Detection of recombinant breakpoint in the genome of human enterovirus E11 strain associated with a fatal nosocomial outbreak.
The aim of this study was to characterize the genome of a recombinant Enterovirus associated with severe and fatal nosocomial infection; it was typed as Echovirus 11 (E-11) according to the VP1 gene. Enterovirus infection is generally asymptomatic and self-limited, but occasionally it may progress to a more severe clinical manifestation, as in the case described here. Recombination plays a crucial role in the evolution of Enteroviruses (EVs) and has been recognized as the main driving force behind the emergence of epidemic strains associated with severe infection. Therefore, it is of utmost importance to monitor the circulation of recombinant strains for surveillance purposes. Enterovirus-RNA was detected in the serum and liver biopsy of patients involved in the nosocomial cluster by commercial One-Step qRT-PCR method and the Enterovirus strains were isolated in vitro. The EVs typing was determined by analyzing the partial-length of the 5'UTR and VP1 sequences with the web-based open-access Enterovirus Genotyping Tool Version 0.1. The amplicons targeting 5'UTR, VP1 and overlapping fragments of the entire genome were sequenced with the Sanger method. Phylogenetic analysis was performed comparing the VP1 and the full-genome sequences of our strains against an appropriate reference set of Enterovirus prototypes of the Picornaviridae genera and species retrieved from the Enterovirus Genotyping Tool. Recombination analysis was performed using RDP4 software. The Neighbor-Joining tree of the VP1 gene revealed that the 4 patients were infected with an identical molecular variant of Echovirus 11 (E-11). While the phylogenetic and the RDP4 analysis of the full-genome sequences provided evidence that it was a chimeric strain between an E-11 and a Coxsackievirus B (CV-B). The chimeric structure of the E-11 genome might have contributed to the severe infection and epidemic feature of the strain, but further biological characterizations are needed. The evidence reported in this study, highlights the limit of typing techniques based on the VP1 gene, as they fail to identify the emergence of recombinant strains with potentially more pathogenic or epidemic properties, thus providing only partial information on the epidemiology and pathogenesis of Enteroviruses.


Morphology and transport properties of membranes obtained by coagulation of cellulose solutions in isobutanol.
The evolution of structural-morphological transformations of cellulose membranes obtained from solutions in N-methylmorpholine-N-oxide through various temperature isobutanol coagulation baths and subsequent treatment with water and their transport properties were studied. Using SEM, it was found that during coagulation in water and drying of the membranes, a uniform monolithic microheterogeneous texture was formed. The replacement of an aqueous precipitation bath with an isobutanol one leads to the formation of a porous structure with wide pore size and shape distributions. With an increase in precipitant temperature in the as-formed membrane, transverse tunnel cavities are formed with respect to the membrane-forming axis, which collapses when the membrane is washed with water, forming a dense texture with a non-uniform membrane volume. The mechanical properties of the obtained membranes were determined and a mechanism is proposed that allows their values to be correlated with structural-morphological and transport properties.


Experimental studies of sensitization to beryllium, zirconium, and aluminum compounds in the rabbit.
In a study designed to assess the potential sensitizing and granulomagenic capacities of selected metallic salts, rabbits were inoculated intradermally with zirconium aluminum glycinate (ZAG), sodium zirconium lactate (NZL), aluminum chlorhydrate (ACH), BeSO 4, and ovalbumin (OVA) by single and multiple injections. Animals immunized with BeSO4 and with OVA developed delayed skin reactivity as well as antigen-specific alveolar macrophage migration inhibition. Neither single nor multiple injections of ZAG or ACH resulted in clear-cut positive skin reactivity, macrophage migration inhibitory factor (MIF) production, or lymphocyte stimulation. Rabbits inoculated with multiple injections of NZL (500 microng) showed some marginally positive macrophage migration inhibition and skin reactivity. Histologically, ZAG and ACH were found to induce well-organized foreign-body granulomas after intradermal injection in both normal and inoculated rabbits. NZL and BeSO4 also induced skin granulomas, but these were less organized and distinct. Cell viability and ultrastructural studies indicated that BeSO4 was highly toxic for isolated alveolar macrophages in vitro at concentrations above 10 microng/ml, but NZL and ZAG did not exert such an effect at these dose levels. BeSO4 also depressed lymphocyte stimulation in sensitized animals which demonstrated delayed skin reactivity and macrophage migration inhibition.


Implications of phytoplankton chemical composition for zooplankton production: experimental evidence.
Growth and reproduction of twoDaphnia species (Cladocera) from Lake Constance were measured experimentally in a through-flow laboratory system under different food conditions, in order to investigate the effect of food quality on zooplankton populations. The cryptomonadRhodomonas sp. and the diatomStephanodiscus hantzschii were used as food. BothDaphnia species grew well at concentrations of 0.2-2.0 mgC/l ofRhodomonas sp., and 0.4-2.0 mgC/l ofS. hantzschii, whileStephanodiscus concentrations of 0.2 mgC/l did not supportDaphnia growth. Nitrogen content, which was very different in the two algae (C/N ratio = 4.9 forRhodomonas and 10.9 forS. hantzschii), was presumed to be the limiting factor. To test this hypothesis, nitrogen-limitedRhodomonas was offered to the cladocerans and their growth observed: the reduction in algal nitrogen content hindered animals' growth and reproduction. Results suggested that zooplankton production may also be affected by the chemical composition of the food algae, and that nitrogen potentially limits production, even in freshwater environments that are generally not N-limited.


The significance of cadmium in hair. The influence of a recommended washing procedure on the cadmium content of hair of rats experimentally exposed to cadmium.
The impact of a "mild" preanalytical washing procedure on an elevated Cd-content in hair was studied in newly grown hair of rats exposed to a large amount of Cd in their drinking water. A large part of the Cd in hair was removed by this procedure. Agitation by way of ultrasound seems to be no more effective than agitation by mechanical shaking. The effectiveness of washing varied in accordance with the type and duration of exposure.


Intestinal absorption of IgA in the newborn.
The aim of this study was to establish whether or not the newborn can absorb IgA from colostrum, using two feeding regimens. Single radial immunodiffusion on commercial Behring plates was used for IgA quantitation. In group A, 30 mature newborn infants born by vaginal delivery and fully breast fed, cord serum IgA concentration was 0.0990 +/- 0.0294 mg/ml (means +/- SEM). IgA was detectable in 9 of 30 infants. On the 3rd day of life, IgA concentration in serum was 0.3610 +/- 0.0194 mg/ml (means +/- SEM). It was detectable in all 30 infants; on the 5th day of life, its concentration was 0.4293 +/- 0.0365 mg/ml (means +/- SEM). In group B, 39 newborn infants born by cesarean section and fed boiled human milk exclusively, IgA was not detected either in cord, or in venous blood on the 3rd and 5th day of life. The rise of serum IgA in breast-fed newborn infants, highly significant from the 1st to the 3rd day of life (p less than 0.0001), and its increase between the 3rd and 5th day, although not significant, was in distinct contrast to the undetectable serum IgA in newborn infants fed boiled human milk. These data strongly suggest that IgA absorption from colostrum occurs at least until the 3rd day of life.


Biosynthesis of the Ca2+- and Mg2+-dependent adenosine triphosphatase of sarcoplasmic reticulum in cell cultures of embryonic chick heart.
The biosynthesis of the Ca2+- and Mg2+-dependent adenosine triphosphatase of sarcoplasmic reticulum was studied in cell cultures of embryonic chick heart. Rates of synthesis were estimated from the incorporation of tritium-labeled leucine into the ATPase. Newly synthesized ATPase was isolated from cells by immunoprecipitation. Radioactive leucine incorporation into the ATPase was determined by gel electrophoresis of the immunoprecipitates and counting of gel slices containing the ATPase band. Accumulation of the ATPase was estimated from the concentration of Ca2+ and Mg2+-dependent, hydroxylamine-sensitive phosphoprotein in the whole cell membrane fraction of cultured cells. Embryonic heart cells cultured in a medium which permitted cell proliferation showed approximately linearly increasing rates of ATPase synthesis and accumulation/culture plate as the cells proliferated. When cells were cultured in a serum-free medium, cell proliferation was inhibited and there was no sustained increase in the rate of ATPase synthesis or accumulation. Inclusion of isoproterenol or dibutyryl cyclic AMP at concentrations of 10 microM up to 1 mM in serum-free culture medium failed to stimulate significantly ATPase synthesis.


Knowledge and acceptance of hypertension guidelines in clinical practice: experience from Slovenia.
Arterial hypertension, which is an important risk factor for cardiovascular disease, is mainly treated by general practitioners. The initial step in an optimal therapeutic strategy for patients with arterial hypertension is the recognition and acceptance of hypertension guidelines by the physicians themselves. To find out how well Slovene general practitioners know the current hypertension guidelines and to what extent they accept them. Knowledge of current recommendations in hypertension diagnosis, treatment, follow-up and special indications was assessed for 813 general practitioners in Slovenia using a questionnaire. The Slovene National Guidelines were taken as the reference standard. Adequate knowledge of the guidelines' recommendations was defined as correct answers to at least seven out of eleven items; the correct answers had to include the appropriate target blood pressure, the elements of the "minimal diagnostic program" in hypertension and the correct estimation of cardiovascular risk. Acceptance of the guidelines was estimated on a five-grade scale: 5 meaning very useful, 1 meaning useless. A total of 321 questionnaires were suitable for analysis from 327 that were returned (a response rate of 40.2%). The mean number of correct answers was 7.8 (SD, 1.8, range, 4-11), but only 124 (38.8%) of the participating physicians answered the three key questions correctly. The physicians who answered the key questions correctly also answered more of the other questions correctly (6.1 vs. 5.4, p < 0.001). Adequate knowledge of the guidelines was found in 116 (36.8%) of the total study population; mean score for acceptance on the five-grade scale was 4.25. Knowledge of the guidelines was influenced by the physicians' acceptance of the guidelines' recommendations (p = 0.024). No other characteristics of physicians or organizational factors influencing knowledge of the guidelines were identified. Most of the participating physicians (72%) were willing to attend a workshop on managing hypertension and there was no connection between knowledge of the guidelines and willingness to attend the workshop. Knowledge of the hypertension guidelines among Slovene general practitioners is limited, and is comparable to the results of similar studies. The physicians' acceptance of the guidelines is high and correlates with their knowledge of the guidelines. A workshop is an accepted form of continuing medical education among general practitioners.


Multimodal measures of spontaneous brain activity reveal both common and divergent patterns of cortical functional organization.
Large-scale functional networks have been characterized in both rodent and human brains, typically by analyzing fMRI-BOLD signals. However, the relationship between fMRI-BOLD and underlying neural activity is complex and incompletely understood, which poses challenges to interpreting network organization obtained using this technique. Additionally, most work has assumed a disjoint functional network organization (i.e., brain regions belong to one and only one network). Here, we employed wide-field Ca2+ imaging simultaneously with fMRI-BOLD in mice expressing GCaMP6f in excitatory neurons. We determined cortical networks discovered by each modality using a mixed-membership algorithm to test the hypothesis that functional networks are overlapping rather than disjoint. Our results show that multiple BOLD networks are detected via Ca2+ signals; there is considerable network overlap (both modalities); networks determined by low-frequency Ca2+ signals are only modestly more similar to BOLD networks; and, despite similarities, important differences are detected across modalities (e.g., brain region "network diversity"). In conclusion, Ca2+ imaging uncovered overlapping functional cortical organization in the mouse that reflected several, but not all, properties observed with fMRI-BOLD signals.


Rapid detection of lactic acid bacteria by lateral flow immunochromatographic assay.
Lactic acid bacteria (LAB) cause quality deterioration including acidification and production of off-flavor components in food. To rapidly detect LAB, a lateral flow immunochromatographic assay (LFIA) was developed. An antibody (Ab) was obtained using Lactiplantibacillus plantarum as an immunogen, and the LFIA was performed based on this Ab. This showed positive reactions with LAB and a wide range of Gram-positive bacteria. An acid producing ability test using a semiconductor pH sensor was performed in combination with the LFIA. The bacteria testing positive in both the pH test (pH-positive) and the LFIA (LFIA-positive) were LAB. Twenty-three species of LAB in 13 genera could be detected specifically. Fresh foods and their equivalent spoiled foods were cultured for 0, 12, and 24 h, and the time required for the cultures to show LFIA-positive and pH-positive results was investigated. Of the 51 foods, 42 showed shorter culture times for the spoiled food than for the fresh food (spoilage detection rate: 82%). Amplicon analysis detected LAB including Leuconostoc citreum and Leuconostoc gelidum in spoiled foods. As this novel method can detect LAB in approximately 1 h, its use should make it possible to judge the freshness of food before shipping or sale.


Secretion of prorenin by a virilizing ovarian tumor.
A 53-year-old normotensive, normokalemic female presented with a 6-month history of virilization. Estradiol, LH, FSH, urinary-free cortisol, and DHEA-S levels were normal. Pelvic ultrasound and computerized tomography were also within normal limits. Her serum testosterone (551 ng/dl; nl, 20-70) and plasma prorenin (124 ng AI/ml/hr; nl, less than 50) levels were elevated. At surgery, a lipoid/steroid cell tumor of the right ovary was removed. Postoperative testosterone and prorenin levels were normal. Ovarian tumor cells, in culture, produced large amounts of prorenin. Immunohistochemistry localized prorenin and/or renin to tumor cells. Determining plasma prorenin levels may be a useful adjunct in diagnosing or following patients with nonepithelial ovarian tumors. A larger clinical study of prorenin levels in patients with such tumors is needed.


Body mass index, disordered eating behavior, and acquisition of health information: examining ethnicity and weight-related issues in a college population.
To investigate ethnic differences related to weight, the authors assessed body mass index, dysfunctional eating, receipt of health information, and perceived obstacles to healthy lifestyles of 210 ethnically diverse college women. The authors used the Eating Attitudes Test to assess dieting, food preoccupation, and bulimic behaviors. The authors found no ethnic differences in body mass index or disordered eating, but African Americans were more likely than were European Americans and Latina Americans to receive nutrition information from professionals and less likely than European Americans to perceive time as an obstacle. Overall, receipt of health information from a professional was related to fewer disordered eating behaviors; however, the specific eating behavior that was reduced varied by ethnicity. Health professionals should reconsider traditional assumptions of disordered eating behavior as a European American problem and consider cultural appropriateness in the development of effective health programs.


A synergy between mechanosensitive calcium- and membrane-binding mediates tension-sensing by C2-like domains.
When nuclear membranes are stretched, the peripheral membrane enzyme cytosolic phospholipase A2 (cPLA2) binds via its calcium-dependent C2 domain (cPLA2-C2) and initiates bioactive lipid signaling and tissue inflammation. More than 150 C2-like domains are encoded in vertebrate genomes. How many of them are mechanosensors and quantitative relationships between tension and membrane recruitment remain unexplored, leaving a knowledge gap in the mechanotransduction field. In this study, we imaged the mechanosensitive adsorption of cPLA2 and its C2 domain to nuclear membranes and artificial lipid bilayers, comparing it to related C2-like motifs. Stretch increased the Ca2+ sensitivity of all tested domains, promoting half-maximal binding of cPLA2 at cytoplasmic resting-Ca2+ concentrations. cPLA2-C2 bound up to 50 times tighter to stretched than to unstretched membranes. Our data suggest that a synergy of mechanosensitive Ca2+ interactions and deep, hydrophobic membrane insertion enables cPLA2-C2 to detect stretched membranes with antibody-like affinity, providing a quantitative basis for understanding mechanotransduction by C2-like domains.


Metabolite changes in HT-29 xenograft tumors following HIF-1alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo.
The hypoxia-inducible transcription factor (HIF-1alpha) plays a central role in tumor development. PX-478 is an experimental anti-cancer drug known to inhibit HIF-1alpha in experimental tumors. The purpose of this study was to identify MRS-visible metabolic biomarkers for PX-478 response prior to phase I/II clinical trials. Single-voxel in vivo localized (1)H spectra were obtained from HT-29 tumor xenografts prior and up to 24 h after treatment with a single dose of PX-478. Profiles of water-soluble and lipophilic metabolites were also examined ex vivo with both (1)H and (31)P spectroscopy for peak identification and to interrogate the underlying biochemistry of the response. The total choline (tCho) resonance was significantly decreased in vivo 12 and 24 h following treatment with PX-478 and this was confirmed with high-resolution (1)H and (31)P MRS. In non-aqueous extracts, significant reductions in cardiolipin, PtdEtn (phosphatidylethanolamine) and PtdI (phosphatidylinositol) were seen in response to PX-478. Although there were trends to a decrease in lactate (and lipid) resonances in vivo and ex vivo, these changes were not significant. This is in contrast to inhibition of in vitro glucose consumption and lactate production by PX-478 in HT-29 cells. The significant and robust change in tCho has identified this as a potential (1)H MRS-visible biomarker for drug response in vivo while high-resolution spectroscopy indicated that GPC, PC, myoI, PE, GPE, CL, PtdEtn and PtdI are potential ex vivo response biomarkers.


Determination of aloesin in plasma by high-performance liquid chromatography as fluorescent 9-anthroyl derivative.
A sensitive high-performance liquid chromatographic (HPLC) method for the determination of aloesin in plasma was developed. After solid-phase extraction from plasma and derivatization of aloesin and compound AD-1, which was prepared from aloesin as a internal standard, with 9-anthroylnitrile in the presence of quinuclidine, the derivatives were separated on a inertsil ODS-3 column using acetonitrile/methanol/water (3:1:6) as a mobile phase, and detected fluorimetrically at 460 nm with excitation at 360 nm. The detection limit of aloesin was 3.2 ng/ml in plasma (S/N = 3).


Routine blood parameters are helpful for early identification of influenza infection in children.
Routine blood parameters, such as the lymphocyte (LYM) count, platelet (PLT) count, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), lymphocytes multiplied by platelets (LYM*PLT) and mean platelet volume-to-platelet ratio (MPV/PLT), are widely used to predict the prognosis of infectious diseases. We aimed to explore the value of these parameters in the early identification of influenza virus infection in children. We conducted a single-center, retrospective, observational study of fever with influenza-like symptoms in pediatric outpatients from different age groups and evaluated the predictive value of various routine blood parameters measured within 48 h of the onset of fever for influenza virus infection. The LYM count, PLT count, LMR and LYM*PLT were lower, and the NLR and MPV/PLT were higher in children with an influenza infection (PCR-confirmed and symptomatic). The LYM count, LMR and LYM*PLT in the influenza infection group were lower in the 1- to 6-year-old subgroup, and the LMR and LYM*PLT in the influenza infection group were lower in the > 6-year-old subgroup. In the 1- to 6-year-old subgroup, the cutoff value of the LMR for predicting influenza A virus infection was 3.75, the sensitivity was 81.87%, the specificity was 84.31%, and the area under the curve (AUC) was 0.886; the cutoff value of the LMR for predicting influenza B virus infection was 3.71, the sensitivity was 73.58%, the specificity was 84.31%, and the AUC was 0.843. In the > 6-year-old subgroup, the cutoff value of the LMR for predicting influenza A virus infection was 3.05, the sensitivity was 89.27%, the specificity was 89.61%, and the AUC was 0.949; the cutoff value of the LMR for predicting influenza B virus infection was 2.88, the sensitivity was 83.19%, the specificity was 92.21%, and the AUC was 0.924. Routine blood tests are simple, inexpensive and easy to perform, and they are useful for the early identification of influenza virus infection in children. The LMR had the strongest predictive value for influenza virus infection in children older than 1 year, particularly in children older than 6 years with influenza A virus infection.


Chemical constituents, pharmacological action, antitumor application, and toxicity of Strychnine Semen from Strychnons pierriana A.W.Hill.: A review.
The dried and mature seeds of Strychnons pierriana A.W.Hill. have been called Strychnine Semen(S. Semen). It have been used in traditional Chinese medicine for nearly 400 years. In recent decades, scholars at home and abroad have widely used S. Semen in the treatment of tumor diseases, showing good anti-tumor effects. In this paper, the modern research achievements of S. Semen are reviewed, including traditional uses, phytochemistry, pharmacology, and toxicology. In recent years, the research on S. Semen has increased gradually, especially the research on its anti-tumor. This paper not only reviewed the traditional uses, chemical constituents and pharmacological activities of S. Semen, but also comprehensively listed the mechanisms of Strychnos in the treatment of different tumors, providing a review for further research and development of Strychnos resources. A systematic review of the literature on Fuzi was performed using several resources, namely classic books on Chinese herbal medicine and various scientific databases, such as PubMed, the Web of Science, and the China Knowledge Resource Integrated databases. The main constituents of S. Semen include alkaloids, terpenoids, steroids, and their glycosides. Modern studies have proved that S. Semen has a wide range of pharmacological effects, including anti-inflammatory and analgesic, anti-thrombotic, myocardial cell protection, immune regulation, nerve excitation, and anti-tumor effects. Among them, the anti-tumor effect has been the focus of research in recent years. S. Semen have a certain therapeutic effect on many kinds of tumors, such as liver cancer, colon cancer, and stomach cancer in the digestive system, breast, cervical, and ovarian cancer in the reproductive system, myeloma and leukemia in the blood system, and those in the nervous system and the immune system. Strychnine has an inhibitory effect on a variety of tumors. However, modern studies of strychnine are incomplete, and more in-depth studies are needed on its stronger bioactive constituents and potential pharmacological effects. The antitumor effect of Strychnine is worth further exploration.


The cardiac distress inventory: A new measure of psychosocial distress associated with an acute cardiac event.
Many challenges are posed by the experience of a heart attack or heart surgery which can be characterised as 'cardiac distress'. It spans multiple psychosocial domains incorporating patients' responses to physical, affective, cognitive, behavioural and social symptoms and experiences related to their cardiac event and their recovery. Although some measures of the psychological and emotional impacts of a cardiac event exist, none provides a comprehensive assessment of cardiac distress. To address this gap, the study aimed to develop a Cardiac Distress Inventory (CDI) using best practice in instrument design. An item pool was generated through analysis of cognate measures, mostly in relation to other health conditions and through focus group and individual review by a multidisciplinary development team, cardiac patients, and end-users including cardiac rehabilitation co-ordinators. The resulting 144 items were reduced through further reviews to 74 for testing. The testing was carried out with 405 people recruited from three hospitals, through social media and by direct enrolment on the study website. A two-stage psychometric evaluation of the 74 items used exploratory factor analysis to extract the factors followed by Rasch analysis to confirm dimensionality within factors. Psychometric analysis resulted in the identification of 55 items comprising eight subscales, to form the CDI. The subscales assess fear and uncertainty, disconnection and hopelessness, changes to roles and relationships, overwhelm and depletion, cognitive challenges, physical challenges, health system challenges, and death concerns. Validation against the Kessler 6 supports the criterion validity of the CDI. The CDI reflects a nuanced understanding of cardiac distress and should prove to be a useful clinical assessment tool, as well as a research instrument. Individual subscales or the complete CDI could be used to assess or monitor specific areas of distress in clinical practice. Development of a short form screening version for use in primary care, cardiac rehabilitation and counselling services is warranted.


The systemic stress response to thermal injury in children.
Thermal injury is extremely stressful, but data characterizing the endocrine stress response to this injury in children are sparse. The objective of this study was to measure the effects of thermal injury on the levels of stress hormones in children and to assess the temporal changes associated with them. Twenty-three children, 13 girls and 10 boys aged between 5 months and 12 years 3 months (mean, 2 years 11 months), with burns covering 10-61% of their body surface (mean, 20.5%) were studied during the first 5 days following injury. The levels of arginine vasopressin, angiotensin II, cortisol, adrenaline, noradrenaline and dopamine were measured in sequential blood samples obtained from thermally injured children on admission and at specified time intervals during the 5 days of the investigation. At admission the concentrations of all the hormones were high, and varied widely between individual patients. The geometric mean and 95% confidence intervals of admission hormone levels were as follows: arginine vasopressin 18.3 (8.3-40.7) pmol/l; angiotensin II 122.0 (56.0-266.2) pmol/l; cortisol 650.6 (473.0-895.0) nmol/l; dopamine 1.0 (0.1-8.0) nmol/l; adrenaline 6.4 (3.2-12.5) nmol/l and noradrenaline 2.3 (1.3-4.3) nmol/l. Although the concentrations of arginine vasopressin and cortisol returned to normal 24 to 36 h after admission, the levels of angiotensin II, adrenaline and dopamine fluctuated and remained higher than normal throughout the study (108 h). Thermal injury results in the release of abnormally high levels of stress hormones in children. Although there are similarities between some of the data reported here and those reported in adults, higher levels of adrenaline and lower levels of noradrenaline than reported in adults suggest important differences too. These differences may need to be taken into account in the management of burn-injured children.


Contrast material injection protocol with the flow rate adjusted to the heart rate for dual source CT coronary angiography.
To investigate the effect on coronary arterial attenuations of contrast material flow rate adjusted to a patient's heart rate during dual source CT coronary angiography (DSCT-CCTA). A total of 296 consecutive patients (mean age: 58.7 years) undergoing DSCT-CCTA without previous coronary stent placement, bypass surgery, congenital or valvular heart disease were included. The image acquisition protocol was standardized (120 kV, 380 mAs) and retrospective electrocardiograph (ECG) gating was used. Patients were randomly assigned to one of three groups [flow rate: G1: dosage/16, G2: dosage/(scan time +8), G3: fixed flow rate]. The groups were compared with respect to the attenuations of the ascending aorta (AA) above coronary ostia, the left main coronary artery (LM), the proximal right coronary artery (RCA), the left anterior descending artery (LAD), the left circumflex artery (LCX), and the contrast to noise ratio of the LM (LM(CNR)) and the proximal RCA (RCA(CNR)). Correlations between heart rate and attenuation of the coronary arteries were evaluated in three groups with linear regression. There was no significant difference in the three groups among the mean attenuations of AA (P = 0.141), LM (P = 0.068), RCA (P = 0.284), LM(CNR) (P = 0.598) and RCA(CNR) (P = 0.546). The attenuations of the LAD and the LCX in group 1 were slightly higher than those in group 2 and 3 (P < 0.05). In group 1, the attenuations of the AA (P < 0.01), LM (P < 0.01), RCA (P < 0.01), LAD (P = 0.02) and LCX (P < 0.01) decreased, respectively, with an increasing heart rate. A similar finding was detected in group 3 (AA: P < 0.01, LM: P < 0.01, RCA: P < 0.01, LAD: P < 0.01 and LCX: P < 0.01). In contrast, the attenuations of the AA (P = 0.55), LM (P = 0.27), RCA (P = 0.77), LAD (P = 0.22) and LCX (P = 0.74) had no significant correlation with heart rate in group 2. In all three groups, LM(CNR) (P = 0.77, 0.69 and 0.73 respectively) and RCA(CNR) (P = 0.75, 0.39 and 0.61 respectively) had no significant correlation with heart rate. Contrast material flow rate adjusted to heart rate can diminish the influence of heart rate on attenuations of the coronary arteries in DSCT-CCTA.


Tendon lengthening after achilles tendon rupture-passive effects on the ankle joint in a cadaveric pilot study simulating weight bearing.
In recent years, primary Achilles tendon ruptures have increased due to the aging population's participation in physically demanding activities. These injuries commonly occur during recreational sports and frequently lead to a long-term reduction in activity despite treatment. Non-operative methods of treatment for Achilles tendon ruptures may result in the Achilles healing in a lengthened position compared to the pre-injury state. This study uses a cadaveric model that simulates static weight bearing to explore the effect of a lengthened Achilles tendon on ankle joint load distribution. Five lower limb cadaveric specimens were placed on a custom jig, where a 334 N (75 lb) load was applied at the femoral head, and the foot was supported against a plate to simulate static double-leg stance. A pressure mapping sensor was inserted into the ankle joint. A percutaneous triple hemiresection tendo-Achilles lengthening procedure (Hoke procedure) was performed on each specimen to simulate tendon lengthening after conservative treatment. Contact pressure, peak pressure, and center-of-pressure were measured for native and tendon-lengthened conditions. Tendon rupture did not significantly alter average contact pressure, peak contact pressures, or center-of-pressure in the ankle joint compared with native tendon. Achilles lengthening does not significantly change contact pressures of the ankle joint in this model . This result suggests that the passive restraint on ankle joint translation imposed by the Achilles tendon is minimal without muscle activation.


Analysis of oxidative DNA damage and its repair in Polish patients with diabetes mellitus type 2: Role in pathogenesis of diabetic neuropathy.
Distal symmetric polyneuropathy (DSPN) is common complication of type 2 diabetes (T2DM). In this work we investigated the role of oxidative damage in connection with particular polymorphisms of DNA repair genes and their repair capacity. Materials constitute the peripheral blood of patients with T2DM with and without DSPN and control subjects without disturbance of the carbohydrate fraction. The study of gene polymorphisms which products take part in base excision repair (BER) pathway: 726 Val/Ala adenosine diphosphate ribosyl transferase (ADPRT), 324 His/Glu MutYhomolog (MUTYH) and 148 Asp/Glu human apurinic/apyrimidinic endonuclease (APE) was carried out using restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method. The study of DNA damage induced by hydrogen peroxide and the efficiency of their repair was carried out using comet assay. None of the 3 polymorphisms were associated with the risk of DSPN. However, in group of patients together with T2DM and T2DM/DSPN 726 Ala ADPRT allele was significantly susceptible to increased risk of T2DM (OR=1.59; 95% CI: 1.08-2.36). Investigation of DNA damage and repair revealed that T2DM patients have decreased ability to DNA repair. This capacity even drops down in the group of T2DM/DSPN patients compared to subjects with diabetes alone. ADPRT and APE polymorphisms were significantly associated with higher DNA damages (P<0.05) in heterozygous and mutant homozygous in correlation to homozygous wild type, but for MUTYH polymorphism relation was not confirmed. Pathogenesis of T2DM and development of DSPN may be related to oxidative stress connected with BER gene polymorphisms.


Micronutrient content drives elementome variability amongst the Symbiodiniaceae.
Elements are the basis of life on Earth, whereby organisms are essentially evolved chemical substances that dynamically interact with each other and their environment. Determining species elemental quotas (their elementome) is a key indicator for their success across environments with different resource availabilities. Elementomes remain undescribed for functionally diverse dinoflagellates within the family Symbiodiniaceae that includes coral endosymbionts. We used dry combustion and ICP-MS to assess whether Symbiodiniaceae (ten isolates spanning five genera Breviolum, Cladocopium, Durusdinium, Effrenium, Symbiodinium) maintained under long-term nutrient replete conditions have unique elementomes (six key macronutrients and nine micronutrients) that would reflect evolutionarily conserved preferential elemental acquisition. For three isolates we assessed how elevated temperature impacted their elementomes. Further, we tested whether Symbiodiniaceae conform to common stoichiometric hypotheses (e.g., the growth rate hypothesis) documented in other marine algae. This study considers whether Symbiodiniaceae isolates possess unique elementomes reflective of their natural ecologies, evolutionary histories, and resistance to environmental change. Symbiodiniaceae isolates maintained under long-term luxury uptake conditions, all exhibited highly divergent elementomes from one another, driven primarily by differential content of micronutrients. All N:P and C:P ratios were below the Redfield ratio values, whereas C:N was close to the Redfield value. Elevated temperature resulted in a more homogenised elementome across isolates. The Family-level elementome was (C19.8N2.6 P1.0S18.8K0.7Ca0.1) · 1000 (Fe55.7Mn5.6Sr2.3Zn0.8Ni0.5Se0.3Cu0.2Mo0.1V0.04) mmol Phosphorous-1 versus (C25.4N3.1P1.0S23.1K0.9Ca0.4) · 1000 (Fe66.7Mn6.3Sr7.2Zn0.8Ni0.4Se0.2Cu0.2Mo0.2V0.05) mmol Phosphorous -1 at 27.4 ± 0.4 °C and 30.7 ± 0.01 °C, respectively. Symbiodiniaceae isolates tested here conformed to some, but not all, stoichiometric principles. Elementomes for Symbiodiniaceae diverge from those reported for other marine algae, primarily via lower C:N:P and different micronutrient expressions. Long-term maintenance of Symbiodiniaceae isolates in culture under common nutrient replete conditions suggests isolates have evolutionary conserved preferential uptake for certain elements that allows these unique elementomes to be identified. Micronutrient content (normalised to phosphorous) commonly increased in the Symbiodiniaceae isolates in response to elevated temperature, potentially indicating a common elemental signature to warming.


Recurrent nocardiosis in solid organ transplant recipients: An evaluation of secondary prophylaxis.
Immunocompromised individuals are at risk for Nocardia infection, with a recurrence rate of approximately 5%. Solid organ transplant (SOT) recipients often receive secondary prophylaxis due to their requirement of lifelong immunosuppression. However, data supporting this practice is sparse. We sought to evaluate Nocardia recurrence in SOT recipients, specifically evaluating secondary prophylaxis. We conducted a retrospective cohort study of SOT recipients diagnosed with nocardiosis from 2000 through 2020. We included adult SOT recipients who completed their course of Nocardia therapy and had at least 6 months of posttherapy follow-up. The primary outcome was Nocardia recurrence, which included relapse and reinfection. One hundred two patients met inclusion criteria. Sixty-six (64.7%) were male and mean age was 58.6 ± 11.7 years. Most common SOT types were kidney (46.1%), heart (18.6%), kidney-pancreas (11.8%), and lung (10.8%). Most common sites of infection were lung (85.3%), skin (17.6%), and brain (14.7%). Secondary prophylaxis was utilized in 53 (52.0%) patients. Trimethoprim-sulfamethoxazole (TMP-SMX) single-strength daily was the most common prophylaxis agent and dose. Five patients (4.9%) experienced Nocardia recurrence, three of which were receiving secondary prophylaxis at time of recurrence. Two recurrences were with the same Nocardia species. Factors associated with recurrence were lung transplantation (p = .011), chronic lung disease (p = .032), and treatment ≤120 days (p = .006). Time from treatment completion to recurrence ranged from 107 to 875 days. Nocardia recurrence in SOT recipients is an uncommon event. TMP-SMX secondary prophylaxis is incompletely protective and recurrence may be dependent upon other factors. Further study of secondary prophylaxis is warranted.


Monoclonal antibodies to polymorphic epitopes on Ia antigens: three independent groups of determinants expressed on DRw6 homozygous cells.
Murine monoclonal antibodies directed against polymorphic epitopes on HLA-linked antigens were readily obtained following a single immunization with DRw6-homozygous cells. Five antibodies directed against class II antigens were isolated. Two precipitated DC-like molecules and 3 DR-like molecules from the immunizing lymphoblastoid cell line. Analysis of association with HLA-DR antigens in a panel of 60 individuals revealed 2 antibodies directed against the DC1 specificity (S1, R1) and one against the MT2 specificity (R3). Antibodies S2 and S3 showed significant association with DRw6 (chi 2 = 30.27) and DRw6 and w8 (chi 2 = 18.86), respectively. An analysis of 29 haplotypes indicated that epitopes defined by these monoclonal antibodies appear to identify polymorphic determinants on three independent gene products which can be encoded by a single HLA haplotype.


Reduced expression of cyclin D2 is associated with poor recurrence-free survival independent of cyclin D1 in stage III non-small cell lung cancer.
Compared to well-known function of cyclin D1 in lung cancer, the role of cyclin D2 is not clear. This study was aimed at understanding the clinicopathological significance of cyclin D2 in primary non-small cell lung cancer (NSCLC). We retrospectively analyzed expression statuses of cyclin D1, cyclin D2, p16, p21, p27, Ki-67, and phospho-pRb (Ser-807/811) using immunohistochemistry in 626 NSCLCs. Cyclin D2 was expressed in normal lung tissue, and its expression was reduced in 170 (27%) of 626 NSCLCs with a median duration of follow-up of 64 months. Mean phospho-pRb (Ser-807/811) levels were not associated with expression levels of cyclin D2 (P=0.15). The relationship between recurrence and the reduced expression of cyclin D2 was not homogenous by stage (Breslow-Day test for homogeneity, P=0.04). Reduced expression of cyclin D2 was not associated with patient's prognosis in 370 stage I, 112 stage II, and 18 stage IV NSCLCs. However, for 126 stage III NSCLCs, reduced expression of cyclin D2 was adversely associated with recurrence-free survival (RFS) (hazard ratio [HR]=3.71, 95% CI=1.54-13.17; P=0.01), independent of histology and expression of cyclin D1. The reduced expression of cyclin D2 was not associated with the overexpression of cyclin D1 (P=0.65). The present study suggests that reduced expression of cyclin D2 in stage III NSCLC may be associated with poor RFS. And, cyclin D2 may have a distinct role from cyclin D1 in NSCLC.


The reliability of physical performance measures in peripheral neuropathy.
The purpose of this study was to evaluate the test-retest reliability of select physical performance measures among people with peripheral neuropathy (PN). 20 PN patients (12 women, 8 men, mean age=68.4+/-12.5 years) were assessed on two separate occasions. Plantar pressure sensitivity was determined with a monofilament of known strength. Functional capacity and mobility were measured by the 6-min walk (6MW) and timed up-and-go (TUG) tests, respectively. Standing balance was evaluated by computing the average velocity (VEL) and area enclosing 95% of the body COP (A95) while participants stood quietly with eyes closed for multiple trials of varying length. Isokinetic knee extensor and flexor peak torque (KEPT, KFPT) were measured with an dynamometer during five maximal voluntary contractions. Plantar sensitivity and all measures of physical function demonstrated significant reliability. High reliability was observed for the 6MW (ICC=0.94) and the two-trial average TUG (ICC=0.99). Similarly, KEPT and KFPT were highly reliable whether using the top trial, or averaging the three best trials (ICCs>0.96). Averaging multiple standing balance trials generally increased ICC values, with 30s trials appearing to possess the highest reliability. Despite the heterogeneity of the PN population, select measures of physical performance are highly reliable and therefore recommended for use when examining physical function in these patients.


Arthroscopic Surgical Techniques for the Management of Proximal Biceps Injuries.
Current arthroscopic surgical techniques for the management of proximal biceps tendon disorders encompass 3 commonly advocated procedures: proximal biceps anchor reattachment (superior labrum anterior to posterior or SLAP repair), biceps tenotomy, and arthroscopic biceps tenodesis. The indications for each procedure vary based on injury pattern, symptomatic presentation, concomitant pathologic abnormality, and most notably, patient factors, such as age, functional demand, and specific sport or activity participation. Outcomes after SLAP repair are generally favorable, although recent studies have found biceps tenodesis to be the preferred treatment for certain patient populations.


Comparative Case Study of Efficacy of Oral Bilastine Monotherapy to Concomittant Administration of Oral Bilastine with Probiotic in Patients with Allergic Rhinitis.
Allergic rhinitis continues to pose a global burden in both adult and paediatric population and requires adequate medical therapy to avoid long term complications making it a challenging concern. This prompts the need to find a suitable and appropriate treatment regimen for this condition. To study the clinical efficacy of Oral Bilastine and Probiotics in patients with allergic rhinitis. To compare the effectiveness of Bilastine monotherapy to Oral Bilastine combined with Probiotics in patients with allergic rhinitis. Total of 100 patients were selected and randomized into two groups- Group 1 and Group 2 and were treated with Oral Bilastine 20 mg OD and Oral Bilastine 20 mg with Oral Probiotics OD (Lactobacillus fermentum & L. paracasei - 4 billion cells) respectively to maintain uniformity. Baseline scoring and follow up scoring after 6 weeks was done using the Total symptom score, Absolute eosinophil count and Nasal smear eosinophil count and were evaluated and documented as per their response to treatment. A significant reduction was observed in the severity of symptoms especially nasal obstruction, sneezing in patients of both groups along with extra nasal symptoms, with average mean score in Group 1 being 7.72 before treatment that reduced to 3.66 and that of Group 2 from 9.32 to 5.02. The mean score of Group 2 was greater in both before and after treatment which is highly significant. (p < 0.001). Monotherapy with Oral Bilastine has proven in relieving allergic symptoms. Addition of Oral Probiotics along with Bilastine has shown to have synergistic effect in further improving overall symptoms in allergic rhinitis.


[Diagnosis and therapy of stool incontinence].
Incontinence may have different causes. First it is necessary to diagnose any underlying muscular defects. Neurologic lesions and coordinative disturbances should also be excluded. A great variety of methods are available for treatment. In fact conservative therapy alone will very often be successful. In all traumatic lesions of the sphincter muscle, surgical reconstruction is the method of choice if the defect is not too large. In cases of extensive sphincter destruction, an artificial anorectal sphincter implant or dynamic graciloplasty may be options. In all cases with no or only small muscular defects, sacral nerve stimulation should be offered to the patient. Plicating techniques such as pre- or postanal repair have lost their therapeutic attractiveness at present. Therefore in any case of incontinence, the correctly structured stoma still has a place. To date it is not possible to confirm how much new methods such as bulking agents may contribute to the treatment of incontinence.


Medical management for chronic atherosclerotic peripheral arterial disease.
The generalized term 'peripheral vascular disease' (PVD) may be used to refer to vascular disorders in any non-coronary arterial bed. The more specific term 'peripheral arterial disease' (PAD) is used to refer to a more specific process, atherosclerotic disease of the lower extremities. PAD is common. Conservative estimates suggest more than 8 million Americans may be affected by PAD. Since atherosclerosis is a systemic process, PAD should be identified as a coronary heart disease risk equivalent. However, PAD remains an under-diagnosed and under-recognized risk for cardiovascular morbidity and mortality. PAD symptoms may range from non-specific ambulatory leg complaints, to typical symptoms of intermittent claudication to critical limb ischaemia with rest pain, gangrene or ulceration. These symptoms directly impact quality of life and may affect functional capacity. There are two therapeutic goals for patients with PAD: first, to reduce the risk of cardiovascular events and second, to manage the lower extremity symptoms. This manuscript reviews the medical management of patients with PAD, briefly discussing the goals of cardiovascular risk factor modification and then focusing on pharmacological management strategies for patients with intermittent claudication and critical limb ischaemia.


Impact of sodium-glucose cotransporter-2 inhibitors on the risk of hip fracture in older patients in Japan using a nationwide administrative claims database: A matched case-control study.
Some clinical trials have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors are associated with fracture risk. However, this notion remains controversial. This study aimed to evaluate hip fracture risk after the use of SGLT2 inhibitors while controlling for factors that may affect fracture risk. Furthermore, hip fracture risk is evaluated in relation to the SGLT2 inhibitors component and its concomitant use with other antidiabetic agents. Using large-scale real-world data, this case-control study investigated hospitalized patients between January 2018 and December 2020. Patients were aged 65-89 years and had been prescribed with SGLT2 inhibitors at least twice. Patients with hip fracture (cases) and those without (controls) were identified via 1:3 matching according to sex, age (±3 years), hospital size classification, and number of concomitant antidiabetic agents. Exposure to SGLT2 inhibitors of the cases and controls was compared with the use of multivariate conditional logistic regression. After matching, 396 cases and 1081 controls were identified. The adjusted odds ratio for patients receiving treatment with SGLT2 inhibitors was 0.83 (95% confidence interval: 0.55-1.26), indicating no increase in hip fracture risk. Additionally, no increased risk was observed with respect to SGLT2 inhibitors by component or concomitant use with other antidiabetic agents. Our study showed that SGLT2 inhibitors do not increase hip fractures in older patients. However, because the risk assessment of SGLT2 inhibitors by component and their concomitant use with other antidiabetic agents is based on a limited number of patients, it is important to interpret the results with caution. Geriatr Gerontol Int 2023; 23: 418-425.


Iron deficiency in pregnant women in Ibarapa District of Western Nigeria.
Ninety-nine pregnant women with anaemia (haematocrit less than 0.30) were detected by antenatal screening in Ibarapa District. Studies on 23 anaemic women and 17 non-anaemic women from the same clinic on the same day showed that eight out of 23 anaemic women had a transferrin saturation of less than 15%. The mean level (19.5%) for the anaemic patients was significantly less than that found in the nonanaemic controls; mean 33.0% (P less than 0.01). Bone marrow studies on 32 anaemic women revealed megaloblastic change and absent iron in 27 of the 32 patients. In a trial of parenteral iron treatment in 66 patients the mean haematocrit of Imferon treated patients rose from 0.27 to 0.32 in 6 weeks but remained at 0.28 or less in the controls. There was a significant difference between the iron-treated group and the comparable group receiving no imferon (P less than 0.001 at 6 weeks). The method of using parenteral iron treatment to make a diagnosis of iron deficiency anaemia is discussed together with the possible advantages and disadvantages of giving iron.


Does surgical plethysmographic index-guided analgesia affect opioid requirement and extubation time? A systematic review and meta-analysis.
This meta-analysis of all relevant clinical trials investigated surgical plethysmographic index (SPI)-guided analgesia's efficacy under general anesthesia for perioperative opioid requirement and emergence time after anesthesia. PubMed, Embase, Web of Science, and Cochrane Library were searched up to January 2022 to identify clinical trials comparing SPI-guided and conventional clinical practice for patients who underwent general anesthesia. With the random-effects model, we compared intraoperative opioid consumption, emergence time, postoperative pain, analgesia requirement, and incidence of postoperative nausea and vomiting (PONV). Thirteen randomized controlled trials (RCTs) (n = 1314) met our selection criteria. The overall pooled effect sizes of all RCTs indicated that SPI-guided analgesia could not significantly reduce opioid consumption during general anesthesia. SPI-guided analgesia accompanied with hypnosis monitoring could decrease intraoperative opioid consumption (standardized mean difference [SMD] - 0.31, 95% confidence interval [CI] - 0.63 to 0.00) more effectively than SPI without hypnosis monitoring (SMD 1.03, 95% CI 0.53-1.53), showing a significant difference (p < 0.001). SPI-guided analgesia could significantly shorten the emergence time, whether assessed by extubation time (SMD - 0.36, 95% CI - 0.70 to - 0.03, p < 0.05, I2 = 67%) or eye-opening time (SMD - 0.40, 95% CI - 0.63 to - 0.18, p < 0.001, I2 = 54%). SPI-guided analgesia did not affect the incidence of PONV, postoperative pain, and analgesia management. SPI-guided analgesia under general anesthesia could enhance recovery after surgery without increasing the postoperative complication risk. However, it did not affect intraoperative opioid requirement. Notably, SPI-guided analgesia with hypnosis monitoring could effectively reduce intraoperative opioid requirement.


A model for signal transmission in an ear having hair cells with free-standing stereocilia. II. Macromechanical stage.
A model of the signal-processing properties of the macromechanical system of the alligator-lizard middle and inner ear is developed. The model is based on measurements (as a function of tone frequency) of ossicular and basilar-membrane motion and of acoustic input-admittance at the tympanic membrane before and after alterations of middle-ear and inner-ear structures. From the structure of the ear, we formulate an equivalent electric network consisting of six admittance blocks and two transformers. The admittance blocks represent the mechanical properties of particular structures, e.g. the tympanic membrane (TM), the ossicle, the TM-ossicular joint, the vestibule, the basilar membrane and the helicotrema. The transformers represent the conversions from acoustical to mechanical variables performed by the TM-ossicular system and by the columella footplate. The block admittances and transformer ratios are inferred from the measurements, and each admittance is approximated by a network with a few simple elements. The resulting model fits the experimental results satisfactorily, allows correlations between specific structures and response behavior, and predicts the macromechanical transfer function. This transfer function acts as the first stage of a model of the alligator-lizard auditory periphery (Weiss et al., Weiss and Leong, 1985, Hearing Res. 20, 131-138, 157-174, 175-195). In the model the frequency dependence of basilar-membrane motion (1) is determined primarily by the tympanic membrane and extracolumella in the middle frequencies and (2) is affected by the helicotrema at low frequencies and the TM-ossicular joint at high frequencies.


Machine learning: an approach to preoperatively predict PD-1/PD-L1 expression and outcome in intrahepatic cholangiocarcinoma using MRI biomarkers.
To investigate the preoperative predictive value of non-invasive imaging biomarkers for programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) expression and outcome in intrahepatic cholangiocarcinoma (ICC) using machine learning. PD-1/PD-L1 expression in 98 ICC patients was assessed by immunohistochemistry, and their prognostic effects were analysed using Cox regression and Kaplan-Meier analysis. Radiomic features were extracted from MRI in the arterial and portal vein phases, and three sets of Radiomics score (Radscore) with good performance were derived respectively as biomarkers for predicting PD-1, PD-L1 expression and overall survival (OS). PD-1 and PD-L1 expression models were developed using the Radscore (arterial phase), clinico-radiological factors and clinical factors, individually and in combination. The imaging-based OS predictive model was constructed by combining independent predictors among clinico-radiological, clinical factors and OS Radscore. Pathology-based OS model using pathological and clinical factors was also constructed and compared with imaging-based OS model. The highest area under the curves of the models predicting PD-1 and PD-L1 expression was 0.897 and 0.890, respectively. PD-1+ and PD-L1+ cases had worse outcomes than negative cases. The 5-year survival rates of PD-1+ and PD-1- cases were 12.5% and 48.3%, respectively (p<0.05), whereas the 5-year survival was 21.9% and 39.4% for PD-L1+ and PD-L1- cases, respectively (p<0.05). The imaging-based OS model involved predictors of clinico-radiological 'imaging classification', radiomics 'Radscore' from arterial phase and carcinoembryonic antigen (CEA) level (C-index:0.721). It performed better than pathology-based model (C-index: 0.698) constructed by PD-1/PD-L1 expression status and CEA level. The imaging-based OS model is potential for practice when the pathology assay is unavailable and could divide ICC patients into high-risk and low-risk groups, with 1-year, 3-year and 5-year survival rates of 57.1%, 14.3% and 12.4%, and 87.8%, 63.3% and 55.3%, respectively (p<0.001). MRI radiomics could derive promising and non-invasive biomarker in evaluating PD-1/PD-L1 expression and prognosis of ICC patients.


Partial arousals from hibernation in hedgehogs in outdoor hibernacula.
Thermal properties of hibernacula and sequences of arousals have been studied in four adult hedgehogs for seven months starting in October. Departures and entries to the nesting chamber were continuously monitored together with ambient temperature and the temperature in the hibernacula.During the two first months of the experimental period nest departures were intermittently recorded, predominantly in the two females which also occasionally foraged. The longest periods spent continuously in the hibernaculum ranged from 129 to 178 days. The natural hibernation season for Danish hedgehogs was found to comprise the six months from October onwards when there is little shelter where hedgehogs normally roam.Ambient temperatures recorded were -11 to +13° C being subzero for half the total time measured. The nest temperatures generally were higher, and above 0° C during 78-99% of total time, most commonly ranging from 0° to 4° C and thus reflecting deep hibernation.Between December and May spontaneous increases in nest temperatures amounting to 7-26° C (average 18° C) and bringing these temperatures to 10-29.5° C were recorded in 58 cases. Fiftyfour arousals did not involve departure from the hibernaculum (partial arousals). In the remaining cases (full arousals) the preceding rewarming lasted 4 1/2-6 1/2 h and nest departures amounted to 10,2 and 5 min in one female hedgehog and 90 min in another.The hedgehogs showed 12-18 arousals, the mean duration of which was 34-44 h. The high energy expenditure associated with arousals however, was found to last on average 21 h during each arousal. It is hypothesized that the body temperature during arousals chiefly was below 35-37° C.The time between arousals was 3-15 days. Periods in hibernation averaged 7-8 days in the females and 9-10 days in the heavier males, being generally longest in January-February. Neither arousals nor re-entries into deep hibernation occurred at any particular time of the day. It is suggested that for undisturbed hedgehogs arousals are induced and controlled by endogenous factors. In conclusion it is stressed that future studies on hibernation should recognize the importance of individual variability in the response pattern and focus interest on the endogenous factors which govern this important process.


On-Surface Synthesis of Unsaturated Hydrocarbon Chains through C-S Activation.
We use an on-surface synthesis approach to drive the homocoupling reaction of a simple dithiophenyl-functionalized precursor on Cu(111). The C-S activation reaction is initiated at low annealing temperature and yields unsaturated hydrocarbon chains interconnected in a fully conjugated reticulated network. High-resolution atomic force microscopy imaging reveals the opening of the thiophenyl rings and the presence of trans- and cis-oligoacetylene chains as well as pentalene units. The chemical transformations were studied by C 1s and S 2p core level photoemission spectroscopy and supported by theoretical calculations. At higher annealing temperature, additional cyclization reactions take place, leading to the formation of small graphene flakes.


Electron-spin domains: magnetic enhancement of superconductivity.
An inhomogeneous superconducting state, not yet conclusively identified, was predicted by Fulde and Ferrell and Larkin and Ovchinnikov (FFLO) to arise in superconductors with strong Pauli limiting, a consequence of the electrons' Zeeman (spin) energy in a magnetic field. Radovan et al. propose that the observed cascades of steps in magnetization of the heavy fermion superconductor CeCoIn5, within the recently discovered second low-temperature state, are due to transitions between Landau-level (LL) states with different m-quanta vortices, expected under certain conditions when the magnetic field is swept within the FFLO state. The authors then conclude that the observed steps in magnetization constitute a proof that the low-temperature state in CeCoIn5 is indeed an FFLO state. We argue that this interpretation of the observed steps in magnetization cannot be supported on either quantitative or qualitative grounds.


Thermal unfolding studies of cold adapted uracil-DNA N-glycosylase (UNG) from Atlantic cod (Gadus morhua). A comparative study with human UNG.
Uracil-DNA N-glycosylase (UNG; EC 220.127.116.11) from Atlantic cod (cUNG) possesses cold adapted features like increased catalytic efficiency and reduced temperature optimum for activity compared to its warm-adapted homologue human UNG (hUNG). Here, we present the first thermal stability analysis of cUNG and hUNG by differential scanning calorimetry (DSC), and the results showed that cUNG is less stable than hUNG and unfolds at a melting temperature (T(m)) 9° lower than its warm-adapted homologue. In addition, an ion-pair (D183-K302) suggested to be crucial for global stability of hUNG was investigated by biochemical characterization and DSC of four mutants (cUNG G183D and cUNG G183D-R302K, hUNG D183G and hUNG D183G-K302R). The hUNG mutants with an expected disruption of the ion-pair showed a slight increase in stability with concomitant reduction in the enzyme activity, while the apparent introduction of the ion-pair in cUNG caused a reduction in the enzyme activity but no increase in stability. Because the mutants did not behave as expected, the phenomenon was further investigated by crystal structure determination. Indeed, the crystal structure of the hUNG D183G-K302R mutant revealed that compensating interactions for the loss of the ion-pair were generated close to and in regions distant from the mutation site. In conclusion, the reduced stability of cUNG supports the suggested requirement of a flexible structure for improved activity at low temperatures. Furthermore, the lack of a direct correlation between enzyme activity and global stability of the mutants supports the significance of distributing locally flexible and/or rigid regions for modulation of enzyme activity.


Predictive value of shock index variants on 30-day mortality of trauma patients in helicopter emergency medical services: a nationwide observational retrospective multicenter study.
The original shock index (SI) has been further developed to increase its prognostic value. We aimed to evaluate the predictive value of different SI variants on 30-day mortality among severely injured trauma patients in pre-hospital critical care settings. Adult trauma patients in the national Helicopter Emergency Medical Services (HEMS) registry were evaluated based on the primary outcome of 30-day mortality. SI, SIA (SI multiplied by age), SI/G (SI divided by Glasgow Coma Scale (GCS)), SIA/G (SI multiplied by age and divided by GCS), and SS (SI divided by oxygen saturation) were calculated based on the first vital signs measured at the time of HEMS contact. The area under the receiver operating curve (AUROC) was calculated for each SI variant. In total 4108 patients were included in the study. The overall 30-day mortality was 13.5%. The SIA/G and SI/G had the highest predictive ability (AUROC 0.884 [95% CI 0.869-0.899] and 0.8000 [95% CI 0.7780-0.8239], respectively). The SIA/G yielded good predictive performance between 30-day survivors and non-survivors in the pre-hospital critical care setting.


Solid-phase synthesis of new pyrrolobenzodiazepine-chalcone conjugates: DNA-binding affinity and anticancer activity.
A new class of C8-linked pyrrolo[2,1-c][1,4]benzodiazepine-chalcone conjugates have been prepared by employing a solid-phase synthetic protocol. In this strategy an intramolecular aza-Wittig reductive cyclization approach has been utilized. Interestingly, some of these molecules have shown enhanced DNA-binding affinity and promising anticancer activity on a large number of human cancer cell lines.


Botulinum toxin to avoid component separation in midline large hernias.
The goal of our study was to compare results in patients with large midline incisional hernia using modified anterior component separation versus preoperative botulinum toxin and following Rives repair, with a focus on surgical site occurrences, possibility of fascial closure, duration of hospital stay, and hernia recurrence rate. From to March 2016 to June 2019, a prospective comparative study was performed in 80 consecutive patients with large midline incisional hernias and hernia transverse diameters between 11 and 17 cm under elective hernia repair at our tertiary center. Two groups were analyzed prospectively: 40 patients with preoperative botulinum toxin administration and following open Rives repair (botulinum toxin group) were compared with 40 patients who underwent open component separation during that period (component separation group). All large midline incisional hernias were classified W3, with mean transverse and longitudinal defect diameters of 14.9 cm (11.8-16.5) and 24 cm (11-28), respectively. Complete fascial closure was possible in all patients in the preoperative botulinum toxin group. No complications occurred during the administration of preoperative botulinum toxin, but surgical site complications were most frequent in the component separation group, especially skin necrosis (12.5%, P = .020). At a median of 19.6 months (range, 11-35) of postoperative follow-up, 2 cases of hernia recurrence (8.9%) were reported, all of them in the component separation group. Botulinum toxin allows getting a successful downstaging from surgical repair to Rives technique in patients with large midline incisional hernia, especially with hernia transverse diameters between 11 and 17 cm. These results contribute to minimize disadvantages associated to the anterior component separation.


Potassium concentration in the inner sulcus is perilymph-like.
Using potassium-selective microelectrodes and an improved observation technique, it is shown that the potassium concentration in the fluid of the inner sulcus of the guinea pig is like that of perilymph. The implications for the common concepts about the role of potassium in the cochlea are discussed.


Tellurite biotransformation and detoxification by Shewanella baltica with simultaneous synthesis of tellurium nanorods exhibiting photo-catalytic and anti-biofilm activity.
Tellurite reducing bacterial strain was isolated from Zuari estuary, Goa India which could tolerate 5.5 mM potassium tellurite with a minimum inhibitory concentration of 6 mM. This strain was designated as GUSDZ9 and was identified as Shewanella baltica (accession number: MF350629) based on 16S rRNA gene sequencing and BLAST analysis. The Diethyl-dithiocarbamate based colorimetric analysis clearly demonstrated a complete reduction of 2 mM tellurite to elemental tellurium during the late stationary phase. Te Nanoparticles (TeNPs) biosynthesis which initiated at early log phase (i.e. 4 h) was evidently monitored through colour change and a peak due to surface plasmon resonance at 210 nm using UV-Vis spectroscopic analysis. X-ray crystallographic studies and transmission electron microscopy revealed unique nano-rods with a diameter ranging from 8 to 75 nm. Energy dispersive X-ray analysis further confirmed the presence of pure tellurium. The biogenic TeNPs at 10 and 5 µg/mL evidently demonstrated 90% degradation of methylene blue dye and anti-biofilm activity against potential Gram-positive and Gram-negative human pathogens respectively. The alkaline comet assay revealed time and dose-dependent genotoxicity at concentrations higher than 15 µg/mL of TeNPs. This study clearly demonstrated the potential of Shewanella baltica strain GUSDZ9 in bioremediation of toxic tellurite through bio-reduction into elemental tellurium and involvement of biogenic TeNPs in the photo-catalytic reduction of methylene blue and anti-biofilm activity. This is the first report of its kind on the synthesis of biogenic TeNPs from Shewanella baltica demonstrating photo-catalytic, anti-biofilm activity as well as genotoxicity.


Incidence and survival for hepatic, pancreatic and biliary cancers in England between 1998 and 2007.
Hepatic, pancreatic and biliary (HPB) cancers are a group of diverse malignancies managed ideally in specialist centres. This study describes recent patterns in the incidence and survival of HPB cancers in England over a ten year period (1998-2007). Data on 99,379 English patients (50,656 males; 48,723 females) diagnosed with HPB cancers between 1998 and 2007 were extracted from the National Cancer Data Repository. Data were divided into six site-specific cancer groups; pancreas, ampulla of Vater, biliary tract, primary liver, gallbladder and duodenum. Age-standardised incidence rates (per 100,000 European standard population, (ASR(E))) were calculated for each of the six groups by year of diagnosis and by socioeconomic deprivation. Survival was estimated using the Kaplan-Meier method. The largest group was pancreatic cancers (63%), followed by primary liver (14%) and biliary cancers (13%). ASR(E) were highest for pancreatic and primary liver cancers whereas cancers of the gallbladder, duodenum and ampulla of Vater had a very low incidence. Over time the incidence of all six groups remained relatively stable, although primary liver cancer increased slightly in males. Incidence rates were higher in males than in females in all groups except gallbladder cancer, and all six groups had a higher incidence in the more deprived quintiles. Overall survival was poor in each of the HPB cancer groups. HPB tumours are uncommon and are associated with poor long term survival reflecting the late stage at presentation. Incidence patterns suggest variable rates linked to socioeconomic deprivation and highlight a male predominance in all sites except the gallbladder. Identification of high risk populations should be emphasised in initiatives to raise awareness and facilitate earlier diagnosis.


Quadratus femoris muscle edema in children.
To assess the prevalence and clinical relevance of quadratus femoris muscle edema (QFME) in pediatric pelvic MRI. The axial T2-W with fat saturation sequence of pelvic/hip MRI examinations of pediatric patients (≤ 18 years) and a control group of young adults aged 19-45 years was retrospectively and independently evaluated by two musculoskeletal radiologists for the presence of QFME in each hip. Demographics, indication for imaging studies, and pain location were documented. The prevalence of QFME was compared between the groups on a patient level and on a hip level. The study group included 119 children (164 MRI examinations; F:M 1:1.08, mean age 11.4 ± 3.6 years), and 120 young adults, > 18, < 45 years old, served as controls (F:M 1:0.9, mean age 33.7 ± 6.4 years). QFME was significantly more prevalent among the study compared to the control group, both on a patient level (15% and 4.2%, respectively, p < 0.05) and on a hip level (12.1% and 2.5%, respectively, p < 0.05). This significant difference was also seen in the subgroup of MRI studies performed for orthopedic indications but not for non-orthopedic indications. There was no correlation between the side of localized pain and the side with QFME. QFME is significantly more prevalent in pediatric patients compared to adults under 45 years old, especially in subjects scanned for orthopedic indications. The clinical relevance of QFME in children and adolescents is unclear.


Graded perturbations of metabolism in multiple regions of human brain in Alzheimer's disease: Snapshot of a pervasive metabolic disorder.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder that displays pathological characteristics including senile plaques and neurofibrillary tangles. Metabolic defects are also present in AD-brain: for example, signs of deficient cerebral glucose uptake may occur decades before onset of cognitive dysfunction and tissue damage. There have been few systematic studies of the metabolite content of AD human brain, possibly due to scarcity of high-quality brain tissue and/or lack of reliable experimental methodologies. Here we sought to: 1) elucidate the molecular basis of metabolic defects in human AD-brain; and 2) identify endogenous metabolites that might guide new approaches for therapeutic intervention, diagnosis or monitoring of AD. Brains were obtained from nine cases with confirmed clinical/neuropathological AD and nine controls matched for age, sex and post-mortem delay. Metabolite levels were measured in post-mortem tissue from seven regions: three that undergo severe neuronal damage (hippocampus, entorhinal cortex and middle-temporal gyrus); three less severely affected (cingulate gyrus, sensory cortex and motor cortex); and one (cerebellum) that is relatively spared. We report a total of 55 metabolites that were altered in at least one AD-brain region, with different regions showing alterations in between 16 and 33 metabolites. Overall, we detected prominent global alterations in metabolites from several pathways involved in glucose clearance/utilization, the urea cycle, and amino-acid metabolism. The finding that potentially toxigenic molecular perturbations are widespread throughout all brain regions including the cerebellum is consistent with a global brain disease process rather than a localized effect of AD on regional brain metabolism.


Impaired cerebral and systemic hemodynamics under cognitive load in young hypotensives: a transcranial Doppler study.
Reduced sympathetic outflow and deficits in cerebral hemodynamics have been considered as possible factors mediating the impaired cognitive performance in essential hypotension. However, the relationship between systemic blood pressure (BP), cerebral blood flow and cognitive functioning is still poorly understood. The present study was aimed at clarifying the physiological processes underlying cerebral and systemic hemodynamics in young hypotensives during cognitive engagement. Doppler sonography blood flow velocities in both middle cerebral arteries were measured from 17 hypotensives and 15 normotensives during a working memory task. Impedance cardiographic and BP measures were also recorded continuously. Lower increases in systolic and diastolic BP were observed in hypotensives. However, no evidence of lower sympathetic control was found for this group, as assessed by pre-ejection period. Flow velocity in middle cerebral arteries showed a lower increase in hypotensives throughout the task. Moreover, significant positive correlations between BP changes and blood flow velocities in middle cerebral arteries during the task were obtained for this group only, suggesting a less effective cerebral autoregulation. No difference was found between groups in task performance. Results suggest that during cognitive challenge hypotensives show impaired hemodynamic adjustments, both central and peripheral. However, such alterations do not directly affect cognitive performance, at least under moderate cognitive load.


Investigation of polymerisation shrinkage strain, associated cuspal movement and microleakage of MOD cavities restored incrementally with resin-based composite using an LED light curing unit.
To investigate the polymerisation shrinkage strain, associated cuspal movement, degree of conversion (DC) and cervical gingival microleakage of mesio-occlusal-distal (MOD) cavities restored with four resin-based composite (RBC) filling materials placed incrementally using a light emitting diode (LED) light curing unit (LCU). Standardised extensive MOD cavity preparations on extracted teeth were performed on 40 sound upper premolar teeth. Restoration of the teeth involved the placement of RBCs in eight increments with the appropriate bonding system before irradiation using an LED LCU. Buccal and palatal cusp deflections at each stage of polymerisation were recorded using a twin channel deflection measuring gauge. Following restoration, the teeth were thermocycled, immersed in a 0.2% basic fuchsin dye for 24 h, sagittally sectioned and examined for cervical microleakage. The DC was determined using a Fourier transform infra-red (FT-IR) spectrometer. No significantly difference (P=0.677) in cuspal movement was recorded for Z100 (13.1+/-3.2 microm) compared with Filtek Z250 (8.4+/-3.5 microm), P60 (7.3+/-3.8 microm) and Admira (6.7+/-2.7 microm). The LED LCU deflections were compared with a halogen LCU used in a conventional (Fleming GJP, Hall D, Shorthall ACC, Burke FJT. Cuspal movement and microleakage in premolar teeth restored with posterior filling materials of varying reported volumetric shrinkage values. Journal of Dentistry, 2005;33:139-146) and soft-start mode (Fleming GJP, Cara RR, Palin WM, Burke FJT. Cuspal movement and microleakage in premolar teeth restored with posterior filling materials cured using 'soft-start' polymerization. Dental Materials, 2006, , in press) and a significant reduction in cuspal movement was identified for curing type and material type (P<0.001 and P=0.002, respectively). No significant differences were noted between the four RBC materials investigated when the DC or microleakage scores were examined for the LED LCU. It would appear that irradiation of RBCs using the LED LCU offered a significant reduction in associated cuspal movement in large MOD cavities. However, the microleakage scores following polymerisation were significantly increased with dye penetration into the pulp chamber from the axial wall evident in teeth restored with the LED LCU.


Pulmonary IgG4-related disease and colon adenocarcinoma: possible paraneoplastic syndrome.
Malignancy has a complicated association with immunoglobulin G4-related disease (IgG4-RD) both being an item in the differential diagnosis as well as malignancy occurring in the background of IgG4-RD in the same organ. However, recently there is evidence of higher rates of distant malignancy in patients with IgG4-RD. Here we report a case of pulmonary IgG4-RD potentially consistent with a paraneoplastic phenomenon which improved with treatment of the underlying colon adenocarcinoma.


The intermediate filament proteins of rabbit normal epidermal Merkel cells are cytokeratins.
Four hundred Merkel cells (MC) have been studied by double-label immunofluorescence using: (1) a monoclonal antibody which has been previously demonstrated to react with MC and (2) antisera and monoclonal antibodies against the 5 types of intermediate filaments. It was demonstrated that MC did not react with vimentin, desmin, glial acidic fibrillary protein, or neurofilament antisera. A strong staining of MC was observed with 2 antisera and 2 monoclonal antibodies against keratin. The cytokeratin polypeptide pattern of MC is probably similar to that of simple epithelia. These findings attest to the epithelial nature of MC.


DBP-PSSM: Combination of Evolutionary Profiles with the XGBoost Algorithm to Improve the Identification of DNA-binding Proteins.
DNA-binding proteins play important roles in a variety of biological processes, such as gene transcription and regulation, DNA replication and repair, DNA recombination and packaging, and the formation of chromatin and ribosomes. Therefore, it is urgent to develop a computational method to improve the recognition efficiency of DNA-binding proteins. We proposed a novel method, DBP-PSSM, which constructed the features from amino acid composition and evolutionary information of protein sequences. The maximum relevance, minimum redundancy (mRMR) was employed to select the optimal features for establishing the XGBoost classifier, therefore, the novel model of prediction DNA-binding proteins, DBP-PSSM, was established with 5-fold cross-validation on the training dataset. DBP-PSSM achieved an accuracy of 81.18% and MCC of 0.657 in a test dataset, which outperformed the many existing methods. These results demonstrated that our method can effectively predict DNA-binding proteins. The data and source code are provided at https://github.com/784221489/DNA-binding.


Partial laryngectomy and reconstruction with rotation of the epiglottis in the treatment of a rare laryngeal schwannoma: a case report.
Neurogenic tumors of the larynx are rare, with few cases having been reported in the literature. Schwannomas are responsible for 0.1% of all benign tumors of the larynx. They arise in the sheaths of the peripheral, autonomic, and cranial nerves. The objective of this report is to describe a case of a bulky laryngeal schwannoma, the surgical procedure for its removal, and the long-term patient follow-up. A 19-year-old Brazilian woman presented to our institution with a complaint of progressive dyspnea over the preceding year, as well as dysphonia, dysphagia for solids, and globus pharyngeus. Direct rigid laryngoscopy showed a supraglottic tumor obstructing approximately 90% of the larynx. With the symptoms progressing to severe dyspnea, an emergency tracheostomy was performed. After infusion of intravenous contrast, magnetic resonance imaging revealed a mass lesion with intense, heterogeneous contrast enhancement along the posterior wall of the hypopharynx, blocking all of the lumen and measuring 2.8 cm and 2.2 cm at its largest diameters. The image suggested a neoplastic lesion. The patient underwent open surgery for tumor resection. Her postsurgical recovery was uncomplicated. Histopathology and immunohistochemistry revealed the tumor to be a laryngeal schwannoma. The definitive diagnosis of laryngeal lesions can be difficult, and histopathology plays a pivotal role. Laryngeal schwannomas are rare; however, tumors can become large and may ultimately lead to airway obstruction.


Diversification in the Mexican horned lizard Phrynosoma orbiculare across a dynamic landscape.
The widespread montane Mexican horned lizard Phrynosoma orbiculare (Squamata: Phrynosomatidae) represents an ideal species to investigate the relative impacts of Neogene vicariance and Quaternary climate change on lineage diversification across the Mexican highlands. We used mitochondrial DNA to examine the maternal history of P. orbiculare and estimate the timing and tempo of lineage diversification. Based on our results, we inferred 11 geographically structured, well supported mitochondrial lineages within this species, suggesting P. orbiculare represents a species complex. Six divergences between lineages likely occurred during the Late Miocene and Pliocene, and four splits probably happened during the Pleistocene. Diversification rate appeared relatively constant through time. Spatial and temporal divergences between lineages of P. orbiculare and co-distributed taxa suggest that a distinct period of uplifting of the Transvolcanic Belt around 7.5-3 million years ago broadly impacted diversification in taxa associated with this mountain range. To the north, several river drainages acting as filter barriers differentially subdivided co-distributed highland taxa through time. Diversification patterns observed in P. orbiculare provide additional insight into the mechanisms that impacted differentiation of highland taxa across the complex Mexican highlands.


Best Practices on Big Data Analytics to Address Sex-Specific Biases in Our Understanding of the Etiology, Diagnosis, and Prognosis of Diseases.
A bias in health research to favor understanding diseases as they present in men can have a grave impact on the health of women. This paper reports on a conceptual review of the literature on machine learning or natural language processing (NLP) techniques to interrogate big data for identifying sex-specific health disparities. We searched Ovid MEDLINE, Embase, and PsycINFO in October 2021 using synonyms and indexing terms for (a) "women," "men," or "sex"; (b) "big data," "artificial intelligence," or "NLP"; and (c) "disparities" or "differences." From 902 records, 22 studies met the inclusion criteria and were analyzed. Results demonstrate that the inclusion by sex is inconsistent and often unreported, although the inclusion of men in these studies is disproportionately less than women. Even though artificial intelligence and NLP techniques are widely applied in healthresearch, few studies use them to take advantage of unstructured text to investigate sex-related differences or disparities. Researchers are increasingly aware of sex-based data bias, but the process toward correction is slow. We reflect on best practices on using big data analytics to address sex-specific biases in understanding the etiology, diagnosis, and prognosis of diseases.


Pemetrexed, oxaliplatin and bevacizumab as first-line treatment in patients with stage IV non-small cell lung cancer.
Oxaliplatin has less haematological toxicity than cisplatin and carboplatin. The combination of pemetrexed, oxaliplatin and bevacizumab appeared well tolerated and active as second- or third-line treatment in a previous phase II study. Its role as first-line therapy remains to define. From August 2008 to May 2011, consecutive chemo-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) received pemetrexed 500mg/m(2), oxaliplatin 100mg/m(2) and bevacizumab 7.5mg/kg every 3 weeks for 6 cycles, in the outpatient setting. Maintenance therapy including pemetrexed and bevacizumab was given to patients with non-progressive disease. The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, progression-free survival (PFS) and overall survival (OS). Thirty-eight patients (50% males, median age: 55 years, range 38-76) received a total of 199 cycles (median per patient: 6, range 2-6), plus 98 cycles of maintenance therapy. Twenty patients (52.6%) had a PS of 2, and 6 (15.8%) had brain metastases. The most frequent toxicities were hypertension (all grades: 42.1%) and peripheral neuropathy (grade 2-3: 21.1%). Haematological toxicities included grade 4 neutropenia, grade 3 anaemia and thrombopenia (5.3% each). Neither febrile neutropenia nor arterial thrombo-embolic event occurred. The objective response rate was 55.3% (95%CI: 39.5-71.1). The median PFS and OS were 6.2 (95%CI: 5.4-9.0) and 14.6 (95%CI: 9.8-19.5) months, respectively. In this single centre experience, the combination of pemetrexed, oxaliplatin and bevacizumab was well tolerated and had promising activity as first-line therapy in unselected patients with stage IV non-squamous NSCLC.


Conservation linkages of endangered medicinal plant and exploration of phytochemicals, pharmaceutical screening and in silico validation against diabetics using in vivo wild and in vitro regenerated plant Boucerosia diffusa Wight.
Boucerosia diffusa Wight. is an important endangered medicinal plant belonging to the family Asclepiadaceae. In this study, an efficient protocol has been developed for B. diffusa using nodal explants for callus induction and direct organogenesis. The optimal callus induction (83.7%) was observed on 0.6 mg/L 2,4-dichlorophenoxyacetic acid (2,4-D) in Murashige and Skoog medium. The shoot regeneration was observed on different concentrations and combinations of 6-benzylaminopurine (BAP) and 2,4-D using shoot induction (88.5%) was observed on 0.5 mg/L BAP and 0.6 mg/L 2,4-D. Maximum root induction frequency (85.6%) was obtained on 0.6 mg/L α-naphthalene-acetic acid (NAA) and 0.5 mg/L BAP. The fully developed plants were acclimatized (98.86% survival rate) and transferred to natural photoperiod conditions. The phytochemical and pharmacological activity was determined in in vitro-regenerated plants (IRP) and was compared to in vivo wild plants (IWP). The primary and the secondary metabolite contents of bioactive compounds were significantly higher in the methanolic extract of IRP. A comparative antioxidant activity study shows IRP exhibited better scavenging activity. The antidiabetic activity of α- amylase (IC50 - 71.56 ± 15.4 µg/mL) and α-glucosidase (IC50 - 82.94 ± 12.84 µg/mL) inhibitor activity also exhibited maximum in methanolic extract of IRP. Furthermore, chemical composition was analyzed using gas chromatography-mass spectroscopy (GC-MS). Antibacterial activity against human pathogenic bacteria, IRP methanolic extracts showed a maximum zone of inhibition (75 µg/mL) observed against Salmonella typhi (23.5 ± 0.5 mm) compared to the IWP. Molecular docking analysis of B. diffusa inhibition of antidiabetic activity showed better affinity in β-Sitosterol. The online version contains supplementary material available at 10.1007/s13205-023-03645-5.


[An update on glucocorticoid-induced osteoporosis].
Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis. Moreover, it is the most common reason for an osteoporosis among young adults. The clinical use of oral glucocorticoids increases the fracture incidence already within three months after starting the therapy. There does not seem to be a lower threshold: even doses as low as 2,5 mg of prednisone equivalent increase the risk of fractures. Adequate diagnostic and therapy are able to significantly reduce the resulting fracture risk. This article will discuss the pathophysiology of glucocorticoid-induced osteoporosis and give a summary of the current recommendations including the recently updated German guidelines.


Effect of alcohol and aldehyde dehydrogenase gene polymorphisms on alcohol-associated hypertension: the Guangzhou Biobank Cohort Study.
The effects of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 genotypes on the alcohol-blood pressure association are unclear. We examined the association of ADH2 or ALDH2 genotypes with blood pressure in older Chinese men. Based on the Guangzhou Biobank Cohort Study (GBCS), 4792 men with valid ADH2, ALDH2 genotypes were included, and genotyping of rs1229984 ADH2 and rs671 ALDH2 (AA, AG/GA or GG) was performed using a Sequenom Mass-Array platform. Information on socio-demographics and lifestyle factors, including alcohol use, was obtained from a questionnaire, and blood pressure was measured. Among alcohol drinkers, systolic and diastolic blood pressure (SBP and DBP) and mean arterial pressure (MAP) were highest for men with the GG ADH2 genotype (136.6, 77.9 and 97.5 mm Hg, respectively), followed by those with the (AA/AG ADH2+GG ALDH2) genotype (133.4, 77.6 and 96.2 mm Hg, respectively) and then the (AA/AG ADH2+AA/AG ALDH2) genotype (SBP=132.6, DBP=76.6 and MAP=95.2 mm Hg) (P for trend ranged 0.025-0.035). After adjustment for potential confounders, as well as frequency or amount of alcohol use, men with the GG ADH2 genotype were more likely to have hypertension (odds ratio (OR)=1.62, 95% confidence interval 1.15-2.28) as were men with the (AA/AG ADH2+AA/AG ALDH2) genotype (OR=1.40, 95% confidence interval 1.01-1.96) compared with men with the (AA/AG ADH2+GG ALDH2) genotype). ADH2 or ALDH2 genotypes were unrelated to hypertension among those who never drink alcohol. ADH2 genotype influences blood pressure and risk of hypertension among male alcohol drinkers, suggesting that the hypertensive effect of alcohol is due to ethanol rather than acetaldehyde.


Pleural Empyema in Six Horses: A Retrospective Case Series.
The clinical findings of pleural empyema in six horses were retrospectively studied using epidemiological, clinical pathology, microbiological, ultrasound, and post-mortem data. The clinical findings included tachycardia (n = 3/6), tachypnea (n = 6/6), cyanotic mucosa (n = 2/6), hyperthermia (n = 4/6), inspiratory or mixed dyspnea (n = 6/6), presence of fluid and/or pleural rubbing (n = 2/6) and coarse crackling on auscultation (n = 4/6). Horses demonstrated leukocytosis (16.22 × 103/µL) with neutrophilia (12.32 × 103/µL) and hyperfibrinogenemia (633.33 mg/dL) and an increase in urea (69.80 mg/kg) and globulins (5.22 g/dL). The pleural fluid exhibited exudate (n = 5/6). The pathogens isolated from transtracheal wash (TTW) and/or pleural effusion included Aspergillus fumigatus, Enterobacter cloacae, alpha and beta hemolytic Streptococcus, Pseudomonas aeruginosa, Salmonella sp., Streptococcus equi subsp. zooepidemicus, and beta hemolytic Staphylococcus. The in vitro tests of microbial sensitivity of the isolates revealed that ceftiofur (5/6) and penicillin (3/6) were the most effective drugs. The fatality rate was 83% (5/6). The main post-mortem finding was the presence of fibrin in the pleural cavity with adhesion between the parietal and visceral pleura. These results show that pleural empyema is a complex disease pathophysiology that is refractory to conventional treatment.


Disrupting the CXCL12/CXCR4 axis disturbs the characteristics of glioblastoma stem-like cells of rat RG2 glioblastoma.
Glioblastoma stem-like cells (GSC) have been shown to promote tumor growth, tumor-associated neovascularization, therapeutic resistance, and metastasis. CXCR4 receptors have been found involved in the proliferation, metastasis, angiogenesis, and drug-resistant characteristics of glioblastoma. However, the role of CXCR4 in modulating the stem-like cell properties of rat glioblastoma remains ambiguous. To explore the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we disrupted the CXCR4 signaling by using small hairpin interfering RNA (shRNA). To investigate the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we used a spheroid formation assay to assess the stem cell self-renewal properties. A western blot analysis and PCR arrays were used to examine the genes involved in proliferation, self-renewal, and cancer drug resistance. Finally, DNA content and flow cytometry, an immunohistochemical analysis, and methylcellulose colony formation, in vitro invasive and intracranial injection xenograft assays were employed to examine the disruptive effect of CXCR4 on the characteristics of GSCs of the RG2 cell line. Disrupting CXCR4 inhibited the proliferation of RG2 cells both in vitro and in vivo. The spheroid formation assay indicated that CXCR4 was vital for the self-renewal of RG2 GSCs. Disrupting the CXCL12/CXCR4 pathway also reduced the expression of GSC cell markers, including Nestin, ABCG2, and musashi (Msi), and the expression of genes involved in regulating stem cell properties, including Oct4, Nanog, maternal embryonic leucine zipper kinase (MELK), MGMT, VEGF, MMP2, and MMP9. The chemokine receptor CXCR4 is crucial for maintaining the self-renewal, proliferation, therapeutic resistance, and angiogenesis of GSCs of rat RG2 glioblastoma.


Wideband polarization splitter and rotator with large fabrication tolerance and simple fabrication process.
We propose and demonstrate a polarization splitter and rotator (PSR) built on a silicon-on-insulator platform. The PSR is constructed with a tapered waveguide followed by a 2×2 multimode interferometer and can be simply fabricated in a single lithography and etching step. A low insertion loss (<2.5 dB with minimum insertion loss of 0.6 dB) and a low polarization crosstalk (<-12 dB) over a wide operation bandwidth (~100 nm) with a large fabrication tolerance (>50 nm) are experimentally demonstrated.


Expression of multiple Transient Receptor Potential channel genes in murine 3T3-L1 cell lines and adipose tissue.
Calcium and its signaling have a role in adipogenesis. Transient Receptor Potential (TRP) channels are non-selective cation channels with a high permeability to calcium. In the present study the expression of multiple TRP channels on mouse 3T3-L1 preadipocyte and adipocyte cells, white (WAT) and brown (BAT) adipose tissues was investigated using real time PCR (RT-PCR). TRPV1, TRPV3, TRPM8, TRPC4, TRPC6 were differentially expressed in preadipocytes and adipocytes suggesting their significance in adipogenesis. Genes for multiple TRP channels were also expressed in murine WAT and BAT, out of which TRPV4, TRPV6 and TRPC6 showed differential expression. Present study demonstrates the expression of TRP channels in mouse cell lines and adipose tissues.