrospective and prospective studies. Among 1866 retrospective cases, duodenal lymphangiectasia was endoscopically suspected in 59 cases (3.2%), and histologically confirmed in 35 cases (1.9%). No clinical evidence of malabsorption was noted in the duodenal lymphangiectasia cases. The "scattered pinpoint white spots" type was the most frequently found endoscopic feature (40.0%). Duodenal lymphangiectasia was persistent in seven of 10 individuals who underwent repeat endoscopy after a median of 12 months. Among 134 prospective cases, duodenal lymphangiectasia was histologically confirmed in 12 cases (8.9%). There was no significant clinical difference between groups with and without duodenal lymphangiectasia. Lymphatic duct dilatation was histologically more severe in the "focal small whitish macule or nodule" type than in the other types. Duodenal lymphangiectasia without clinical evidence of malabsorption is not extremely rare among cases undergoing routine upper gastrointestinal endoscopy.


Short-chain phosphatidylethanolamines: physical properties and susceptibility of the monomers to phospholipase A2 action.
The homologous series of optically active short-chain phosphatidylethanolamines (PE) from dibutyryl-PE to dioctanoyl-PE was synthesized. In addition, two monomeric short-chain phospholipid analogues that are not degraded by phospholipase A2 (1,2-bis[(butylcarbamyl)oxy]-sn-glycero-3-phosphocholine and the corresponding ethanolamine derivative) were synthesized. In contrast to the short-chain phosphatidylcholines (PC), short-chain PE's have defined solubilities in water. No break below the solubility limit was found in surface tension plots, suggesting that these compounds exist as monomers in aqueous solution. Only when a significant fraction of the molecules is negatively charged can they form micelles by themselves. Cobra venom phospholipase A2 hydrolyzes monomeric short-chain PE's at about the same rate as short-chain PC's but hydrolyzes long-chain PC's much more rapidly than long-chain PE's. The hydrolysis of short-chain PE's is found to be activated by phosphocholine-containing compounds only in the presence of an interface; in its absence phosphocholine-containing compounds can act as competitive inhibitors. Possible explanations for this phenomenon are considered.


French consumers know the benefits of pulses, but do not choose them: An exploratory study combining indirect and direct approaches.
Pulses present nutritional advantages for human health, and also contribute to food security and environmental sustainability. Despite these beneficial properties, the consumption of pulses in France has decreased over the past century. This study explores the representation of pulses among French non-vegetarian consumers, using both an indirect approach, with scenarios evoking real-life situations, and a direct approach, with an online questionnaire. For the indirect approach, based on six different scenarios, the 120 participants composed dishes by selecting three food images out of the twenty provided. One week later, for the direct approach, the same participants completed a questionnaire, with ten questions about food products, using the same images. Results showed that spontaneous selection of pulses was low for all dish-composition situations, coherent with the low consumption of pulses declared in the questionnaire. Among possible barriers to pulse consumption were dislike of pulses, preparation difficulty, and perception of pulses as a food for vegetarians. Participants possessed theoretical knowledge about the benefits of pulses, but this knowledge seemed not to be applied to dish-composition situations. Results also highlighted the complementarity of these two methods, providing deeper understanding of consumer food habits in relation to pulses. Based on these findings, several levers are proposed to increase pulse consumption: improving familiarity with pulses, using the context of consumption, formulating trendy and innovative products, and promoting pulses as a "food for all".


Prothrombin gene mutation G20210A, homocysteine, antiphospholipid antibodies and other hypercoagulable states in ocular thrombosis.
The purpose of the present study was to determine whether using an extended panel of laboratory tests increases the detection of a hypercoagulable state in patients with ocular thromboses. Twenty consecutive patients with ocular thromboses (vein, artery, or choriocapillaris occlusions) underwent testing for activated protein C resistance/factor V Leiden, prothrombin G20210A, lupus anticoagulant, anticardiolipin antibodies, hyperhomocysteinemia, and deficiencies of protein C, protein S, and antithrombin. For each patient, we selected two age-matched and gender-matched individuals without ocular thromboses as controls. Sixteen of the 20 patients (80%) had one or more laboratory tests that supported a hypercoagulable condition. Prothrombin G20210A (P < 0.02) and hyperhomocysteinemia (P < 0.0006) were significantly more frequent in ocular thrombosis patients compared with controls. The most common condition was antiphospholipid antibody syndrome, present in 40% of patients (confirmed by repeat testing at least 6 weeks later), but this did not reach statistical significance compared with the controls. No patients with ocular thromboses had hereditary abnormalities of protein S, protein C, or antithrombin. In conclusion, an extended panel of laboratory tests improved the detection of a hypercoagulable state in ocular thromboses. Testing for homocysteine, antiphospholipid antibodies, and the prothrombin G20210A mutation should be considered in patients with ocular thromboses.


[Congenital cervical thymic cyst].
Congenital cervical thymic cysts are a very rare cause of tumor of the neck in children. They can exceptionally induce a laryngeal compression. Actual identification of the tumor may sometimes be made only after surgery and histologic examination. Evolution is benign. Their existence seems to be related to the persistence of thymic remnants in the neck.


Strontium-89 chloride (Metastron) for palliative treatment of bony metastases. The University of Minnesota experience.
Strontium-89 chloride (Metastron) is an FDA-approved treatment for palliation of cancer pain. We evaluated blood count changes and pain relief in 28 patients with widespread painful bony metastasis treated with strontium-89 at the University of Minnesota Hospital and Clinics. Eighteen patients had prostate cancer (all hormone-refractory cancer), seven patients had breast cancer, and three patients had lung cancer, all previously treated with either radiation, chemotherapy, or a combination of the two. Serial blood counts were performed weekly up to 8 weeks and at 12 weeks after administering Metastron. Pain scale and blood values were monitored simultaneously. The mean baselines of hemoglobin (Hgb), white blood count (WBC), and platelets (Plts) were 11.4, 5900, and 258,000, respectively. The mean dose of Metastron was 3 mCi (range 2.2-4.4). The median time (range) to nadir was about 6 weeks. The percentage reductions relative to baseline were 32% (range 0-72%) for WBC; 14% (range 0-50%) for Hgb; 15% (range 0-47%) for the red blood cell (RBC) count; and 40% (range 0-85%)for Plts. We did not find a close relationship among the baseline blood count, reduction of subsequent blood counts, or previously irradiated active bone marrow volume. The median time of survival was 23 weeks (range 2-66 weeks). At 12 weeks, 29% of patients had moderate to dramatic improvement of pain, 32% had some relief of pain, and 50% had no improvement in pain. Thirty-two percent of the treated patients required additional palliative external beam radiation to their bony lesions within the study period. Our results show that Metastron for palliation for bony metastases should be used with caution because of moderate to severe bone marrow toxicity, especially in platelets, associated with its use. Careful evaluation of patients given Metastron is needed to assess accurately its full benefit.


Stable carbon isotope fractionation during aerobic biodegradation of chlorinated ethenes.
Stable isotope analysis is recognized as a powerful tool for monitoring, assessing, and validating in-situ bioremediation processes. In this study, kinetic carbon isotope fractionation factors (epsilon) associated with the aerobic biodegradation of vinyl chloride (VC), cis-1,2-dichloroethylene (cDCE), and trichloroethylene (TCE) were examined. Of the three solvents, the largest fractionation effects were observed for biodegradation of VC. Both metabolic and cometabolic VC degradation were studied using Mycobacterium aurum L1 (grown on VC), Methylosinus trichosporium OB3b (grown on methane), Mycobacterium vaccae JOB5 (grown on propane), and two VC enrichment cultures seeded from contaminated soils of Alameda Point and Travis Air Force Base, CA. M. aurum L1 caused the greatest fractionation (epsilon = -5.7) while for the cometabolic cultures, epsilon values ranged from -3.2 to -4.8. VC fractionation patterns for the enrichment cultures were within the range of those observed for the metabolic and cometabolic cultures (epsilon = -4.5 to -5.5). The fractionation for cometabolic degradation of TCE by Me. trichosporium OB3b was low (epsilon = -1.1), while no quantifiable carbon isotopic fractionation was observed during the cometabolic degradation of cDCE. For all three of the tested chlorinated ethenes, isotopic fractionation measured during aerobic degradation was significantly smaller than that reported for anaerobic reductive dechlorination. This study suggests that analysis of compound-specific isotopic fractionation could assist in determining whether aerobic or anaerobic degradation of VC and cDCE predominates in field applications of in-situ bioremediation. In contrast, isotopic fractionation effects associated with metabolic and cometabolic reactions are not sufficiently dissimilar to distinguish these processes in the field.


Does the Organization of Plastic Surgery Units into Independent Departments Affect Academic Productivity?
There is an increased push for plastic surgery units in the United States to become independent departments administered autonomously rather than as divisions of a multispecialty surgery department. The purpose of this research was to determine whether there are any quantifiable differences in the academic performance of departments versus divisions. Using a list of the plastic surgery units affiliated with the American Council of Academic Plastic Surgeons, unit Web sites were queried for departmental status and to obtain a list of affiliated faculty. Academic productivity was then quantified using the SCOPUS database. National Institutes of Health funding was determined through the Research Portfolio Online Reporting Tools database. Plastic surgery departments were comparable to divisions in academic productivity, evidenced by a similar number of publications per faculty (38.9 versus 38.7; p = 0.94), number of citations per faculty (692 versus 761; p = 0.64), H-indices (9.9 versus 9.9; p = 0.99), and National Institutes of Health grants (3.25 versus 2.84; p = 0.80), including RO1 grants (1.33 versus 0.84; p = 0.53). There was a trend for departments to have a more equitable male-to-female ratio (2.8 versus 4.1; p = 0.06), and departments trained a greater number of integrated plastic surgery residents (9.0 versus 5.28; p = 0.03). This study demonstrates that the academic performance of independent plastic surgery departments is generally similar to divisions, but with nuanced distinctions.


[Leucine aminopeptidase crystals from the bovine pancreas].
Crystals of leucinaminopeptidase from bovine pancreas were obtained. Space group (P6322), parameters of the cell a-b-132 A, c = 122 A and distribution of spot intensities on precessional X-ray patterns were in full agreement with corresponding parameters for leucinaminopeptidase crystals from bovine eye lens. A conclusion is drawn about similarity between the spatial structures of leucinaminopeptidase from bovine pancreas and eye lens.


Comparison between the International Classification of Primary Care and the International Classification of Diseases Classifications in Primary Care in Korea.
The International Classification of Primary Care-2 (ICPC-2) is a classification method designed for primary care. Although previous studies have found that ICPC-2 is a useful tool for demonstrating the relationship between patients' expectations and health providers' diagnoses, its utility of ICPC-2 has yet to be fully studied in Korea. This study aimed to evaluate the practicality of ICPC-2 in Korean primary care. The study was conducted at primary care clinics in Seoul and Gyeonggi areas from October to November 2015. Third-year family medicine residents examined and analyzed the medical records of patients who visited primary care physicians using ICPC-2, and the results were compared with those obtained using the International Classification of Diseases-10 (ICD-10) (Korean version: Korean Standard Classification of Diseases-7). A total of 26 primary care physicians from 23 primary care clinics participated in the study. Furthermore, 2,458 ICD-10 codes and 6,091 ICPC-2 codes were recorded from the data of 1,099 patients. The common disease codes were vasomotor and allergic rhinitis (J30), according to ICD-10, and acute upper respiratory infection (R74) in ICPC-2. Comparing disease status by body systems, the proportion of gastrointestinal disease with ICD-10 codes was significantly higher than that with ICPC-2 codes (P<0.001). Furthermore, patients with >4 diagnoses accounted for 36% of the ICD-10 classifications, whereas those with >4 diagnoses accounted for 4% of the ICPC-2 classifications. Introducing ICPC as a complementary means for diagnosing common diseases could be a practical approach in Korean primary care.


Dysregulation of Lipid Metabolism in Mkp-1 Deficient Mice during Gram-Negative Sepsis.
Mitogen-activated protein kinase phosphatase (Mkp)-1 exerts its anti-inflammatory activities during Gram-negative sepsis by deactivating p38 and c-Jun N-terminal kinase (JNK). We have previously shown that Mkp-1+/+ mice, but not Mkp-1-/- mice, exhibit hypertriglyceridemia during severe sepsis. However, the regulation of hepatic lipid stores and the underlying mechanism of lipid dysregulation during sepsis remains an enigma. To understand the molecular mechanism underlying the sepsis-associated metabolic changes and the role of Mkp-1 in the process, we infected Mkp-1+/+ and Mkp-1-/- mice with Escherichia coli i.v., and assessed the effects of Mkp-1 deficiency on tissue lipid contents. We also examined the global gene expression profile in the livers via RNA-seq. We found that in the absence of E. coli infection, Mkp-1 deficiency decreased liver triglyceride levels. Upon E. coli infection, Mkp-1+/+ mice, but not Mkp-1-/- mice, developed hepatocyte ballooning and increased lipid deposition in the livers. E. coli infection caused profound changes in the gene expression profile of a large number of proteins that regulate lipid metabolism in wildtype mice, while these changes were substantially disrupted in Mkp-1-/- mice. Interestingly, in Mkp-1+/+ mice E. coli infection resulted in downregulation of genes that facilitate fatty acid synthesis but upregulation of Cd36 and Dgat2, whose protein products mediate fatty acid uptake and triglyceride synthesis, respectively. Taken together, our studies indicate that sepsis leads to a substantial change in triglyceride metabolic gene expression programs and Mkp-1 plays an important role in this process.


Chikungunya virus nonstructural protein 2 inhibits type I/II interferon-stimulated JAK-STAT signaling.
Chikungunya virus (CHIKV) is an emerging human pathogen transmitted by mosquitoes. Like that of other alphaviruses, CHIKV replication causes general host shutoff, leading to severe cytopathicity in mammalian cells, and inhibits the ability of infected cells to respond to interferon (IFN). Recent research, however, suggests that alphaviruses may have additional mechanisms to circumvent the host's antiviral IFN response. Here we show that CHIKV replication is resistant to inhibition by interferon once RNA replication has been established and that CHIKV actively suppresses the antiviral IFN response by preventing IFN-induced gene expression. Both CHIKV infection and CHIKV replicon RNA replication efficiently blocked STAT1 phosphorylation and/or nuclear translocation in mammalian cells induced by either type I or type II IFN. Expression of individual CHIKV nonstructural proteins (nsPs) showed that nsP2 was a potent inhibitor of IFN-induced JAK-STAT signaling. In addition, mutations in CHIKV-nsP2 (P718S) and Sindbis virus (SINV)-nsP2 (P726S) that render alphavirus replicons noncytopathic significantly reduced JAK-STAT inhibition. This host shutoff-independent inhibition of IFN signaling by CHIKV is likely to have an important role in viral pathogenesis.


Takotsubo Cardiomyopathy-Induced Cardiac Free Wall Rupture: A Case Report and Review of Literature.
Takotsubo cardiomyopathy (TCM) is an acquired form of cardiomyopathy that is commonly seen among post-menopausal women. It is characterized by left ventricular apical ballooning, electrocardiographic changes and mild elevation of cardiac enzymes in the absence of significant coronary artery stenosis. TCM usually has benign course. However, on rare instance, it can result in life-threatening and fatal complications including acute cardiogenic shock, ventricular arrhythmias and ventricular wall rupture. We herein report a case of a 77-year-old female who developed TCM complicated with massive pericardial effusion and cardiac arrest. The patient died and autopsy revealed normal coronaries with a slit-like rupture on the antero-apical surface of the heart extending into the papillary muscle. The clinical course, labs and angiographic findings preceding the cardiac rupture will be outlined. A thorough literature review including review of 14 previously reported case reports of TCM complicated with cardiac rupture will be included.


Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group.
Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwinia chrysanthemi ASNase (Erwinia) substitution was approved in 2011 for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown. Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to Erwinia but receiving all doses versus not receiving all ASNase doses. We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; P = .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with Erwinia substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; P = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P = .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; P = .03). Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.


What We Learned about COVID-19 So Far? Notes from Underground.
The novel coronavirus pandemic poses a major global threat to public health. Our knowledge concerning every aspect of COVID-19 is evolving rapidly, given the increasing data from all over the world. In this narrative review, the Turkish Thoracic Society Early Career Taskforce members aimed to provide a summary on recent literature regarding epidemiology, clinical findings, diagnosis, treatment, prevention, and control of COVID-19. Studies revealed that the genetic sequence of the novel coronavirus showed significant identity to SARS-CoV and MERS-CoV. Angiotensin-converting enzyme 2 receptor is an important target of the SARS-CoV-2 while entering an organism. Smokers were more likely to develop the disease and have a higher risk for ICU admission. The mean incubation period was 6.4 days, whereas asymptomatic transmission was reported up to 25 days after infection. Fever and cough were the most common symptoms, and cardiovascular diseases and hypertension were reported to be the most common comorbidities among patients. Clinical manifestations range from asymptomatic and mild disease to severe acute respiratory distress syndrome. Several patients showed typical symptoms and radiological changes with negative RT-PCR but positive IgG and IgM antibodies. Although radiological findings may vary, bilateral, peripherally distributed, ground-glass opacities were typical of COVID-19. Poor prognosis was associated with older age, higher Sequential Organ Failure Assessment score, and high D-dimer level. Chloroquine was found to be effective in reducing viral replication in vitro. Likewise, protease inhibitors, including lopinavir/ritonavir, favipiravir, and nucleoside analogue remdesivir were proposed to be the potential drug candidates in COVID-19 management. Despite these efforts, we still have much to learn regarding the transmission, treatment, and prevention of COVID-19.