Modulation of radiochemoimmunotherapy-induced B16 melanoma cell death by the pan-caspase inhibitor zVAD-fmk induces anti-tumor immunity in a HMGB1-, nucleotide- and T-cell-dependent manner.
One prerequisite that radiotherapy (RT) and chemotherapy (CT) result in anti-tumor immune responses is triggering of immunogenic cell death forms such as necroptosis. The latter is inducible by inhibition of apoptosis with the pan-caspase inhibitor zVAD-fmk. The design of multimodal therapies that overcome melanoma's resistance to apoptosis is a big challenge of oncoimmunology. As hints exist that immune stimulation by hyperthermia (HT) augments the efficacy of melanoma therapies and that tumors can be sensitized for RT with zVAD-fmk, we asked whether combinations of RT with dacarbazine (DTIC) and/or HT induce immunogenic melanoma cell death and how this is especially influenced by zVAD-fmk. Necroptosis was inducible in poorly immunogenic B16-F10 melanoma cells and zVAD-fmk generally increased melanoma cell necrosis concomitantly with the release of HMGB1. Supernatants (SNs) of melanoma cells whose cell death was modulated with zVAD-fmk induced an upregulation of the activation markers CD86 and MHCII on macrophages. The same was seen on dendritic cells (DCs), but only when zVAD-fmk was added to multimodal tumor treatments including DTIC. DCs of MyD88 KO mice and DCs incubated with SNs containing apyrase did not increase the expression of these activation markers on their surface. The in vivo experiments revealed that zVAD-fmk decreases the tumor growth significantly and results in a significantly reduced tumor infiltration of Tregs when added to multimodal treatment of the tumor with RT, DTIC and HT. Further, a significantly increased DC and CD8+ T-cell infiltration into the tumor and in the draining lymph nodes was induced, as well as an increased expression of IFNγ by CD8+ T cells. However, zVAD-fmk did not further reduce tumor growth in MyD88 KO mice, mice treated with apyrase or RAG KO mice. We conclude that HMGB1, nucleotides and CD8+ T cells mediate zVAD-fmk induced anti-melanoma immune reactions in multimodal therapy settings.


Microtubule plus-end loading of p150(Glued) is mediated by EB1 and CLIP-170 but is not required for intracellular membrane traffic in mammalian cells.
Microtubule dynamics and function are regulated, at least in part, by a family of proteins that localize to microtubule plus-ends, and include EB1, CLIP-170 and the dynactin component p150(Glued). Plus-end pools of these proteins, notably dynactin, have been invoked in a number of ;search-and-capture' mechanisms, including the attachment of microtubules to kinetochores during mitosis and to endomembranes prior to the initiation of intracellular transport. Here we show that, in mammalian cells, EB1 is required for the plus-end localization of CLIP-170, and that this is in turn required to localize p150(Glued) to plus-ends. Specific depletion of CLIP-170 results in defects in microtubule dynamics, cell polarization in response to scratch wounding and a loss of p150(Glued) from plus ends. By contrast, removal of p150(Glued) from plus-ends by depletion of either EB1 or CLIP-170 caused no defects in the localization of intracellular organelles, the dynamics of ER-to-Golgi transport, the efficiency of transferrin uptake or the motility of early endosomes or lysosomes. In addition to labelling microtubule plus-ends, we show that GFP-p150(Glued) becomes incorporated into the dynactin complex and labels small, highly dynamic, punctate structures that move along microtubules. A subset of these structures colocalizes with ER-Golgi transport intermediates. Together, these data show that the function of CLIP-170 and p150(Glued) in membrane trafficking is not associated with their plus-end localization.


Heparin-binding growth factors stimulate DNA synthesis in rat alveolar type II cells.
The proliferation of alveolar type II cells is important for repair of the alveolar epithelium after lung injury. We have previously reported that epidermal growth factor (EGF), insulin, cholera toxin, and endothelial cell growth supplement (ECGS) stimulate DNA synthesis of rat alveolar type II cells in culture. ECGS is a crude extract from bovine neural tissue that contains heparin-binding growth factors, and in this report we have compared the effect of ECGS to purified heparin-binding growth factors. ECGS stimulated [3H]thymidine incorporation into type II cells by 3-fold with half-maximal stimulation at 50 micrograms/ml. The purified acidic, class I heparin-binding growth factors, alpha-endothelial cell growth factor (-ECGF) and beta-ECGF stimulated type II cell DNA synthesis by 10-fold and 5-fold, respectively, with half-maximal stimulation at 40 ng/ml. Acidic fibroblast growth factor (FGFa) stimulated [3H]thymidine incorporation by 16-fold with half-maximal stimulation at 20 ng/ml, whereas basic FGF (FGFb) only stimulated type II cell DNA synthesis by 3-fold. Heparin potentiates the mitogenic effect of the acidic heparin-binding growth factors for both endothelial cells and fibroblasts but was found to inhibit FGFa- and FGFb-induced [3H]thymidine incorporation in type II cells by 80% with half-maximal inhibition occurring with 0.4 micrograms/ml and 1.3 micrograms/ml, respectively. When type II cells were cultured in the absence of serum, the heparin-binding growth factors had very little effect on [3H]thymidine incorporation. Only rat high density lipoprotein (HDL), but not insulin, EGF, or transferrin, was found to act synergistically with FGFa in stimulating [3H]thymidine incorporation in type II cells cultured in serum-free medium.(ABSTRACT TRUNCATED AT 250 WORDS)


Pathological validity of esophageal endoscopy. How real is what we see? Myth or reality?
The purpose of this study was to characterize the spectrum of esophageal pathology at a provincial tertiary care hospital and to evaluate these findings with their respective endoscopic diagnoses. The pathology slides of 183 esophageal biopsies for the year 2000 were reviewed and classified as esophagitis, intestinal metaplasia, low or high grade dysplasia, adenocarcinoma, squamous cell carcinoma or normal. One hundred and fifteen cases (63%) had complete concordant results with respective endoscopic reports. Sixty-eight cases (37%) had discordant results with inaccurate recognition of Barrett's esophagus in 9% and of esophagitis with a false positive in 16% and false negative in 7%. Although esophagoscopy remains a primary investigative tool in gastroesophageal diseases, evaluation of erythema, inflammation and esophagitis can be misleading. Pathologically confirmed esophagitis can occur in a 'normal' esophagus. Accurate endoscopic recognition of short-segment Barrett's remains a diagnostic challenge.


Genome-wide polygenic risk impact on intracranial aneurysms and acute ischemic stroke.
Polygenic risk scores (PRSs) have an important relevance to approaches for clinical usage in intracranial aneurysm (IA) patients. Hence, we aimed to develop IA-predicting PRS models including the genetic basis shared with acute ischemic stroke (AIS) in Korean populations. We applied a weighted PRS (wPRS) model based on a previous genome-wide association study (GWAS) of 250 IA patients in a hospital-based multicenter cohort, 222 AIS patients in a validation study, and 296 shared controls. Risk predictability was analyzed by the area under the receiver operating characteristic curve (AUROC). The best-fitting risk models based on wPRSs were stratified into tertiles representing the lowest, middle, and highest risk groups. The weighted PRS, which included 29 GWASs (p < 5×10-8) and two reported genetic variants (p < 0.01), showed a high predictability in IA patients (AUROC = 0.949, 95% CI: 0.933-0.966). This wPRS was significantly validated in AIS patients (AUROC = 0.842, 95% CI: 0.808-0.876; p < 0.001). Two-stage risk models stratified into tertiles showed an increased risk for IA (OR = 691.25, 95% CI: 241.77-1976.35; p = 3.1×10-34; sensitivity/specificity = 0.728/0.963), which was replicated in AIS development (OR = 39.76, 95% CI: 16.91-93.49; p = 3.1×10-17; sensitivity/specificity = 0.284/0.963). A higher wPRS for IA may be associated with an increased risk of AIS in the Korean population. These findings suggest that IA and AIS may have a shared genetic architecture and should be studied further to generate a precision medicine model for use in personalized diagnosis and treatment.


Pycnogenol improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy.
The growing numbers of diabetes cases in the developed world are followed by increasing numbers of people diagnosed with diabetic complications. Diabetic microangiopathies in the eye lead to the development of retinopathy involving gradual loss of vision. Previous studies with Pycnogenol showed effectiveness for stopping progression of preproliferative stages of retinopathy. The aim of our study was to show protective effects of Pycnogenol in early stages of retinopathy, characterized by mild to moderate retinal edema in the absence of hemorrhages or hard exudates in the macula center. Following treatment with Pycnogenol (24 patients) for 3 months, retinal edema score (dilated ophthalmology) and retinal thickness (high resolution ultrasound) showed statistically significant improvement as compared to the placebo group (22 patients), which showed negligible changes to baseline. Laser Doppler flow velocity measurements at the central retinal artery showed a statistically significant increase from 34 to 44 cm/s in the Pycnogenol group as compared to marginal effects in the control group. The major positive observation of this study is the visual improvement, which was subjectively perceived by 18 out of 24 patients in the Pycnogenol group. Testing of visual acuity using the Snellen chart showed a significant improvement from baseline 14/20 to 17/20 already, after 2 months treatment, whereas no change was found in the control group. Pycnogenol taken at this early stage of retinopathy may enhance retinal blood circulation accompanied by regression of edema, which favorably improves vision of patients.


Hypercalcaemia associated with chronic lymphocytic leukaemia in a Giant Schnauzer.
A 7-year-old male Giant Schnauzer was referred with a history of severe vomiting, lethargy, weight loss, polydipsia and polyuria. Detailed investigations revealed leucocytosis with a marked lymphocytosis, mild non-regenerative anaemia, thrombocytopenia, hypercalcaemia and azotaemia. Circulating lymphocytes were small and well-differentiated, and the same lymphoid population was present in bone marrow. Chronic lymphocyctic leukaemia with associated paraneoplastic hypercalcaemia was diagnosed. Immunohistochemical staining of a bone marrow biopsy revealed a neoplastic B-cell line expressing CD79. The dog responded to therapy with prednisolone and chlorambucil for a period of 8 months.


Heat Pulse Desorption of Low-Volatility Compounds by a Heated N2 Gas Pulse with Mass Spectrometry.
For the thermal desorption of low-volatility compounds, rapid heating followed by instant cooling is desirable to suppress thermal decomposition. In this work, a new thermal desorption method, heat pulse desorption (HPD), was developed. A heated N2 gas pulse (350 °C, 50 ms) was directed to the solid sample surface, and desorbed analytes were ionized by DC corona discharge and mass analyzed by an Orbitrap mass spectrometer. Because heat transfer from the heated N2 gas to the solid surface is not very efficient, desorption of the solid sample occurs at a certain temperature before reaching 350 °C. In short, there is a self-controlling desorption depending on the volatility of each analyte. Because the exit of the copper tube for gas blowing is separated from the sample surface, no carryover occurs, enabling the repetitive analysis of samples. HPD was applied to various compounds such as narcotics, pharmaceutical tablets, and explosives. Because analysis is completed within a few seconds per sample, this method is highly useful for quick and consecutive analysis of real samples, having potential utility in food quality control, counterfeit drugs analysis, and the detection of explosives for safety and security.


Air Pollution, Health Shocks and Labor Mobility.
The health shocks caused by air pollution seriously interfere with people's economic life. Based on the air pollution index and health shock index calculated by the principal component entropy weight method, this article analyzes the impact of air pollution on labor mobility, and adopts the mediation effect model to test the mediation effect of health shocks, using the threshold model to analyze the time and the health shocks threshold effect of air pollution on labor mobility. Its conclusions are as follows: (1) Air pollution has a negative impact on the net inflow of labor mobility, and the net inflow of labor mobility decreases between 24.9% and 44.7% on average for each unit increase in the health shocks of air pollution. (2) The impact of air pollution on labor mobility is all caused by health shocks; the health shocks are also an important factor influencing the decrease in the labor mobility supply across provinces, and the different health levels of the migrating individuals due to air pollution. (3) The health shocks of air pollution have a single-time threshold effect on labor mobility, and the health shocks of air pollution in China have intensified after 2010, confirming that China's Lewis turning point was 2010. (4) The attraction effect of stable and higher regional real income will partially offset the repulsion effect of health shocks of air pollution on labor mobility, when the health-shocks index of air pollution exceeds the threshold value of 1.9873. Finally, the policy implications of the health shocks of air pollution on labor mobility are also formulated.


Comparison evaluation of liquid chromatographic and bioassay methods of analysis for determination of paralytic shellfish poisons in shellfish tissues.
A liquid chromatographic (LC) method was compared with the AOAC mouse bioassay method (18.086-18.092) for determination of paralytic shellfish toxins in shellfish tissues. Shellfish samples were collected from Massachusetts coastal waters as part of a state surveillance program, and extracts of shellfish meat were analyzed for toxins by using both analytical methods. Overall correlation of the LC and bioassay methods is good (r = 0.943), but for samples with toxicities less than 100 micrograms saxitoxin/100 g shellfish meat, the correlation is significantly less (r = 0.531). Limits of detection are 10 micrograms saxitoxin/100 g shellfish meat and 40 micrograms saxitoxin/100 g shellfish meat for the LC and bioassay methods, respectively. Analytical capacity of the LC method is limited to 12 samples/person-day compared with 30 samples/person-day for the bioassay. Sampling capacity of the LC method could be increased by using a fluorescence detector with a wider response range, which would eliminate the need for dilution of concentrated samples.


Conceptual Framework of Mentoring in Low- and Middle-Income Countries to Advance Global Health.
Although mentoring is not a common practice in low- and middle-income countries (LMICs), there is a strong need for it. Conceptual frameworks provide the structure to design, study, and problem-solve complex phenomena. Following four workshops in South America, Asia, and Africa, and borrowing on theoretical models from higher education, this article proposes two conceptual frameworks of mentoring in LMICs. In the first model, we propose to focus the mentor-mentee relationship and interactions, and in the second, we look at mentoring activities from a mentees' perspective. Our models emphasize the importance of an ongoing dynamic between the mentor and mentee that is mutually beneficial. It also emphasizes the need for institutions to create enabling environments that encourage mentorship. We expect that these frameworks will help LMIC institutions to design new mentoring programs, clarify expectations, and analyze problems with existing mentoring programs. Our models, while being framed in the context of global health, have the potential for wider application geographically and across disciplines.


Choices and life chances: feminism and the politics of generational change.
The perception that young women are disengaged from feminist politics has provoked a great deal of tension between feminist generations. Recent feminist research into generational change has largely avoided this tension by focusing on the shifting meanings of feminism and the discrepancy between young women's reluctance to identify as "feminists" and their general acceptance of feminist attitudes toward gender issues. Nevertheless, in an era when gender equity goals seem to be if not slipping backwards then lacking urgency, young women are less likely to identify with a collective feminist politics than are older women. Underpinned by the findings of a major study of the attitudes toward work, family, and retirement of three generations of Australian women, this paper develops an approach that helps explain this reluctance. Drawing on the work of Karl Mannheim, the paper suggests that the cultural currents shaping the consciousness of different generations of women impact significantly on gender identity. The implications of this cultural shift are considered in the context of feminist politics and the contemporary "culture wars."


[Application effects of enhanced computed tomography and three-dimensional reconstruction technology in reconstruction of pediatric post-burn scars with expanded flaps].
Objective: To explore the application effects of enhanced computed tomography (CT) and three-dimensional reconstruction technology in the reconstruction of pediatric post-burn scars with expanded flaps. Methods: From May 2016 to March 2019, 19 children with hypertrophic scars after thermal injuries were admitted to our unit, including 10 boys and 9 girls, aged from 4 years and 5 months to 15 years and 11 months. The area of scars ranged from 5 cm×4 cm to 23 cm×9 cm. One or more skin and soft tissue expanders with suitable volume and shape were implanted into the normal skin area around scar of children. Three to six months later, enhanced CT and three-dimensional reconstruction were performed before the second stage operation to obtain three-dimensional images of the vascular branches in the donor site for expanded flaps to be cut, so as to determine the course and distribution of the vascular branches and guide the design of expanded flaps. According to the design scheme, the resection of scar, removal of expanders, and excision and transfer of flaps were performed to repair the wounds after scar resection. The area of flaps ranged from 6 cm×4 cm to 25 cm×10 cm. The donor site was closed directly. The number of flaps was counted. The anatomical structure, vascular distribution, and adverse reactions during enhanced CT and three-dimensional reconstruction of site for expanded flaps to be cut, the survival of expanded flaps and the follow-up after the second-stage operation were observed. Results: A total of 48 expanded flaps were designed and excised in 19 children. The anatomical structure of the site for expanded flaps to be cut and the adjacent spatial position relationship were visually observed through the three-dimensional reconstruction after enhanced CT, and no adverse reactions were observed. Arterial branch blood supply or venous return was observed in 29 sites for expanded flaps to be cut. All the expanded flaps survived well without blood supply disorder after the second stage operation. The children were followed up for 6 months to 1 year and 6 months after the second stage operation. The appearance of the flaps was natural, and the color and thickness of the flaps were similar to those of the surrounding normal skin, except for one child with obvious linear scar. Conclusions: Enhanced CT and three-dimensional reconstruction can assist the vascular assessment of the expended flaps, which is helpful for rational design of the flap excision and transfer protocol to improve the survival rate of flaps. Thus, it has certain clinical application value in the reconstruction of post-burn scar in children with expanded flaps.


Digital health in pain assessment, diagnosis, and management: Overview and perspectives.
Managing pain is essential for social, psychological, physical, and economic reasons. It is also a human right with a growing incidence of untreated and under-treated pain globally. Barriers to diagnosing, assessing, treating, and managing pain are complicated, subjective, and driven by patient, healthcare provider, payer, policy, and regulatory challenges. In addition, conventional treatment methods pose their own challenges including the subjectivity of assessment, lack of therapeutic innovation over the last decade, opioid use disorder and financial access to treatment. Digital health innovations hold much promise in providing complementary solutions to traditional medical interventions and may reduce cost and speed up recovery or adaptation. There is a growing evidence base for the use of digital health in pain assessment, diagnosis, and management. The challenge is not only to develop new technologies and solutions, but to do this within a framework that supports health equity, scalability, socio-cultural consideration, and evidence-based science. The extensive limits to physical personal interaction during the Covid-19 pandemic 2020/21 has proven the possible role of digital health in the field of pain medicine. This paper provides an overview of the use of digital health in pain management and argues for the use of a systemic framework in evaluating the efficacy of digital health solutions.


[Effects of mildronate (quaterin) on hemodynamics in spontaneous and artificial heart rhythm in patients with ischemic heart disease].
Central hemodynamic parameters under the effect of mildronate were examined in 62 patients suffering from coronary heart disease, 35 of these with acute myocardial infarction complicated by acute left-ventricular insufficiency and 20 with atherosclerotic cardiosclerosis with chronic cardiac insufficiency. The drug effect was assessed in two groups of patients after a single intravenous injection of 0.5-3 g. In group 1 (n = 53) mildronate effect on central hemodynamic parameters was assessed in spontaneous cardiac rhythm. Variously directed statistically unreliable hemodynamic shifts were revealed, related to heart rhythm changes. In group 2 (n = 9) the drug effect on heart rhythm was eliminated with the use of two-chamber electrocardiostimulation, and various hemodynamic regimens with hypo-, eu-, and hyperkinetic circulation types were artificially created by changing the A-V interval. Mildronate had no effect on the hemodynamics during two-chamber electrocardiostimulation.


[Magnitude of mortality from cervical cancer in the Brazilian Northeast and socioeconomic factors].
To analyze the time trend of cervical cancer mortality based on adjusted or unadjusted mortality data and to investigate the association between these data and socioeconomic indicators in women aged 20 years or older in the Brazilian Northeast (in capitals and non-capital cities) during the period from 1996 to 2005. All deaths from cervical cancer recorded in the Brazilian Health Ministry's Mortality Data System (SIM) were included in the study. Also included were the cervical cancer deaths identified after the adjustment process. Simple linear regression was used to analyze the time trends for mortality and their correlations (Pearson) with selected socioeconomic indicators. The highest mortality coefficients with unadjusted data were observed in capitals and the lowest were observed in non-capital cities. Conversely, the highest mortality coefficients with adjusted data were observed in non-capital cities. Similarly, the lowest unadjusted mortality rates were observed in the states with the most poverty, illiteracy, fertility, and child mortality, whereas the highest unadjusted mortality rates were observed in the regions with the best social indicators. Adjusted mortality rates showed a negative association with the indicators describing better living conditions, and a positive association with the indicators describing worse living conditions. The use of unadjusted mortality data may lead to underestimation of cervical cancer rates and compromise the interpretations of comparative analyses of the magnitude, distribution, and factors associated with this disease. The magnitude of cervical cancer should be reassessed at least in the Brazilian Northeast. However, the findings show that positive results have been obtained with early detection efforts in Brazil.


Dyslipidemia and maternal obesity: Prematurity and neonatal prognosis.
To identify the changes caused by dyslipidemia and obesity in pregnancy suggesting causes for premature birth, and the prognosis for the newborn. Systematic review based on the Medline, Lilacs, Embase and Cochrane library databases between 1996 and 2016. The search for studies included the following keywords: "dyslipidemia, pregnancy, obesity, preterm birth." A protocol was programmed and a protocol for inclusion/exclusion of studies was implemented. Of the 5,789 articles initially selected between March 1996 and July 2016, only 32 were in accordance with the established criteria. Of these, 28.12% discussed risk factors of prematurity; 37.50%, metabolic alterations and gestational dyslipidemia; 21.87%, dyslipidemic complications in preterm birth; and 12,50%, lipid metabolism, glycemic and placental transfer. There is a reduced adaptation of obese pregnant women to the metabolic changes of gestation. This favors dyslipidemic intercurrences in the mother, which, directly or indirectly, suggests the occurrence of premature births and high lipid transfer to the fetus. Therefore, preterm newborns, whose mothers were dyslipidemic during pregnancy, have greater risk of epicardial fat, both in early (first year of life) and in later (adult) phases of life.


Coarse-to-Fine Semantic Segmentation From Image-Level Labels.
Deep neural network-based semantic segmentation generally requires large-scale cost extensive annotations for training to obtain better performance. To avoid pixel-wise segmentation annotations that are needed for most methods, recently some researchers attempted to use object-level labels (e.g., bounding boxes) or image-level labels (e.g., image categories). In this paper, we propose a novel recursive coarse-to-fine semantic segmentation framework based on only image-level category labels. For each image, an initial coarse mask is first generated by a convolutional neural network-based unsupervised foreground segmentation model and then is enhanced by a graph model. The enhanced coarse mask is fed to a fully convolutional neural network to be recursively refined. Unlike the existing image-level label-based semantic segmentation methods, which require labeling of all categories for images that contain multiple types of objects, our framework only needs one label for each image and can handle images that contain multi-category objects. Only trained on ImageNet, our framework achieves comparable performance on the PASCAL VOC dataset with other image-level label-based state-of-the-art methods of semantic segmentation. Furthermore, our framework can be easily extended to foreground object segmentation task and achieves comparable performance with the state-of-the-art supervised methods on the Internet object dataset.


Patients responding to phosphodiesterase type 5 inhibitor therapy: what do their sexual partners know?
Phosphodiesterase type 5 (PDE5) inhibitors are an efficacious therapy in men with erectile dysfunction (ED). There are only a few studies that also focus on the participating couples during PDE5 inhibitor therapy. To determine to what extent patients personally informed their sexual partners about their ongoing PDE5 inhibitor therapy. Likelihood of informing the female partner by the patient himself about the use of PDE5 inhibitors. A total of 216 men (mean age 62.3 years) with ED were successfully treated with PDE5 inhibitors in three independent centers. After an interval of at least 3 months of successful ED therapy, all patients were asked by questionnaire whether their sexual partners were informed of their PDE5 inhibitor therapy. Eighty-two percent of the patients were exclusively involved in one stable sexual relationship, 9.7% of the men admitted to having changing sexual partners, and 6% did not give any information at all about their sexual partners. Twenty percent of the men had a severe ED (International Index of Erectile Function [IIEF-5] <11). Forty-nine percent showed a moderate ED (IIEF-5 11-16) and 31% suffered a mild ED (IIEF-5 >16). PDE5 inhibitor medication was used 1.2 times/month by men with a severe ED, 2.1 times/month by patients with a moderate ED, and 2.9 times/month by men with a mild ED. Forty-one (93%) of the 44 patients with a severe ED informed their sexual partners that they were taking PDE5 inhibitors. In the patient group with moderate ED, 49 (47%) of 105 patients and only 14 (21%) of 67 of the patients with mild ED shared this information with their partners. Less than 40% of the patients suffering a moderate or mild ED using PDE5 inhibitors shared this information with their partners. It seems that patients find ED so disturbing that many patients do not inform their partners of PDE5 inhibitor use.


Photodynamic therapy of esophageal varices: experimental studies in animal veins, and first clinical cases.
Endoscopic injection sclerotherapy and endoscopic variceal ligation have been found to have shortcomings in the treatment of esophageal varices. In this study the effectiveness of photodynamic therapy (PDT) in the obliteration of veins was investigated to evaluate its potential in the treatment of esophageal varices. Auricular margin veins of rabbits were irradiated by copper vapor laser after intravenous injection of 10 mg/kg of hematoporphyrin monomethyl ether (which is a hematoporphyrin derivative) into the rabbits. Control groups included rabbits that received irradiation only, that received injection of photosensitizer only, and that received injection sclerotherapy (using sodium morrhuate). The treated areas were observed macroscopically and also identified using with ultrasonic miniprobe. Biopsies were performed and the specimens were examined microscopically after hematoxylin-eosin staining and Victoria blue staining. In addition, two patients with newly visible veins within the esophageal wall after endoscopic injection sclerotherapy underwent PDT. Intravenous injection of 5 mg/kg of hematoporphyrin monomethyl ether was given, and the newly visible veins were endoscopically irradiated by copper vapor laser. Endoscopic re-examination was performed 1 month later to evaluate the therapeutic effect. Thrombi of the auricular margin vein were formed and blood flow was obstructed after PDT. Thrombus formation and diffused necrosis of adjacent tissue was found after injection of sodium morrhuate. On ultrasonic examination, the lumina of the veins showed a slightly higher echo after PDT compared with a lower echo before treatment, which was another sign of thrombus formation. The rabbit ears showed a diffused low echo after injection of sodium morrhuate, indicating diffuse necrosis. On microscopic observation, destruction of the endothelium and formation of thrombus was seen after PDT. Further observation of specimens stained with Victoria blue showed that the layer of elastic fiber was intact. After injection of sodium morrhuate, extensive necrosis of tissue was seen microscopically. No macroscopic, ultrasonic, or microscopic change was found in the rabbits that received irradiation only or injection of photosensitizer only. The rate of thrombus formation in rabbits that received PDT was significantly higher than that in the rabbits that received irradiation only or injection of photosensitizor only ( P = 0.015, P = 0.015), and comparable to that in the rabbits that received sclerotherapy ( P = 0.467). In the clinical study, at endoscopy 1 month after PDT both the number and the "red sign" of newly visible veins were found to have decreased. No adverse effect was found. PDT can destroy the endothelium of the vein, result in thrombus formation, and eventually obliterate the vein. It is potentially a new method for the treatment of esophageal varices.


Narrowing performance gap between rural and urban hospitals for acute myocardial infarction care.
Rural communities experience significant barriers to quality healthcare, including disparities in medical care following acute myocardial infarctions (AMI). This study sought to determine if the population density of the county where Medicare patients were hospitalized following AMI predicted short-term outcomes and to quantify longitudinal changes in hospital performance on quality of care metrics. Hospital-level data was queried from the 2012 and 2018 Centers for Medicare & Medicaid Services archives. Each hospital was classified based on residing county using the National Center for Health Statistics Rural-Urban Continuum Codes (RUCC). Variations and longitudinal changes in risk-adjusted outcomes and quality of care metrics were stratified by RUCC classification and analyzed. Among the 4798 hospitals identified, rural hospitals had significantly higher risk-adjusted 30-day mortality (rs = 0.095, p < 0.001) and decreased statin prescribed at discharge (rs = -0.066, p = 0.004). Only aspirin (R2 = 0.003, p = 0.024) and statin (R2 = 0.006, p = 0.001) prescribed at discharge were correlated with improved 30-day mortality. Despite these differences, from 2012 to 2018 the performance gap between rural and urban hospitals narrowed for all but one quality of care metric, with concurrent 1.83% [95% CI 1.76-1.90] and 3.37% [95% CI 3.30-3.44] reductions in mortality and hospital readmissions, respectively. In the United States, only modest variations currently exist between rural and urban hospitals in the medical care of AMI. Although the performance gap has narrowed, new strategies to improve timely and effective care are necessary to alleviate residual cardiovascular healthcare disparities in rural communities.


[Castleman disease with pericardial location. Third case of the literature].
An intra-thoracic mass is a diagnostic challenge. We report the clinical case of an intra-thoracic mass which was incidentally detected in a 14-year old adolescent after a chest X-rays. The clinical investigation revealed a pericardial tumor. The immunohistological examination was consistent with Castleman disease. The rarity of this location was confirmed in the literature with only two cases previously published, to our knowledge.


Microcystic meningioma of the fourth ventricle in a dog.
A 5-year-old female cross-breed dog was presented with a 1-month history of progressive changes in the posture of the head and in the gait. At neurological examination the dog showed a central vestibular syndrome lateralized to the left. MRI showed a space occupying lesion within the fourth ventricle, characterized by iso- to hypointensity in T1 and hyperintensity in T2 with a heterogeneous contrast uptake. Histologically, a neoplasia composed of meningothelial cells forming compact whorls with slight atypia, and stellate cells delimitating microcysts containing eosinophilic fluid was observed. Neoplastic cells were positive for vimentin and negative for GFAP and FVIII. A diagnosis of intraventricular microcystic meningioma was achieved. Intraventricular meningiomas in dogs are rarely encountered and reports of meningiomas within the fourth ventricle have not yet been described. Although choroid plexus tumor is the most frequent neoplasia localized in the fourth ventricle, intraventricular meningioma should be included in the differential diagnoses.


Utilitarianism, poverty and development of disabled people.
This study aims to analyze the influences of human development factors in the experience of disabled people based on social scenarios of inequality. The data collected were standardized and allocated in thematic categories. The analysis was based on liberal utilitarianism. The conclusion is that there is legislation in Brazil that guarantees the disabled people's development in areas such as health, education and work. However despite the attempts of decision makers in combating discriminatory behaviors and the theory based on equity, these people still face difficulties in breaking the barrier of poverty and achieving all humans rights deserved.


[Torsion of the hydatid of Morgagni].
We present 22 cases of torsion of the hydatid of Morgagni, attended in our hospital in the space of seven years (1981-1988), which were subjected to emergency operation. The ages ranged from 6 months to 16 years, with an average age of 9 years. The typical symptomatology was the sudden appearance of acute pain, located most frequently in the left side, accompanied by vegetative symptoms, without the existence of fever and micturition syndrome. The most significant exploratory diagnostic element in torsion of the hydatid of Morgagni prior to surgery is the palpation of a painful nodule on the upper pole of the testicle and which corresponds to the twisted hydatid. We outline the guidelines for diagnosis and treatment used, emphasising the importance of early surgery as the means of suppressing the symptomatology and forestalling complications, besides confirming the diagnosis.


When It Comes to Screen Golf and Baseball, What Do Participants Think?
Screen golf and baseball activities have been popular as virtual game content and sport activities, but no one has cogently explained why they are attractive to Korean urban society. Our research team analyzed the decision-making process for participating in screen golf and baseball through a widely used technology acceptance model (TAM) to explain the relationship between perceived ease of use, perceived usefulness, personal attitude, and individual intention. Structural equation modeling (SEM) verified five hypotheses established through a literature review, and 400 effective samples obtained through online surveys provided material for analysis. As a result of the analysis, perceived usefulness was the most important variable leading to participation in virtual reality sports. Based on this finding, we could conclude that the successful popularization of virtual reality sports depends on the development of applications sophisticated enough to provide practical usefulness to participants, such as physical posture correction and an improvement in personal athletic skills.


Role of c-jun expression increased by heat shock- and ceramide-activated caspase-3 in HL-60 cell apoptosis. Possible involvement of ceramide in heat shock-induced apoptosis.
Ceramide has emerged as a lipid mediator in apoptosis induced by a variety of stresses. As we previously showed that the activation of AP-1, a nuclear transcription factor was indispensable to ceramide-induced apoptosis in human leukemia HL-60 cells (Sawai, H., Okazaki, T., Yamamoto, H., Okano, H., Takeda, Y., Tashima, M., Sawada, H., Okuma, M., Ishikura, H., Umehara, H., and Domae, N. (1995) J. Biol. Chem. 270, 27326-27331), the role and mechanism of heat shock (HS)-increased c-jun expression in apoptosis was here investigated. HS increased morphological changes compatible with apoptosis in human leukemia HL-60 cells, and induced ceramide generation and sphingomyelin hydrolysis with an increase of neutral magnesium-dependent sphingomyelinase activity. When HS failed to induce apoptosis in HS-resistant HL-60 cells, ceramide generation was not detected, suggesting that ceramide was involved in downstream signals required for HS-induced apoptosis. Both HS and N-acetylsphingosine (C(2)-ceramide) increased the expression of c-jun/c-fos mRNAs with the peak 2 h after treatment. When we examined whether the inhibition of c-jun expression by its antisense oligodeoxynucleotides (AS) blocked HS- or C(2)-ceramide-induced apoptosis, AS of c-jun gene inhibited apoptotic morphological changes and DNA fragmentation whereas did not sense oligodeoxynucleotides. Moreover, a synthetic tetrapeptide, acetyl-Asp-Met-Gln-Asp-aldehyde (DMQD-CHO), which inhibited the formation of active form of caspase-3 more efficiently than those of caspase-4, -6, -7, and -8, blocked both caspase-3 like activity, c-jun expression and apoptosis induced by HS or C(2)-ceramide, although DMQD-CHO did not affect HS-induced ceramide generation. These results suggested that the ceramide was generated through sphingomyelin hydrolysis by HS-activated neutral, magnesium-dependent sphingomyelinase and that subsequent c-jun expression through activation of caspase-3 played a role in HS-induced HL-60 cell apoptosis.


Long-term glucose control among type 2 diabetes patients with and without serious mental illness.
Although studies suggest that patients with diabetes with a serious mental illness (SMI) have poor diabetes outcomes, reports conflict regarding the quality of their diabetes care and level of glucose control. In an observational follow-up to our initial cross-sectional study, we compared glucose control (glycosylated hemoglobin [HbA1c]) between patients with diabetes with SMI versus those without SMI at two postbaseline assessments during an approximately 5-year period. Both groups continued to have glucose levels higher than what is considered good control and neither group demonstrated a significant change in mean HbA1c at the two follow-up time points. Those with SMI continued to have lower HbA1c levels than those without SMI even after adjusting for potential confounders. More effective strategies are needed to assist patients with diabetes to improve the management of their glucose levels.


Tapping into the power of coproduction and knowledge mobilisation: Exploration of a facilitated interactive group learning approach to support equity-sensitive decision-making in local health and care services.
We report on a study of a facilitated interactive group learning approach, through Collaborative Implementation Groups (CIGs), established to enhance capacity for equity-sensitive evaluation of healthcare services to inform local decision-making: (1) What was the experience of participants of the CIGs? (2) How was knowledge mobilisation achieved? (3) What are the key elements that enhance the process of coproducing equity-sensitive evaluations? A thematic analysis of qualitative data obtained from focus group (FG) discussions and semistructured interviews exploring the experiences of participants. All FGs included representation of participants from different projects across the programme. Interviews were conducted with a member from each of the teams participating in the first cohort after their final workshop. We identified four themes to illustrate how the approach to delivering intensive and facilitated training supported equity-sensitive evaluations of local healthcare services: (1) Creating the setting for coproduction and knowledge mobilisation; (2) establishing a common purpose, meaning and language for reducing health inequalities; (3) making connections and brokering relationships and (4) challenging and transforming the role of evaluation. We report on the implementation of a practical example of engaged scholarship, where teams of healthcare staff were supported with resources, interactive training and methodological advice to evaluate their own services, enabling organisations to assemble timely practical and relevant evidence that could feed directly into local decision-making. By encouraging mixed teams of practitioners, commissioners, patients, the public and researchers to work together to coproduce their evaluations, the programme also aimed to systematise health equity into service change. The findings of our study illustrate that the approach to delivering training gave participants the tools and confidence to address their organisation's stated aims of reducing health inequalities, coproduce evaluations of their local services and mobilise knowledge from a range of stakeholders. The research question was developed collaboratively with researchers, partner organisations and public advisers (PAs). PAs were involved in meetings to agree on the focus of this research and to plan the analysis. N. T. is a PA and coauthor, contributing to the interpretation of findings and drafting of the paper.


[Transarterial chemoembolization in hepatocellular carcinomas: technique, indications, results].
At time of diagnosis 80% of the patients with hepatocellular carcinoma (HCC) could not be treated with surgical treatments, so that transarterial chemoembolization (TACE) was used as an neoadjuvant or palliative treatment modality. 60 patients were treated with 217 TACE courses, in the mean 3.6 TACE treatments per patient with an 4 week interval. TACE was performed with a dispersion of lipiodol, mitomycin C and spherex. 11 patients (18.3%) were treated in a neoadjuvant protocol with successful ablation. Lipiodol retention and size of the tumors were evaluated by CT and MRI. 60 patients were successful treated with TACE. After treatment a primary high lipiodol retention was displayed and in 68 (63.3%) patients a reduction of the tumor size and in 11 (20%) patients a reduction of tumor growth rate was noted. The 1 year survival rate was 59%. After response to TACE and reducing the tumor size 11 patients could be treated with MR-guided LITT 4 to 6 weeks post embolization. Chemoembolization is a minimal invasive and outpatient treatment protocol for HCC. TACE might be indicated as a palliative treatment to control the diseased liver. If repeated TACE alters the size and structure of primary unresectable HCC TACE expands the indication for MR-guided LITT.


STAT3 induces colorectal carcinoma progression through a novel miR-572-MOAP-1 pathway.
Colorectal carcinoma (CRC) is among the most common causes of death. Recent studies have shown that both STAT3 and miR-572 contribute to CRC progression. STAT3 plays an important role in miRNA expression. Moreover, MOAP-1, which is a pro-apoptotic protein that induces cell death or apoptosis, has a direct correlation with miRNA. Therefore, the current study is designed to explore whether miR-572 and STAT3 are involved in a common pathway and the role of MOAP-1 in this process. The expressions of STAT3, miR-572, and MOAP-1 in human CRC tissues and multiple cell lines were estimated by qRT-PCR or Western blot. MTT, transwell migration, and invasion assays were used to assess cell growth, migration, and invasion, respectively. Dual-luciferase reporter assay was applied to examine the association between miR-572 and MOAP-1. Elevated STAT3 levels were accompanied by increased miR-572 and decreased MOAP-1 levels in primary CRC specimens and cell lines. STAT3 promoted CRC cell growth, migration, and invasion via the upregulated expression of miR-572. Subsequently, miR-572 inhibited MOAP-1 protein expression through an interaction with its 3'UTR. Our study proposes a novel STAT3-miR-572-MOAP-1 pathway involved in the process of CRC progression, which might be a potential target for the development of new preventive and therapeutic approaches against human colorectal cancer.


The Anatomical Basis of Heavy Metal Responses in Legumes and Their Impact on Plant-Rhizosphere Interactions.
Rapid industrialization, urbanization, and mine tailings runoff are the main sources of heavy metal contamination of agricultural land, which has become one of the major constraints to crop growth and productivity. Finding appropriate solutions to protect plants and agricultural land from heavy metal pollution/harmful effects is important for sustainable development. Phytoremediation and plant growth-promoting rhizobacteria (PGPR) are promising methods for this purpose, which both heavily rely on an appropriate understanding of the anatomical structure of plants. Specialized anatomical features, such as those of epidermis and endodermis and changes in the root vascular tissue, are often associated with heavy metal tolerance in legumes. This review emphasizes the uptake and transport of heavy metals by legume plants that can be used to enhance soil detoxification by phytoremediation processes. Moreover, the review also focuses on the role of rhizospheric organisms in the facilitation of heavy metal uptake, the various mechanisms of enhancing the availability of heavy metals in the rhizosphere, the genetic diversity, and the microbial genera involved in these processes. The information presented here can be exploited for improving the growth and productivity of legume plants in metal-prone soils.


Women's stories: ethnic variations in women's attitudes and experiences of menopause, hysterectomy, and hormone replacement therapy.
To increase understanding of women's midlife changes, 23 focus groups were held to investigate the possible ethnic variations in attitude toward and experience with menopause, hysterectomy, and hormone replacement therapy (HRT) in non-Hispanic white, Hispanic, and Navajo women in New Mexico. The medical definition of menopause, no menstrual bleeding for 12 months, did not coincide with the women's definition of menopause as the hormonal fluctuations they experienced before, during, and after any change in their menstrual cycle. More women reported having to fight to have a hysterectomy than having one unnecessarily. Women complained about the lack of information and preparation prior to having a hysterectomy and expressed dissatisfaction with doctor-patient communication, but they were satisfied with their hysterectomy because they felt better after the surgery. Although women in the study reported that menopause and hysterectomy are seldom discussed openly, they all participated freely in the storytelling focus groups. The most traditional women, primarily rural Navajo and newly immigrated Latina, related few or no menopausal symptoms with natural menopause or after hysterectomy. Many of these women had not even heard of HRT. Many women who had been prescribed HRT expressed dissatisfaction with the side effects and dosage. Unsupervised tinkering with the dosage was the rule rather than the exception. The study revealed that women are much more alike than they are different. Traditional women in all ethnic groups had more in common with each other than they did with the least traditional women in their own ethnic group.


Predictors of Recent HIV Testing Among Chinese Men Who Have Sex with Men: A Barrier Perspective.
In China, men who have sex with men (MSM) account for an increasing proportion of new HIV infections. We aim to assess recent HIV testing (in the past 6 months) among Chinese MSM and to identify barriers to testing. A nationwide sample of MSM (n = 1100) from mainland China was recruited. Data on sociodemographics, HIV-related risks, perceived barriers to testing, and testing behaviors were collected. Approximately 30% of MSM had recently undergone HIV testing. With regard to testing, almost half endorsed each of three barriers: did not believe themselves to be at HIV risk, had a fear of being diagnosed HIV positive, and feared their privacy would be violated during testing. Five distinct classes of barriers were identified from the responses. The adjusted multivariable logistic regression model demonstrated that the participants in both the "uncertainty concerning testing sites" and "low risk and privacy violation" classes were less likely to undergo testing than those in the "minimal barrier" class. Men who were unsure of their HIV status were less likely to undergo testing. Furthermore, participants who had multiple male sexual partners and who engaged in substance use over the preceding 6 months were more likely to undergo testing. Distinct subgroups of testing and HIV status varied within the different barrier classifications. Recent HIV testing rates remain low among MSM in China. Barrier factors associated with testing point to the necessity for preventing and controlling HIV, including increasing the privacy of sites or educating MSM on the importance of testing regularly.


[Basic analysis of extracorporeal shock wave lithotripsy of gallstones].
Influence of extracorporeal shock wave lithotripsy (ESWL) on human gallstones placed in dog gallbladders was investigated. After irradiation of shock wave more than 600 times, maximal diameter of residual stones of 10 mm before irradiation was destroyed to 2 mm or less. Levels of serum transaminase (GOT.GPT) were elevated, in parallel with times of shock waves. These results suggested that 600 times of shock waves were enough to destroy one cholesterol stone, diameter of which was about 1 cm. Data of elevation of serum transaminase showed that more than 600 times of shock waves were possible to induce the damage of liver.


Mechanistic basis for catalytic activation of mitogen-activated protein kinase phosphatase 3 by extracellular signal-regulated kinase.
The dual specificity mitogen-activated protein kinase phosphatase MKP3 has been shown to down-regulate mitogenic signaling through dephosphorylation of extracellular signal-regulated kinase (ERK). Camps et al. (Camps, M., Nichols, A., Gillieron, C., Antonsson, B., Muda, M., Chabert, C., Boschert, U., and Arkinstall, S. (1998) Science 280, 1262-1265) had demonstrated that ERK binding to the noncatalytic amino-terminal domain of MKP3 can dramatically activate the phosphatase catalytic domain. The physical basis for this activation has not been established. Here, we provide detailed biochemical evidence that ERK activates MKP3 through the stabilization of the active phosphatase conformation, inducing closure of the catalytic "general acid" loop. In the closed conformation, this loop structure can participate efficiently in general acid/base catalysis, substrate binding, and transition-state stabilization. The pH activity profiles of ERK-activated MKP3 clearly indicated the involvement of general acid catalysis, a hallmark of protein-tyrosine phosphatase catalysis. In contrast, unactivated MKP3 did not display this enzymatic group as critical for the low activity form of the enzyme. Using a combination of Brönsted analyses, pre-steady-state and steady-state kinetics, we have isolated all catalytic steps in the reaction and have quantified the specific rate enhancement. Through protonation of the leaving group and transition-state stabilization, activated MKP3 catalyzes formation of the phosphoenzyme intermediate approximately 100-fold faster than unactivated enzyme. In addition, ERK-activated MKP3 catalyzes intermediate hydrolysis 5-6-fold more efficiently and binds ligands up to 19-fold more tightly. Consistent with ERK stabilizing the active conformation of MKP3, the chemical chaperone dimethyl sulfoxide was able to mimic this activation. A general protein-tyrosine phosphatase regulatory mechanism involving the flexible general acid loop is discussed.


PKG II inhibits PDGF-BB triggered biological activities by phosphorylating PDGFRβ in gastric cancer cells.
Previous studies revealed that type II cGMP-dependent protein kinase G (PKG II) could inhibit the activation of epidermal growth factor receptor (EGFR) which is a widely investigated RTK. PDGFR belongs to family of receptor tyrosine kinases (RTKs) too. However, the effect of PKG II on PDGFR activation is not clear yet. This study investigated potential regulatory effect of PKG II on activation of PDGFRβ and the downstream signaling transductions in gastric cancer. The results from CCK8 assay and Transwell assay indicated that PDGF-BB induced cell proliferation and migration. Activated PKG II reversed the above variations caused by PDGF-BB. Immunoprecipitation and Western blotting results showed that PKG II combined with PDGFRβ and phosphorylated this receptor, and thereby inhibited PDGF-BB induced activation of PDGFRβ, and MAPK/ERK and PI3K/Akt mediated signal transduction pathways. Based on the prediction by phosphorylation site software, Ser643 and Ser712 were mutated to alanine respectively which prevented phosphorylation at these sites. Mutation at Ser712 abolished the inhibitory function of PKG II on PDGFRβ activation but mutation of Ser643 had no such an effect, indicating that Ser712 was PKG II-specific phosphorylating site of PDGFRβ. In conclusion, PKG II inhibited PDGFRβ activation in gastric cancer via phosphorylating Ser712 of this RTK.


Inhibition of hormone secretion in GH-secreting pituitary adenomas by receptor-subtype specific somatostatin analogues in vitro.
The aim of the study was to determine the inhibitory effects of somatostatin analogues with relative specificity to somatostatin receptor subtype 2 (SSTR2) (BIM-23197), subtype 5 (SSTR5) (BIM-23268), and their combination on GH and PRL secretion in acromegalic adenomas in vitro. Three types of answer were observed: 1. In one resistant adenoma no inhibition was achieved. 2. The GH secretion in six adenomas was suppressed significantly more (p < 0.01 or p < 0.001 using Mann-Whitney U-test in concentration range of 10(-12) to 10(-8) mol/l) with SSTR2 specific analogue BIM-23197 with no additive effect of compounds combination. 3. In three adenomas the potency of BIM-23197 and BIM-23268 was almost equal and the combination of these SSTR2 and SSTR5 specific compounds had statistically significant additive effect (p < 0.05 or p < 0.01 in concentration range of 10(-12) to 10(-8) mol/l). PRL secretion of five adenomas was more suppressed with SSTR5 specific BIM-23268 (statistically significant in concentrations 10(-10) to 10(-8) mol/l). In conclusion the somatostatin analogue BIM-23268 had an additive effect on suppression of GH secretion in a subset of adenomas, where both SSTR2 and SSTR5 were involved. This effect was not observed in the majority of tumours, where the inhibitory effect seems to be mediated via SSTR2 only.


Lymphatic cannulation models in sheep: Recent advances for immunological and biomedical research.
Lymphatic cannulation models are useful tools for studying the immunobiology of the lymphatic system and the immunopathology of specific tissues in diseases. Sheep cannulations have been used extensively, as models for human physiology, fetal and neonatal development, human diseases, and for studies of ruminant pathobiology. The development of new and improved cannulation techniques in recent years has meant that difficult to access sites, such as mucosal associated tissues, are now more readily available to researchers. This review highlights the new approaches to cannulation and how these, in combination with advanced omics technologies, will direct future research using the sheep model.


Anterior cervical discectomy and interbody fusion with a dentate titanium cage: An experimental radiological and histopathological study in pigs.
Background - Aim: The distraction and stabilization provided by anterior cervical discectomy and fusion contribute to neural decompression and optimize osteogenesis. A new titanium cervical implant with specific properties was applied through an anterior approach in ten pigs. Implant behavior regarding in situ position and related osteogenesis were evaluated. In this controlled animal study, the progress of fusion and osteogenesis was evaluated after one level cervical interbody fusion with a new titanium cage. Ten pigs underwent anterior cervical discectomy and fusion. No substitutes stimulating osteoblastic activity were used. Plain radiographs were carried out. The animals were euthanised 12 and 14 weeks after the operation respectively. Tissue samples were processed routinely and studied histologically. All pigs survived the surgery. Plain radiographs confirmed implant position. Histological analysis demonstrated fibrous connective tissue formation inside and around the implant which was largely transformed into cartilaginous and osseous tissue. Intervertebral space stabilization remains a parameter of crucial importance for early bone healing after anterior cervical discectomy and fusion. The new titanium alloy cage tested in this experimental study can offer the necessary stabilization for osteogenesis and adequate cervical interbody fusion without the need of growth factors.


[Changes in Pulmonary Hemodynamics Resulted From Long-Term Mechanical Heart Support].
Aim To study the dynamics of right ventricular function and pulmonary hemodynamics in patients with pulmonary hypertension during mechanical circulatory support of the heart.Material and methods A retrospective analysis was performed for 25 implantations of left ventricular assist device performed in the Meshalkin National Medical Research Center from 2006 through 2021. Mechanical assist devices were implanted in 21 men and 4 women (median age, 37.5 [29; 48] years). All patients had severe, NYHA functional class III-IV chronic heart failure refractory to the optimal drug therapy. Invasive measurements showed that mean pulmonary arterial pressure (MPAP) was 50 [44.5; 60] mm Hg, transpulmonary pressure gradient (TPG) was 16 [14; 19] mm Hg, and calculated pulmonary vascular resistance was 5.4 [4.9; 9] Wood units, which is an absolute contraindication (TPG >15 mm Hg or pulmonary vascular resistance >5 Wood units) for heart transplantation (HT).Results Duration of left ventricular support was from 17 to 948 days. For 12 (48 %) patients, the HT was performed at 180-948 days following the implantation of left ventricular assist device; 3 patients are presently waiting for HT; 10 patients died from various complications, 6 of them died during the hospital stage. Already during the early stage after the implantation of the mechanical assist device, pulmonary hemodynamics significantly improved. Thus, in one week, MPAP decreased from 50 [44.5; 60] mm Hg to 36 [33; 38] mm Hg (р=0.012) whereas pulmonary vascular resistance decreased from 5.4 [4.9; 9] to 2.9 [2.4; 3.6] Wood units (р=0.008). Follow-up showed further improvement of pulmonary hemodynamics; at 1 month, MPAP was 29 [27; 30] mm Hg and by the time of HT, MPAP was 2.0 [24.8; 26.3] mm Hg (р=0.01), i.e., reached a normal level, which made it possible to perform HT. Similar dynamics was observed for other variables that reflected pulmonary hemodynamics.Conclusion Mechanical support of the heart is able to alleviate manifestations of pulmonary hypertension in most patients with end-stage heart failure. It is necessary to develop an algorithm for identifying the category of patients with a high risk of progression of right ventricular failure.


Fungal infection and neurodevelopmental outcomes at 18-30 months in preterm infants.
Invasive fungal infection (IFI) is associated with significant mortality and morbidity among preterm infants but there has been no population-based study of long-term neurodevelopmental outcomes. The objective of this study was to examine population-based incidence trends as well as mortality, short term in-hospital morbidity and long-term neurodevelopmental outcomes among preterm infants with IFI, non-fungal infections (NFI) and no infections in Canada. We conducted a retrospective cohort study of 8,408 infants born at <29 weeks gestational age (GA), admitted to Canadian Neonatal Network neonatal intensive care units (NICU) from April 2009 to December 2017, and followed up at 18-30 months corrected age (CA) in Canadian Neonatal Follow-Up Network clinics. We compared mortality, long term neurodevelopmental outcomes and short term in-hospital morbidity among 3 groups of infants (IFI, NFI, and no infections). The incidence of IFI was 1.3%, non-IFI 26.9% and no infections 71.7%. IFI incidence varied between 0.93% and 1.94% across the study period with no significant trend over time. Infants of higher gestational age were significantly (p < 0.01) less likely to have IFI. Among infants with IFI, NFI and no infections, the incidence of the significant neurodevelopmental impairment (sNDI) was 44.26%, 21.63% and 14.84% respectively, while mortality was 50%, 25.35% and 22.25% respectively. Even after risk adjustment for confounders (GA, Score for Neonatal Acute Physiology Version II, ruptured membranes >24 h, maternal antibiotic treatment, antenatal steroid use, cesarean section), infants with IFI had significantly higher odds of sNDI than NFI (aOR: 2.19; 95% CI: 1.23, 3.91) or no infections (aOR: 2.97; 95% CI: 1.55, 5.71), and higher odds of mortality than NFI (aOR: 1.55; 95% CI: 1.07, 2.26) or no infections (aOR: 1.45; 95% CI: 0.97, 2.17). Preterm infants with invasive fungal infections have significantly higher incidence of mortality and adverse neurodevelopmental outcomes than those with non-invasive fungal infections and no infections.


Do scientific advancements lean on the shoulders of giants? A bibliometric investigation of the Ortega hypothesis.
In contrast to Newton's well-known aphorism that he had been able "to see further only by standing on the shoulders of giants," one attributes to the Spanish philosopher Ortega y Gasset the hypothesis saying that top-level research cannot be successful without a mass of medium researchers on which the top rests comparable to an iceberg. The Ortega hypothesis predicts that highly-cited papers and medium-cited (or lowly-cited) papers would equally refer to papers with a medium impact. The Newton hypothesis would be supported if the top-level research more frequently cites previously highly-cited work than that medium-level research cites highly-cited work. Our analysis is based on (i) all articles and proceedings papers which were published in 2003 in the life sciences, health sciences, physical sciences, and social sciences, and (ii) all articles and proceeding papers which were cited within these publications. The results show that highly-cited work in all scientific fields more frequently cites previously highly-cited papers than that medium-cited work cites highly-cited work. We demonstrate that papers contributing to the scientific progress in a field lean to a larger extent on previously important contributions than papers contributing little. These findings support the Newton hypothesis and call into question the Ortega hypothesis (given our usage of citation counts as a proxy for impact).


Differential tumor regression in patients with bilobar hepatic metastases and dual arterial supply: evidence supporting the advantage of intra-arterial over intravenous route of drug delivery.
Two patients with bilobar liver metastases were characterized by dual arterial blood supply to the liver. Treatment of both patients by the administration of chemotherapy, selectively via the arterial branches supplying the respective hepatic lobes bearing the metastases, resulted in differential tumor regression/progression. Thus, while the metastases borne by the arterially infused lobe regressed, the counterpart in the other (systemically infused) lobe showed marked progression. This phenomenon lends strong support to the notion that arterial infusion of chemotherapy in cases of regionally predominant (or confined) neoplastic disease, i.e., in the liver, is superior to the intravenous administration of similar drugs.


The esophagus: do sex and gender matter?
The esophagus has a single rudimentary function of active transport of solids and liquids from the pharynx to the stomach and, rarely, venting of the stomach with retrograde passage of gastric contents into the pharynx. It is void of any digestive, absorptive, metabolic, or endocrine functions. Despite this simplicity of function, sex (biological and physiological characteristics, ie, male versus female) and gender (roles, behaviors, activities, and attributes that a given society considers appropriate, ie, man versus woman) differences exist in both normal esophageal function and esophageal disease. Some components of esophageal function are sex-dependent, and these differences must be considered in the interpretation of functional testing. In esophageal disease, particularly gastroesophageal reflux disease, Barrett esophagus, esophageal cancer, acquired immune deficiency syndrome, and scleroderma, there are sex and gender differences in the pathophysiology and response to treatment. Although discussions of treatment and outcomes might differ between the sexes and genders, there are no important data to support different care on the basis of sex or gender.


Entry of gut lymph into the circulation primes rat neutrophil respiratory burst in hemorrhagic shock.
Endothelial cell injury by polymorphonuclear neutrophil (neutrophil [PMN]) respiratory burst after trauma and hemorrhagic shock (T/HS) predisposes subjects to acute respiratory distress syndrome and multiple organ failure. T/HS mesenteric lymph injures endothelial cell and lymph duct ligation (LDL) before T/HS prevents pulmonary injury. We investigated the role of mesenteric lymph in PMN priming by T/HS. Prospective experiment in rats. University hospital laboratory. Adult male rats. Mesenteric lymph was obtained from rats undergoing T/HS (30 mm Hg, 90 mins) or sham shock (T/SS). Plasma was harvested from uninstrumented control (UC), T/HS, T/SS, and T/HS+LDL rats. PMNs were isolated from UC, T/HS, and T/HS+LDL rats. PMNs from UC rats were incubated in buffer, 1% T/HS lymph, and 1% T/SS lymph. PMNs from UC rats were incubated in UC, T/HS, T/SS, and T/HS+LDL plasma. PMN respiratory burst was initiated by using macrophage inflammatory protein (MIP)-2/platelet-aggregating factor (PAF) or phorbol myristate acetate. Cytosolic calcium ([Ca2+]i) responses to MIP-2/PAF were assayed in PMN from UC, T/HS, and T/HS+LDL rats. PMN preincubated in T/HS lymph showed significant elevations in MIP/PAF-elicited respiratory burst compared with T/HS lymph or buffer only (p <.05; analysis of variance/Tukey's test). T/HS lymph incubation also increased (p <.05) phorbol myristate acetate elicited respiratory burst compared with buffer or T/SS. Preincubation in T/HS plasma increased MIP-2/PAF-elicited respiratory burst (p <.05) compared with UC or T/SS plasma. LDL blocked T/HS priming of respiratory burst. Control PMN [Ca2+]i responses to MIP-2 and PAF were low. T/SS PMN were significantly more responsive, but the T/HS PMN showed still higher responses (p <.01). LDL reversed the priming of [Ca2+]i responses by T/HS (p <.01). PMNs are primed by T/HS lymph but not T/SS lymph and by T/HS plasma but not T/SS plasma. LDL before shock prevents T/HS plasma from priming PMN. The magnitude of respiratory burst found here paralleled the [Ca2+]i responses seen to receptor dependent initiating agonists. Mesenteric lymph is both necessary and sufficient to prime PMN after T/HS in the rat, and it primes PMN in part by enhancing [Ca2+]i responses to G-protein coupled chemoattractants. Mesenteric lymph mediates postshock PMN dysfunction.


Flight pattern induced by temperature in a single-gene mutant of Drosophila melanogaster.
Simultaneous intracellular recordings were made from the six dorsal longitudinal flight muscle (DLM) fibers in the temperature-sensitive mutant of Drosophila melanogaster, shibirets1 (shi). The DLM firing pattern induced by temperature in shi was compared with the DLM pattern of a wild-type fly in stationary flight. The firing pattern, induced at temperatures between about 26 and 27 degrees C, was very similar to that of the wild-type pattern. At higher temperatures, the pattern became abnormal, characterized by many synchronous firings among the fibers and occasional bursting.


The influence of clinical and pharmacological factors on enuresis treatment with imipramine.
1. The aim of this study has been to evaluate the response to imipramine treatment in enuretic children through the use of a series of clinical and pharmacological variables and by applying a multivariate (principal components) analysis technique. 2. The study was carried out on 146 children whose ages ranged from 5 to 14 years, and who received variable doses of imipramine (12.5 to 100 mg day-1). 3. The quantitative variables analyzed were: drug dosage, serum levels of imipramine and its metabolite desipramine, the relationship between them both, the duration of treatment, age and weight. 4. The qualitative variables were: compliance, presence of side-effects, enuretic and/or psychiatric antecedents, intelligence quotient (I.Q.), the existence (or absence) of related pathologies, sex, and the type of enuresis. 5. The response to treatment was quantified by means of the percentage of decrease in frequency of enuresis as compared with the initial frequency. 6. The results obtained show that the variables which are most associated with the reduction of enuresis are, in decreasing order: the dosage of imipramine administered, the duration of treatment, compliance and the level/dose ratio for the sum of the drug and metabolite levels.


An insight into early reproductive processes through the in vivo model of ovum donation.
To gain insight into early reproductive processes we have prospectively designed ovum donation protocols to elucidate several phenomena relating to embryo implantation and pregnancy sustenance. Artificial endometrial cycles with variable follicular phases were induced in 60 recipients by sequential estrogen and progesterone. A total of 964 oocytes were retrieved throughout 43 ovum donation attempts, for an average of 22.4 (range, 16-41) eggs/retrieval. The overall delivery rate per egg retrieval (donors and recipients combined) was 72.1% (31 of 43). The shortest estrogen stimulation (short follicular phase) resulting in ongoing pregnancies was 5 days in duration, while the longest (long follicular phase) was 35 days in duration before progesterone initiation. Utilization of variable length follicular phases, artificially extended the stage of endometrial receptivity to over 4 weeks. To assess the window of implantation, same age embryos were transferred onto endometrium of different maturational stages. Pregnancies were documented with embryo transfers between luteal day 1 (day 15) to luteal day 6 (day 20), extending the window of implantation in the human to at least 6 consecutive days. To evaluate the relative contribution of oocyte quality and endometrial receptivity to pregnancy outcome, common source ova were transferred onto endometrium with variable hormonal exposure. Despite the drastically different follicular phase estradiol levels and periods of exposure, similar delivery rates were attained in donor cycles (29.4%) and recipient cycles during short follicular phases (29.6%). Slightly higher delivery rates (39.4%) were observed with long follicular phases. The comparable pregnancy rates in donors and recipients are attributed to the common source oocytes regardless of endometrial stimulation.


[Trends in nonsteroidal anti-inflammatory drug development and application].
Since the synthesis of salicylic acid, research into the synthesis of new nonsteroidal anti-inflammatory drugs (NSAIDs) has continued in two directions: drugs with higher anti-inflammatory activity and those causing less adverse side-effects. Several very potent classic, non-selective NSAIDs were already available in the 1970's, but problems with their toxicity, especially gastro- and nephrotoxicity, have remained unsolved. The discovery of two cyclooxygenase (COX) isoforms, COX-1 and COX-2, was a breakthrough that led to obtaining the so-called coxibs, which selectively inhibit COX-2. This property makes this kind of NSAID less gastrotoxic than classic, non-selective NSAIDs. Other strategies to reduce the toxic effects of NSAIDs were their applications as prodrugs or purified enantiomers. The latest are the synthesis of classic NSAIDs combined with a chemical group that serves as a nitric oxide donor or the synthesis of double cyclooxygenase/5-lipoxygenase inhibitors. Simple inhibition of prostaglandin (PG) synthesis cannot completely stop the inflammatory process. Therefore new agents are tested for their influence on many other elements of the mechanism of inflammation, e.g. the formation of inflammatory cytokines, free radicals and biogenic amines by the stimulated inflammatory cells. Such pleiotropic activity of an NSAID might increase its anti-inflammatory action.NSAIDs are widely used not only for their anti-inflammatory, but also analgesic, antipyretic, and (as in case of aspirin) anti-coagulating activity. Results of the latest studies suggest that NSAIDs prevent colorectal cancer and may protect against the development of Alzheimer's disease as well. Precise studies of NSAIDs' mechanism of action (e.g. research on the genetic conditions of NSAID metabolism, the discovery of COX-3, studies on microsomal PGE synthase or PG receptors) will probably enable the synthesis of other more selectively acting compounds.


Concerted Cultivation and Adolescent Psychopathology over Time-Mediation of Parent-Child Conflict.
Concerted cultivation is a parenting strategy that parents nurture their children intensively by involving heavily in their children's academic sphere as well as offering them different structured "enrichment" activities so that their children can succeed in the future competitive "rug rat race". While this parenting strategy has been regarded as an effective strategy to promote child and adolescent development, it is deemed to create stress and anxiety for their children. The present study examined the relationship between concerted cultivation and adolescent psychopathology (indexed by depression and anxiety) via parent-child conflict among Chinese adolescents in Hong Kong over time. A sample of 1570 young adolescents (48.5% girls, mean age at time 1 = 12.6, SD = 0.76) were recruited from 19 secondary schools in Hong Kong. Adolescents were invited to fill out a questionnaire that contained measures of concerted cultivation, parent-child conflict, anxiety and depression in two consecutive years. Results from structural equation modeling showed that higher levels of paternal concerted cultivation were associated with higher levels of adolescent psychopathology via increased father-child conflict over time. However, maternal concerted cultivation was linked to greater mother-child conflict but reduced father-child conflict, which was associated with adolescent psychopathology. Rather than regarding concerted cultivation as an effective parenting strategy that promotes adolescent development, the findings indicated that concerted cultivation increased adolescent psychopathology via increased parent-child conflict. The study sheds new light for family practitioners and educators in their awareness of the adverse effects of concerted cultivation and designing appropriate parent education programs for parents.


Iron Phosphate Nanozyme-Hydrogel with Multienzyme-like Activity for Efficient Bacterial Sterilization.
Pathogenic bacteria infections have posed a threat to human health worldwide. Nanomaterials with natural enzymatic activity provide an opportunity for the development of new antibacterial pathways. We successfully constructed iron phosphate nanozyme-hydrogel (FePO4-HG) with the traits of positive charge and macropores. Interestingly, FePO4-HG displayed not only peroxidase-like activity under acidic bacterial infectious microenvironment but also superoxide dismutase-catalase-like synergistic effects in neutral or weak alkaline conditions, thus protecting normal tissues from the peroxidase-like protocol with exogenous H2O2 damage. Furthermore, the positive charge and macropore structure of FePO4-HG could capture and restrict bacteria in the range of ROS destruction. Obviously, FePO4-HG exhibited excellent antibacterial ability against MRSA and AREC with the assistance of H2O2. Significantly, the FePO4-HG + H2O2 system could efficiently disrupt the bacterial biofilm formation and facilitate the glutathione oxidation process to rapid bacterial death with low cytotoxicity. Moreover, FePO4-HG was unsusceptible to bacterial resistance development in MRSA. Animal experiments showed that the FePO4-HG + H2O2 group could efficiently eliminate the MRSA infection and present excellent wound healing without inflammation and tissue adhesions. With further development and optimization, FePO4-HG has great potential as a new class of antibacterial agents to fight antibiotic-resistant pathogens.


Bioanalysis of urine samples after manipulation by oxidizing chemicals: technical considerations.
Drug testing programs are established to help achieve a drug-free work environment, promote fair competition in sport, facilitate harm minimization and rehabilitation programs, better manage patient care by clinicians and service law enforcement authorities. Urine remains the most popular and appropriate testing matrix for such purposes. However, urine is prone to adulteration, where chemicals, especially oxidizing chemicals, are purposely added to the collected urine specimens to produce a false-negative test result. This article will describe the effect of various popular oxidizing adulterants on urine drug test results, the countermeasures taken by laboratories in dealing with adulterated urine samples and the prospect of developing more robust and economical methods to combat urine adulteration in the future.


Judgmental Biases of Individuals with a Fear of Blushing: The Role of Relatively Strict Social Norms.
Blushing-fearful individuals often expect that others will judge them negatively. In two studies, we tested if this could be explained by having relatively strict beliefs about what is appropriate social behaviour. Study 1 used a student sample (n = 74), whereas study 2 compared a clinical treatment-seeking sample of blushing-fearful individuals (n = 33) with a non-anxious control group (n = 31). In both studies, participants were asked to read descriptions of common behaviours that could be considered as breaching the prevailing social norms but not necessarily so. Participants indicated (i) to what extent they considered these behaviours as violating the prevailing norm and (ii) their expectation of observers' judgments. Study 1 showed that strict norms were indeed related to fear of blushing and that the tendency of fearful participants to expect negative judgments could at least partly explain this relationship. Study 2 showed that high-fearful and low-fearful individuals do indeed differ in the strictness of their norms and that especially the norms that individuals apply to themselves might be relevant. These findings may provide fresh clues for improving available treatment options. Blushing-fearful individuals attribute relatively strict social norms to other people about which behaviours are appropriate and which are not and have stricter personal norms as well. Blushing-fearful individuals' tendency to expect overly negative judgments in ambivalent social situations can partly be explained by their relatively strict social norms. Having relatively strict social norms may (also) explain why blushing-fearful individuals report to blush often and intensely. It may be worthwhile to address strict social norms in therapy for fear of blushing.


Minimum Atropine Dosing in Pediatric Patients: Does CRNA Practice Reflect Current Recommendations?
The purpose of this study was to evaluate certified registered nurse anesthetist (CRNA) current pediatric atropine dosing practices. Emphasis was placed on rationale for dosing and knowledge regarding current literature and guidelines. An electronic survey was deployed by the American Association of Nurse Anesthetists (AANA)'s survey department to a total of 2,905 CRNAs who are current AANA members. The survey was completed by 98 CRNAs, of which 67 selected that they do not administer anesthesia to pediatric patients weighing less than 5 kg and were excluded from further survey participation. The responses from the remaining 31 CRNAs were utilized for data analysis (n = 31). Approximately two thirds of participants (64.5%) were unaware of available guidelines pertaining to pediatric dosing of atropine within the last 5 years. A statistically significant difference existed when analyzing whether awareness of guidelines was associated with knowledge of the correct American Heart Association recommended pediatric atropine dose. Providers who were aware of guidelines reported the correct dose 100% of the time, whereas those unaware of guidelines reported the correct dose only 65% of the time (P = .03). Variability in clinical practices and sources guiding practice should be addressed to avoid potential overdosing in the vulnerable neonatal population.


Active inference and epistemic value.
We offer a formal treatment of choice behavior based on the premise that agents minimize the expected free energy of future outcomes. Crucially, the negative free energy or quality of a policy can be decomposed into extrinsic and epistemic (or intrinsic) value. Minimizing expected free energy is therefore equivalent to maximizing extrinsic value or expected utility (defined in terms of prior preferences or goals), while maximizing information gain or intrinsic value (or reducing uncertainty about the causes of valuable outcomes). The resulting scheme resolves the exploration-exploitation dilemma: Epistemic value is maximized until there is no further information gain, after which exploitation is assured through maximization of extrinsic value. This is formally consistent with the Infomax principle, generalizing formulations of active vision based upon salience (Bayesian surprise) and optimal decisions based on expected utility and risk-sensitive (Kullback-Leibler) control. Furthermore, as with previous active inference formulations of discrete (Markovian) problems, ad hoc softmax parameters become the expected (Bayes-optimal) precision of beliefs about, or confidence in, policies. This article focuses on the basic theory, illustrating the ideas with simulations. A key aspect of these simulations is the similarity between precision updates and dopaminergic discharges observed in conditioning paradigms.


Identification of a DNA processing complex from Deinococcus radiodurans.
An efficient DNA strand break repair contributes to the radioresistance of Deinococcus radiodurans, which harbors the DNA repair pathways nearly identical to Escherichia coli. The molecular mechanisms of these proteins functioning in 2 diverse classes of bacteria seem to be different. The macromolecular interactions and formation of multiprotein complexes in vivo have gained significant importance in explaining the mechanism of the complex cellular processes. Here, we report the identification of a novel DNA metabolic protein complex from D. radiodurans. A similar complex has, however, not been found in E. coli. Mass spectrometric analysis showed the presence of a few known DNA repair proteins, molecular chaperones, and a large number of uncharacterized proteins from D. radiodurans R1. Biochemical and immunoblotting results indicated the presence of the protein promoting DNA repair A, DNA polymerase, Mg2+, and (or) Mn2+ -dependent 5'-->3' exonuclease activity along with protein kinase activity and phosphoproteins. DNA ligase activity was completely dependent upon the ATP requirement, as no ligase activity was seen in the presence of NAD as a cofactor. These results suggest the molecular interactions of the known DNA repair proteins with uncharacterized proteins in the macromolecular complex and the regulation of DNA degradation with the involvement of ATP and protein kinase functions.


Histone deacetylase inhibitors induce growth suppression and cell death in human rhabdomyosarcoma in vitro.
A group of histone deacetylase inhibitors has been shown to be effective in suppressing the growth of a variety of transformed cell lines in vitro and in vivo. The effects of two of these agents, suberoylanilide hydroxamic acid (SAHA) and suberoyl-3-aminopyridineamide hydroxamic acid (pyroxamide), were investigated for their growth-suppressive effects on rhabdomyosarcoma (RMS) cells. Dose-response experiments of two RMS cell lines, RD (embryonal) and RH30B (alveolar), were performed with SAHA (0.25-3.0 micro M) and pyroxamide (1.25-20.0 micro M). Both agents caused a dose-dependent decrease in viable cell number and an increase in percentage of dead cells over time. Exposure of the RMS cells to SAHA and pyroxamide resulted in an accumulation of acetylated histones with increasing doses by Western blot analysis. Additionally, there was an induction of p21/WAF1 at 15 and 24 h when the cells were cultured with SAHA (2.0 micro M) or pyroxamide (20.0 micro M), concentrations that were tested because they successfully induced inhibition of cell growth and initiated cell death in both RMS cell lines. An increase in nuclei with hypodiploid or sub-G(1) fraction was found by flow cytometry with increasing doses of both SAHA (0.25-3.0 micro M) and pyroxamide (1.25-20.0 micro M) over time. This finding is consistent with DNA fragmentation and cell death by apoptosis. SAHA and pyroxamide induce growth suppression and cell death in human RMS in vitro. Accumulation of acetylated histones and induction of p21/WAF1 expression are observed in cells exposed to either agent.


The effect of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors on progression of gastric cancer: systematic review and meta-analysis.
Angiotensin receptor blockers (ARB), as well as angiotensin-converting enzyme inhibitors (ACEI), are mostly used as therapy for hypertension and cardiovascular disease. However, they can increase the risk of cancer progression including gastric cancer. Here we aimed to analyze the assessment between ARB and ACEI on the progression of gastric cancer. Cochrane Library, PubMed and EMBASE were searched for articles and abstracts describing ARBs, ACEIs, and incidence of gastric cancer. Risk ratio, hazard ratio and 95% confidence interval (CI) were extracted from each outcome by using a random-effects model. Six studies met our inclusion criteria. These results demonstrated that there is a significant association between ARB with gastric cancer progression (risk ratio = 0.63; 95% CI, 0.5-0.7; P = 0.00; I 2 = 27.299; df (Q) = 2; Q-value = 2.75). However, there was not any link between ACEIs and gastric cancer development (risk ratio = 1.1; 95% CI, 0.92-1.31; P = 0.26; I 2 = 0.00; df (Q) = 3; Q-value = 1.26). All these findings indicated that using the ARBs has raised the progression of gastric cancer in these patients.


Survival after Endoscopic Valve Therapy in Patients with Severe Emphysema.
Endoscopic valve therapy leads to an improvement of lung function, exercise tolerance, and quality of life in a selected cohort of patients with advanced emphysema. So far, only few data exist on the long-term outcome. This analysis evaluated the impact of valve therapy on the survival of emphysema patients. Survival rates of emphysema patients who underwent valve therapy were assessed according to their radiological outcome following valve placement. From 2005 to 2013, 449 emphysema patients (mean age 64 ± 7 years) underwent valve therapy and were followed for a mean time of 37.3 ± 21.3 months. A total of 128 patients (29%) developed complete lobar atelectasis, 34 out of these also experienced a pneumothorax; 50 patients (11%) developed pneumothorax without lobar atelectasis, and 261 patients (58%) target lobe volume reduction or no volume change. Patients with atelectasis showed significantly better baseline forced expiratory volume in 1 second (%), residual volume (L), total lung capacity (L), and transfer factor for carbon monoxide (%; all p < 0.05), but there was no significant difference in the BODE score (p = 0.195). Patients with valve-induced lobar atelectasis had a significant survival benefit compared to patients without atelectasis (p = 0.009; 5-year survival rate 65.3 vs. 43.9%). The advent of pneumothorax in 84 patients did not influence survival (p = 0.52). Lobar atelectasis following endoscopic valve therapy is associated with a survival benefit.


Age, fertility and reproductive behavior in cuban crocodiles, Crocodylus rhombifer, at the Smithsonian's National Zoological Park.
The Smithsonian's National Zoological Park (NZP) has a long history with Cuban crocodiles, Crocodylus rhombifer, beginning in 1900's when the first animals arrived at the NZP. Today, the Zoo has two breeding groups of C. rhombifer and has observed and analyzed reproductive behavior and fertility rates over the last three years. Fertility rates were determined initially by observing the formation of an opaque band that forms on the shell of a fertile egg, called banding. The fertility rates by banding were later compared to the observation made after opening the eggs to verify fertility. In addition to tracking fertility, nesting and agonistic behavior were also observed. Several notable observations were documented over the same period. These included a male predating a nesting female's eggs, increased aggression between two females housed together, the continued development of a partially banded egg, and the discovery of 19 additional egg shells post oviposition by both females in the enclosure. Here we discuss the nest phenology, fertility and behavior of the five exhibited C. rhombifer at the Smithsonian's National Zoological Park over a 3-year period. Zoo Biol. 34:278-284, 2015. © 2015 Wiley Periodicals Inc.


MOR23 promotes muscle regeneration and regulates cell adhesion and migration.
Odorant receptors (ORs) in the olfactory epithelium bind to volatile small molecules leading to the perception of smell. ORs are expressed in many tissues but their functions are largely unknown. We show multiple ORs display distinct mRNA expression patterns during myogenesis in vitro and muscle regeneration in vivo. Mouse OR23 (MOR23) expression is induced during muscle regeneration when muscle cells are extensively fusing and plays a key role in regulating migration and adhesion of muscle cells in vitro, two processes common during tissue repair. A soluble ligand for MOR23 is secreted by muscle cells in vitro and muscle tissue in vivo. MOR23 is necessary for proper skeletal muscle regeneration as loss of MOR23 leads to increased myofiber branching, commonly associated with muscular dystrophy. Together these data identify a functional role for an OR outside of the nose and suggest a larger role for ORs during tissue repair.


Misoprostol administered sublingually at a dose of 12.5 μg versus vaginally at a dose of 25 μg for the induction of full-term labor: a randomized controlled trial protocol.
Various methods are currently used for the induction of labor. Nevertheless, the most effective method with the fewest side effects remains to be established. Misoprostol, administered vaginally, has been routinely used for this purpose; however, other forms of administration are being proposed, including the use of sublingual tablets. No studies have yet compared the effectiveness and safety of 12.5-μg misoprostol administered sublingually compared to a 25-μg vaginal dose of the drug for the induction of labor. A triple-blind, multicenter, placebo-controlled, randomized clinical trial will be conducted in Brazil at the Instituto de Medicina Integral Prof. Fernando Figueira and at the Assis Chateaubriand Maternity Teaching Hospital of the Federal University of Ceará. A total of 140 patients with full-term pregnancies, a live fetus, a Bishop score ≤ 6 and a recommendation of induction of labor will be randomized to one of two groups. One group will receive 12.5-μg sublingual tablets of misoprostol and placebo vaginal tablets, while the other group will receive placebo sublingual tablets and vaginal tablets containing 25 μg of misoprostol. The principal endpoint is the rate of tachysystole. The secondary endpoints are vaginal delivery within 24 h of induction, uterine hyperstimulation, Cesarean section, severe neonatal morbidity or perinatal death, severe maternal morbidity or maternal death, and maternal preference regarding the route of administration of the drug. Student's t-test, and the chi-square test of association or Fisher's exact test, as appropriate, will be used in the data analysis. Risk ratios and their respective 95% confidence intervals will be calculated. Misoprostol has been identified as a safe, inexpensive, easily administered option for the induction of labor, with satisfactory results. An experimental study has shown that misoprostol administered sublingually at a dose of 25 μg appears to be effective and is associated with greater maternal satisfaction when labor is induced in women with an unfavorable cervix. Nevertheless, the rate of tachysystole remains high; therefore, further studies are required to determine the ideal dose and the ideal interval of time between doses. ClinicalTrial.gov, NCT01406392 .


Occurrence of antibodies against Neospora caninum and/or Toxoplasma gondii in dogs with neurological signs.
This study aimed to evaluate occurrences of antibodies against Neospora caninum and Toxoplasma gondii in dogs with neurological signs. Blood samples from 147 dogs were collected: 127 from owned dogs (attended at the Veterinary Teaching Hospital of the Federal University of Paraná (HV-UFPR) and at private veterinary clinics in the city of Curitiba), and 20 from stray dogs found in Curitiba's metropolitan region. The dogs presented one or more of the following neurological signs: seizures, paresis or paralysis, ataxia, behavioral abnormalities, sensory and somatic disorders and chorioretinitis. The samples were analyzed by means of the indirect fluorescent antibody test (IFAT), at a cutoff dilution of 1:50. Out of the 147 samples obtained, 17 (11.56%) were seropositive for N. caninum, 31 (21.08%) for T. gondii and four (2.72%) for both protozoa. Serum titration on the positive animals showed that 54.83% (17/31) and 41.18% (7/17) had titers ≥ 1:200 against T. gondii and N. caninum, respectively. A significant difference in seropositivity for T. gondii (P = 0.021; OR = 2.87; CI = 1.1 > 2.8 > 7.4) was observed between owned dogs (18.11%) and stray dogs (40%). Inclusion of serological tests for neosporosis and toxoplasmosis is recommended in diagnosing neurological diseases in dogs.