BPA disrupted the testis testosterone levels by interfering ER enrichments within StAR 5' flanking region in rare minnow Gobiocypris rarus.
Bisphenol A (BPA) is a widely used endocrine disruptor, which has attracted much attention due to its harmful effects on male reproduction. To investigate the interference of BPA on steroid synthesis in males, male rare minnows (Gobiocypris rarus) were exposed to 15 μg L-1 BPA for 7, 14 and 21 d. Meanwhile, a positive control group was performed with 25 ng L-1 17α-ethynyl estradiol (EE2). Results showed that BPA exposure induced lower testosterone (T) levels, while affecting the transcripts of steroidogenic gene StAR. Moreover, BPA induced abnormal germ cells proliferation in the testis in rare minnow. Transcriptome analysis showed that 354 transcripts significantly differentially expressed after BPA exposure for 14 d, several of them were enriched in the signaling pathways of cell cycle process, PPAR signaling pathway, the steroid synthesis pathway and estrogen signaling pathway. BPA significantly increased estrogen receptor (ER) levels and induced abnormal protein levels of PPARγ. BPA disrupted the StAR expression by interfering ER enrichments within StAR 5' flanking region. Additionally, our study also revealed that BPA and EE2 might have different mechanisms for interfering with steroid hormone levels and germ cells proliferation in the testis.


Identification of epithelial cells in bronchoalveolar lavage.
1. Damage to the bronchial epithelium occurs after the inhalation of toxic substances and allergens, and through virus infections and it may lead to increased desquamation of epithelial cells in bronchoalveolar lavage (BAL). 2. In this study we compared two methods of staining the epithelial cells of BAL, the conventional cytochemical May Grunwald-Giemsa stain (MGG) and an immunocytochemical technique using a monoclonal antibody anti-human cytokeratin (CK) detected with APAAP immuno-alkaline phosphatase. BAL was obtained from 13 subjects and the epithelial cells were cytocentrifuged either immediately after collection (fraction A) or after washing (fraction B). 3. Higher percentages of epithelial cells were identified in fraction A with CK (20.0 +/- 5.1%) than in fraction A with MGG (11.2 +/- 2.3%), which recognized only ciliated epithelial cells. In fact a proportion of CK-positive cells (34%) in fraction A were not ciliated. Underestimation of epithelial cells by MGG compared to CK was more pronounced in fraction B (8.0 +/- 2.9% and 22.9 +/- 3.0%, respectively) as there was a relative loss of ciliated CK+ cells after washings. 4. These results suggest that immunocytochemical staining with an anti-cytokeratin monoclonal antibody is more sensitive than using the MGG stain in detecting epithelial cells in BAL.


Etiology and management of postpartum hypertension-preeclampsia.
Postpartum hypertension can be related to persistence of gestational hypertension, preeclampsia, or preexisting chronic hypertension, or it could develop de novo postpartum secondary to other causes. There are limited data describing the etiology, differential diagnosis, and management of postpartum hypertension-preeclampsia. The differential diagnosis is extensive, and varies from benign (mild gestational or essential hypertension) to life-threatening such as severe preeclampsia-eclampsia, pheochromocytoma, and cerebrovascular accidents. Therefore, medical providers caring for postpartum women should be educated about continued monitoring of signs and symptoms and prompt management of these women in a timely fashion. Evaluation and management should be performed in a stepwise fashion and may require a multidisciplinary approach that considers predelivery risk factors, time of onset, associated signs/symptoms, and results of selective laboratory and imaging findings. The objective of this review is to increase awareness and to provide a stepwise approach toward the diagnosis and management of women with persistent and/or new-onset hypertension-preeclampsia postpartum period.


Two Hybrid Au-ZnO Heterostructures with Different Hierarchical Structures: Towards Highly Efficient Photocatalysts.
A new paradigm for photocatalysts based on two different hierarchically structured honeycomb and porous cylindrical Au-ZnO heterostructures was successfully developed via a straightforward and cost-effective hydrothermal method under different preparation conditions, which can be promising for industrial applications. The photocatalytic performance of all as-prepared samples under the illumination of sunlight was evaluated by the photocatalytic degradation of rhodamine B (RhB) and malachite green (MG) aqueous solutions. The results show that the photocatalytic degradation efficiency of RhB and MG was 55.3% and 40.7% for ZnO, 95.3% and 93.4% for the porous cylindrical Au-ZnO heterostructure, and 98.6% and 99.5% for the honeycomb Au-ZnO heterostructure, respectively. Compared with those from the ZnO, the results herein demonstrate an excellent reduction in the photoluminescence and improvement in the photocatalysis for the Au-ZnO hybrids with different morphologies. These results were attributed not only to the greatly improved sunlight utilization efficiency due to the surface plasmon resonance (SPR) absorption of Au nanoparticles in the visible region coupled with the UV light utilization by the ZnO nanostructures and multi-reflections of the incident light in the pore structures of their interior cavities but also to the high charge separation efficiency and low Schottky barrier generated by the combination of Au nanoparticles and ZnO micromaterials. Moreover, the honeycomb Au-ZnO heterostructure had a high Au content, surface area and surface oxygen vacancy (OV), which enabled photocatalytic properties that were higher than those of the porous cylindrical Au-ZnO heterostructures. In addition, two different formation mechanisms for the morphology and possible photocatalytic mechanisms are proposed in this paper.


"Specific" binding of [3H]imipramine to protease-sensitive and protease-resistant sites.
A number of 5-hydroxytryptamine (5-HT) uptake inhibitors have been shown to displace the binding of [3H]imipramine to rat cortical membranes in a complex manner with Hill slopes less than unity. Norzimeldine displaced the binding of [3H]imipramine in a biphasic manner with IC50 values for the two components of about 30 nM and 30 microM. This latter site alone was found in tissues that had been treated with a protease. Binding to both of these sites was displaced by 10 microM desipramine. The protease-sensitive [3H]imipramine binding sites were found to be saturable, high-affinity binding sites with a KD of 8 nM. The number of these sites varied between brain regions and was positively correlated with the regional distribution of [14C]5-HT but not [3H]noradrenaline uptake. This was not the case however for the protease-resistant but desipramine-displaceable binding sites. Since most previous [3H]imipramine binding studies have been performed with high concentrations of desipramine (10 microM) to define "specific binding," these data would suggest that either protease-sensitivity or displacability by 1 microM norzimeldine would give more reliable estimates of the specific binding.


AIM2 Inflammasome Activation Contributes to Aortic Dissection in a Sporadic Aortic Disease Mouse Model.
The absent in melanoma 2 (AIM2) inflammasome induces pyroptosis, tissue inflammation, and extracellular matrix destruction. We tested the hypothesis that the AIM2 inflammasome contributes to aortic aneurysm and dissection (AAD) development by promoting pyroptosis in smooth muscle cells (SMCs). We examined AIM2 expression in aortic tissues from patients with ascending thoracic aortic aneurysm (ATAA) and aortic dissection (ATAD) and from organ donor controls. AIM2's role in AAD development was evaluated in AIM2-deficient mice in a sporadic AAD model induced by challenging mice with a high-fat diet and angiotensin II infusion. The direct effects of dsDNA on SMC death in vitro were studied. Western blot analyses showed that AIM2 was increased in ATAD compared to ATAA and control tissue. Immunofluorescence demonstrated increased AIM2 in SMCs and macrophages in the aortic media and adventitia of dissected tissue. Increased AIM2 abundance was associated with increased cleavage of caspase-1 and cleavage of gasdermin-D, indicating activation of pyroptosis. In a mouse model of sporadic AAD induced by high-fat diet and angiotensin II infusion, AIM2-deficient mice showed significant reduction in aortic dissection, but not aneurysm formation in all aortic segments, versus wild-type mice. Finally, treating cultured human aortic SMCs with double-stranded DNA induced AIM2 expression, caspase-1 cleavage, and gasdermin-D cleavage; these effects were reduced by silencing AIM2 and caspase-1 genes, suggesting involvement of the AIM2 inflammasome in cytosolic DNA-induced activation of SMC pyroptosis. Activation of the AIM2 inflammasome cascade contributes to aortic degeneration and dissection, in part, by activating pyroptosis.


Histologic assessment of mesh fixation following laser-assisted tissue soldering in a lapine model.
Wound histology and mesh bioincorporation following intraperitoneal fixation using laser-assisted soldering was evaluated. 2.8-3.2 kg NZW rabbits underwent laparotomy. Controls had 2x2 cm segments of Mersilene stapled to peritoneum. Group 2 segments were affixed with 55% collagen solder onlay by fiber-coupled diode laser (1.43 +/- 10 micro, 2.5 W CW, 4 mm spot, 60 degrees C set temperature). Group 4 had Mersilene inlaid into melted solder. Group 3 had solder-embedded Vicryl mesh affixed. Animals were euthanized at 0, 2, 4, 6 weeks. Fixed sections were assessed for integrity, inflammation, and fibrosis using H & E, Masson's Trichrome and Evans Van Gieson staining. Histology demonstrated cell types, local mesh reaction, and progressive evidence of solder reabsorption mimicking normal healing and bioincorporation. Mersilene groups demonstrated normal arrangement of collagen-rich layers around mesh. Collagen-based tissue soldering permits normal wound healing and may mitigate use of staples. Further development of this strategy is warranted.


A novel index of whole body antilipolytic insulin action.
Assessment of antilipolytic insulin action is important in obesity research, but extensive isotopic tracer studies are not always feasible. We evaluated whether an index of antilipolytic insulin action could be derived from readily available insulin and glycerol concentrations obtained during clamps or oral glucose tolerance tests (OGTT). We evaluated data collected from 29 subjects who had undergone a 3-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m(2)/min) with infusion of [(2) H5 ]glycerol to calculate the glycerol rate of appearance (GLYRA). Exponential decay curves for GLYRA across insulin concentrations were generated for each individual and suppression of lipolysis was calculated as the insulin concentration needed to half-maximally suppress GLYRA (GLYRA EC50). Areas under the curve for glycerol (GLYAUC) and insulin (INSAUC) were calculated and their products (INSAUC × GLYAUC) were calculated as an index of insulin suppression of lipolysis. The clamp index was highly correlated with GLYRA EC50 (r = 0.862, P < 0.001), as was an OGTT-derived index (r = 0.720, P < 0.01). These findings suggest that the products of the insulin and glycerol AUC from either a clamp or an OGTT are good biomarkers of the antilipolytic action of insulin and are comparable with direct measurement by isotopic tracer methods.


Ginsenoside Rb1 rescues anxiety-like responses in a rat model of post-traumatic stress disorder.
Single prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), induces alterations in the hypothalamic-pituitary-adrenal axis. Korean red ginseng, whose major active component is ginsenoside Rb1 (GRb1), is one of the widely used traditional anxiolytics. However, the efficacy of GRb1 in alleviating PTSD-associated anxiety-like abnormalities has not been investigated. The present study used several behavioral tests to examine the effects of GRb1 on symptoms of anxiety in rats after SPS exposure and on the central noradrenergic system. Male Sprague-Dawley rats received GRb1 (10 or 30 mg/kg, i.p., once daily) during 14 days of SPS. Daily GRb1 (30 mg/kg) administration significantly increased the number and duration of open-arm visits in the elevated plus maze (EPM) test, reduced the anxiety index, increased the risk assessment, reduced grooming behaviors in the EPM test, and increased the total number of line crossings of an open field after SPS. The higher dose of GRb1 also blocked SPS-induced decreases in hypothalamic neuropeptide Y expression, increases in locus coeruleus tyrosine hydroxylase expression, and decreases in hippocampal mRNA expression of brain-derived neurotrophic factor. These findings suggest that GRb1 has anxiolytic-like effects on both behavioral and biochemical symptoms similar to those observed in patients with PTSD.


[Nuchal translucency measurement--an effective method for early recognition of fetal disease?].
In recent years, an increasing amount of experience has been collected in measuring the nuchal translucency (NT) of the fetus in early pregnancy. While all fetuses develop a measurable collection of fluid in the area of the neck between the 11th and 14th weeks of pregnancy, the fact that fetuses with chromosomal disorders, cardiac defects, and syndromal diseases, in particular, reveal an above-average incidence of increased NT has been noticed. By processing our own patient data from the past two years, we intend to elucidate the question of whether NT measurement is a sensible investigation for the early detection of fetal problems. NT measurements were carried out in 199 fetuses; these measurements were standardized according to the guidelines of the Foetal Medicine Foundation in London, in whose multicentric study we are participating. The patients were under the care of our prenatal diagnosis and therapy department and were referred to us from external sources. NT within the reference range was determined in 152 fetuses; NT exceeded the reference value in 47 fetuses. Of those fetuses with increased NT, 7 fetuses revealed a chromosomal anomaly, 1 foetus was suffering from a cardiac defect, 3 fetuses were suffering from other organ abnormalities, and 3 fetuses were determined to be suffering from syndromal disease. None of the fetuses whose NT measurements were within the reference range was discovered to be suffering from any of the above-mentioned problems. Even this relatively small group of patients reveals that NT measurement is a very effective filter for detecting certain fetal diseases during the early fetal period.


Large-Area Two-Dimensional Plasmonic Meta-Glasses and Meta-Crystals: a Comparative Study.
The geometrical arrangement of metallic nanoparticles plays a crucial role on the optical response of nanoplasmonic samples due to particle-particle interactions. In this work, large-area, two-dimensional meta-glasses (random arrangements) and meta-crystals (periodic arrangements) made of identical metallic nanoparticles are investigated for three different particle densities of 5, 10, and 15 discs/μm2. A direct comparison between random and periodically ordered arrays is presented. The comparison clearly shows that the particle density has the largest influence on the extinction spectra for both periodic and random samples, and that for equal densities, the optical response away from diffraction effects is strikingly similar in both cases. The role of the radial density function and minimum particle distance is also determined. This study elucidates the role of the particle-particle interactions on the response of plasmonic nanoparticles and indicates how to control position and shape of the plasmonic resonance.


Sphincter-preserving operations following preoperative chemoradiation: an alternative to abdominoperineal resection for lower rectal cancer?
Sphincter-preserving operations (SPO) for lower rectal cancer are on the rise. In the study reported here, we compared the oncologic outcomes of patients who underwent sphincter-preserving operations following preoperative chemoradiation for lower rectal cancer with the outcome for patients who underwent abdominoperineal resection (APR). This prospective study included 87 patients who underwent proctectomy with curative intent for locally advanced rectal cancer that was located less than 6 cm from the anal verge. Forty-four patients had APR with no preoperative treatment. Forty-three patients underwent concurrent chemoradiation therapy (CCRT) consisting of preoperative 5-fluorouracil-based chemotherapy and pelvic radiation (4500-5040 cGy); this was followed 6 weeks later by surgery (SPO/CCRT). The oncologic outcomes between the two groups were compared, and factors affecting survival were evaluated. The median follow-up period was 56.2 months. The overall postoperative complication rates did not significantly differ between SPO/CCRT and APR (32.6% versus 34.2%; p = 0.879). Also, there were no significant differences in the overall recurrence rate (20.9% versus 20.5%; p = 0.956) and 5-year overall survival rate (70.8% versus 62.9%; p = 0.189) between the two groups. By multivariate analysis, only the pathologic N stage was significantly associated with overall survival (p < 0.001). Sphincter-preserving operation with CCRT could be another option for the treatment of locally advanced lower rectal cancer in patients who are clinically considered for APR, with no deterioration of oncologic outcomes. For patients undergoing curative resection for lower rectal cancer, the pathologic N stage can provide valuable prognostic information about survival.


Data for serum 1,5 anhydroglucitol concentration in different populations.
1,5 anhydroglucitol (1,5-AG), is a nonmetabolized 1-deoxy form of glucose, originate mainly from the diet. 1,5-AG is a biomarker to detect and magnify hyperglycemic excursions (postprandial hyperglycemia) in diabetic patients. Concentrations of 1,5-AG has been applied as supporting biomarker to diagnosis of the major forms of diabetes (type 1, type 2, and gestational). The serum 1,5-AG reference interval is relevant to the appropriate clinical application of this biomarker. This article contains data regards to serum concentration of the biomarker primarily for healthy subjects, capture from the literature, in different populations. Correlation analysis between 1,5-AG and markers associated with diabetes and its complication were presented. The data was complementary to the study "Reference intervals for serum 1,5-anhydroglucitol in children, adolescents, adults, and pregnant women" (Welter et al., 2018). The data present in this article improve the comparisons for 1,5-AG in different conditions and methodologies.


Stabilization of a steerable sheath during retrograde access to antegrade-oriented branches in complex endovascular aortic aneurysm repair.
During branched endovascular aneurysm repair, cannulation of the visceral target vessels through antegrade branches and insertion of bridging stents are frequently done from an upper extremity access. A retrograde femoral approach is a challenging alternative when an antegrade approach is not preferred. Herein, we describe a technique to increase stability of a steerable sheath, using a single suture, for bridging antegrade-facing branches from a retrograde access. This technique secures the sheath's deflected tip and provides more pushability to the steerable sheath.


Linking transcriptional dynamics of CH4-cycling grassland soil microbiomes to seasonal gas fluxes.
Soil CH4 fluxes are driven by CH4-producing and -consuming microorganisms that determine whether soils are sources or sinks of this potent greenhouse gas. To date, a comprehensive understanding of underlying microbiome dynamics has rarely been obtained in situ. Using quantitative metatranscriptomics, we aimed to link CH4-cycling microbiomes to net surface CH4 fluxes throughout a year in two grassland soils. CH4 fluxes were highly dynamic: both soils were net CH4 sources in autumn and winter and sinks in spring and summer, respectively. Correspondingly, methanogen mRNA abundances per gram soil correlated well with CH4 fluxes. Methanotroph to methanogen mRNA ratios were higher in spring and summer, when the soils acted as net CH4 sinks. CH4 uptake was associated with an increased proportion of USCα and γ pmoA and pmoA2 transcripts. We assume that methanogen transcript abundance may be useful to approximate changes in net surface CH4 emissions from grassland soils. High methanotroph to methanogen ratios would indicate CH4 sink properties. Our study links for the first time the seasonal transcriptional dynamics of CH4-cycling soil microbiomes to gas fluxes in situ. It suggests mRNA transcript abundances as promising indicators of dynamic ecosystem-level processes.


An investigation on the mediating role of coping strategies on locus of control-- wellbeing relationship.
The relationship among coping strategies, locus of control, and workplace wellbeing is examined. The model hypothesizes that coping strategies mediate the relationship between locus of control and work place well being. To test the model, data was collected from 154 software professionals using separate tools to assess coping strategies, locus of control and work place wellbeing. Model fit for the collected data was examined using structural equation modeling technique with the help of AMOS. Results support the view that coping strategies mediate the relationship between locus of control and work place wellbeing. While the path between locus of control and wellbeing is significant, the path between coping distraction and wellbeing is not significant.


Predicting human behavior toward members of different social groups.
Disparities in outcomes across social groups pervade human societies and are of central interest to the social sciences. How people treat others is known to depend on a multitude of factors (e.g., others' gender, ethnicity, appearance) even when these should be irrelevant. However, despite substantial progress, much remains unknown regarding (i) the set of mechanisms shaping people's behavior toward members of different social groups and (ii) the extent to which these mechanisms can explain the structure of existing societal disparities. Here, we show in a set of experiments the important interplay between social perception and social valuation processes in explaining how people treat members of different social groups. Building on the idea that stereotypes can be organized onto basic, underlying dimensions, we first found using laboratory economic games that quantitative variation in stereotypes about different groups' warmth and competence translated meaningfully into resource allocation behavior toward those groups. Computational modeling further revealed that these effects operated via the interaction of social perception and social valuation processes, with warmth and competence exerting diverging effects on participants' preferences for equitable distributions of resources. This framework successfully predicted behavior toward members of a diverse set of social groups across samples and successfully generalized to predict societal disparities documented in labor and education settings with substantial precision and accuracy. Together, these results highlight a common set of mechanisms linking social group information to social treatment and show how preexisting, societally shared assumptions about different social groups can produce and reinforce societal disparities.


An animal model for studying cone function in retinal detachment.
In people, retinal detachment often leads to a significant loss in cone-based vision. Most of the animal models commonly used for studying the consequences of retinal detachment have rod-dominated retinas. The purpose of this investigation was to evaluate the possibility that the ground squirrel, a rodent with a heavily cone-dominated retina, might provide a useful model for studying cone function in retinal detachment. Corneal ERGs were recorded from ground squirrels for large-field temporal modulations presented on a computer-controlled color monitor. Modulations were chosen to selectively stimulate either of the two classes of cone found in the ground squirrel retina. Under these test conditions, large and reliable cone ERGs could be readily recorded. In animals in which the retina had been surgically detached, the loss of cone signal was directly related to the number of cones in the detachment zone relative to the total cone population and that relationship did not differ for short-wavelength sensitive (S) and middle-wavelength sensitive (M) cones. Surgical reattachment produced a progressive recovery of cone-based signals. The ground squirrel seems likely to provide a useful animal model for studying the dynamics of cone function in retinal detachment and subsequent events.


Blockchain knowledge selection under the trapezoidal fermatean fuzzy number.
Blockchain knowledge signifies a useful fundamental knowledge to safeguard faith in transboundary transmittals for main banks and financial institutions. In the study of group decision-making, the most important issue is how to coordinate opinions from different blockchains to reach a compromise under uncertainty. To tackle uncertainties surrounding multi-attribute group decision-making (MAGDM) problems in real-life scenes, we introduce a trapezoidal fermatean fuzzy set which generalizes trapezoidal fuzzy sets and fermatean fuzzy sets. The trapezoidal fermatean fuzzy model enables the degrees of membership, abstention, and non-membership to be expressed by linguistic terms. We define the operational laws of trapezoidal fermatean fuzzy numbers, and Einstein aggregation operator based on the trapezoidal fermatean fuzzy number. This makes it more flexible and descriptive to model the attitudes of Blockchain knowledge in MAGDM applications. Since multi-input arguments are interconnected and Blockchain knowledge has a lot of options perception, we also define the TOPSIS technique to facilitate the fusion of trapezoidal fermatean fuzzy information. With the aid of the trapezoidal fermatean fuzzy-TOPSIS technique, the main goal of this research is to present a general MAGDM framework by integrating the step with the complex proportional assessment. A trapezoidal fermatean positive ideal solution always wants the maximum value of the benefit criteria and the minimum value of the cost criteria. On the other hand, the trapezoidal fermatean negative ideal solution always wants the maximum value of the cost criteria and the minimum value of the benefit criteria. An integrated trapezoidal fermatean fuzzy-TOPSIS framework is established. In the proposed decision framework, the trapezoidal fermatean fuzzy-TOPSIS method is utilized to identify the subjective weights of decision attributes, and the trapezoidal fermatean fuzzy-TOPSIS approach is used to rank alternatives. Lastly, a case study concerning blockchain knowledge assessment is presented to demonstrate that the suggested scheme is feasible and effective. Furthermore, sensitivity and comparison analyses are conducted to show the robustness and superiority of the proposed method.


Immature granulocytes index as early marker of sepsis.
Sepsis induces the recruitment of immature neutrophils into the circulation. An immature granulocyte percentage (IG%) count greater than 3% has been shown to be an indicator for the risk of sepsis. The aim of this study was to evaluate the IG% as predictor of sepsis compared to blood culture results and sepsis diagnostic confirmation. The study included individuals (n = 301) of both sexes aged ≥18 years who underwent Hospital São Lucas examinations between January and November 2017. For all the patients, IG%, as well as blood culture results, were evaluated. All examinations were obtained from Clinical Laboratory database. Data were analyzed through the SPSS program version 18.0. There was statistical association between blood culture and IG% results (P = 0.009) and between sepsis confirmation and IG% on Pearson chi-square test (P < 0.001). An IG% cutoff point of 2.0% was able to exclude sepsis based on clinical diagnosis with a specificity of 90.9% and a sensitivity of 38.5%. The cutoff value in ROC analyses of IG% based on blood culture results was 0.3% and 0.4% based on clinical diagnosis. Our study demonstrated that IG% <2.0% are helpful on the exclusion of sepsis diagnosis with a very high specificity (90.9%). The IG% is a useful additional marker for sepsis diagnosis allowing the early initiation of therapy and better possibilities of recovery.


What does evolutionary theory add to stereotype theory in the explanation of attractiveness bias?
Maestripieri et al. seem to put forth an argument in which they become vulnerable to some of the same criticisms that they level against stereotype theory As a result, the explanatory utility of their account of attractiveness bias comes into question, and it is unclear whether it offers anything superior to stereotype theory in conceptual soundness.


Parathyroid hormone (hPTH 1-38) stimulates the expression of UBP41, an ubiquitin-specific protease, in bone.
Parathyroid hormone (PTH) stimulates bone formation in both animals and humans, and the expression of a number of genes has been implicated in the mediation of this effect. To discover new bone factors that initiate and support this phenomenon, we used differential display reverse transcription polymerase chain reaction (DDRT-PCR) and screened for genes, which are differentially expressed in osteoblast-enriched femoral metaphyseal primary spongiosa of young male rats after a single subcutaneous (s.c.) injection of hPTH (1-38) (8 microg/100 g). We found and cloned one full-length cDNA, which encodes a putative 348 amino acid protein. Sequence analysis of this protein demonstrates a 98, 93.7, and 82.5% identity with mouse, human, and chicken ubiquitin-specific protease UBP41, respectively. Northern blot analysis confirmed that a 3.8-4 kb UBP41 mRNA transcript was rapidly increased 1 h after acute hPTH (1-38) exposure in both metaphyseal (6- to 8-fold) and diaphyseal (3-fold) bone, but returned to control levels by 24 h after exposure. In contrast, continuous exposure to hPTH (1-38), resulted in a rapid and sustained elevation of UBP41 mRNA. PTH (1-31), which stimulates intracellular cAMP, and PTHrP (1-34) both induced UBP41 mRNA expression; whereas PTH analogs (3-34) and (7-34), that do not stimulate cAMP, had no effect on UBP41 expression. UBP41 mRNA expression was also rapidly induced 1 h after injection of PGE2, but returned to the control level by 6 to 24 h. In vitro, UBP41 mRNA is expressed in primary osteoblasts (metaphyseal and diaphyseal derived) and in the osteoblast-like cell lines UMR106, ROS17/2.8, and BALC. PTH (1-38) treatment induced UPB41 expression (3.6- to 13-fold) in both primary cultures of osteoblasts and in UMR106 cells. Further analysis in UMR 106 cells demonstrated that PGE2, forskolin and dibutyryl cAMP increased UBP41 mRNA expression 4-, 4.5-, and 2.4-fold, respectively. Tissue distribution analysis of UBP41 mRNA detected transcripts in brain, heart, skeletal muscle, kidney, liver, and testis. Together, these results demonstrate that UBP41, an ubiquitin-specific protease, is selectively upregulated in bone by the osteotropic agents PTH, PTHrP, and PGE2, possibly via the PKA/cAMP pathway. We speculate that the rapid induction of UBP41 in response to these physiological regulators contributes to the mechanism by which either the structure, activity, half-life or localization of essential proteins are modified to maintain bone homeostasis.


The proteasome: a novel target for cancer chemotherapy.
The ubiquitin-proteasome system is an important regulator of cell growth and apoptosis. The potential of specific proteasome inhibitors to act as novel anti-cancer agents is currently under intensive investigation. Several proteasome inhibitors exert anti-tumour activity in vivo and potently induce apoptosis in tumour cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-kappaB transcriptional activity, proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis. Proteasome inhibitors also exhibit some level of selective cytotoxicity to cancer cells by preferentially inducing apoptosis in proliferating or transformed cells or by overcoming deficiencies in growth-inhibitory or pro-apoptotic molecules. High expression of oncogene products like c-Myc also makes cancer cells more susceptible to proteasome inhibitor-induced apoptosis. The induction of apoptosis by proteasome inhibitors varies between cell types but often occurs following an initial accumulation of short-lived proteins such as p53, p27, pro-apoptotic Bcl-2 family members or activation of the stress kinase JNK. These initial events often result in a perturbation of mitochondria with concomitant release of cytochrome c and activation of the Apaf-1 containing apoptosome complex. This results in activation of the apical caspase-9 followed by activation of effector caspases-3 and -7, which are responsible for the biochemical and morphological changes associated with apoptosis.


Rolling circle amplification (RCA)-based DNA hydrogel.
DNA hydrogels have unique properties, including sequence programmability, precise molecular recognition, stimuli-responsiveness, biocompatibility and biodegradability, that have enabled their use in diverse applications ranging from material science to biomedicine. Here, we describe a rolling circle amplification (RCA)-based synthesis of 3D DNA hydrogels with rationally programmed sequences and tunable physical, chemical and biological properties. RCA is a simple and highly efficient isothermal enzymatic amplification strategy to synthesize ultralong single-stranded DNA that benefits from mild reaction conditions, and stability and efficiency in complex biological environments. Other available methods for synthesis of DNA hydrogels include hybridization chain reactions, which need a large amount of hairpin strands to produce DNA chains, and PCR, which requires temperature cycling. In contrast, the RCA process is conducted at a constant temperature and requires a small amount of circular DNA template. In this protocol, the polymerase phi29 catalyzes the elongation and displacement of DNA chains to amplify DNA, which subsequently forms a 3D hydrogel network via various cross-linking strategies, including entanglement of DNA chains, multi-primed chain amplification, hybridization between DNA chains, and hybridization with functional moieties. We also describe how to use the protocol for isolation of bone marrow mesenchymal stem cells and cell delivery. The whole protocol takes ~2 d to complete, including hydrogel synthesis and applications in cell isolation and cell delivery.


[Preventive bone mineral density measurement in postmenopausal women. Differentiation of treatment of recommendations Guidelines of the Umbrella Organization for Osteology ("Dachverband Osteologie")].
Osteopenia (OP) or osteoporosis (OST) was diagnosed by bone densitometry (DXA) in postmenopausal women free of known skeletal disorders and without acute fracture. DVO guidelines were applied to define therapeutic indication. The study included 94 women aged 59-81 years. Fracture or operation ≤12 months, malignant tumor, ovariectomy, and drugs such as cortisone, strontium, fluorides, bisphosphonates, SERMs, estrogens, and steroids were exclusion criteria. The lowest T-score at the spine, femoral neck, or total hip was decisive. The indication for therapy was determined by evaluating age, BMD, and other risk factors. Using the WHO criteria 22.3% (n=21) had normal BMD, 52.1% (n=49) had OP, and 25.6% (n=24) had OST. According to "Dachverband Osteologie" (DVO) guidelines, 28 women (29.8%) of the whole group needed therapy. Of the 28 women receiving therapy, 9 had OP and 19 had OST. Therapy was indicated in 18.4% for OP and 79.2% for OST. A preventive measurement of BMD with DXA provides a benefit for postmenopausal women. Combinatory assessment and consideration of other risk factors allows identification of women who might benefit from early treatment.


Single-incision cochlear implantation and hearing evaluation in piglets and minipigs.
Various animal models have been established and applied in hearing research. In the exploration of novel cochlear implant developments, mainly rodents have been used. Despite their important contribution to the understanding of auditory function, translation of experimental observations from rodents to humans is limited due to the size differences and genetic variability. Large animal models with better representation of the human cochlea are sparse. For this reason, we evaluated domestic piglets and Aachen minipigs for the suitability as a cochlear implantation animal model with commercially available cochlear implants. Four domestic piglets (two male and two female) and six Aachen minipigs were implanted with either MED-EL Flex24 or Flex20 cochlear implants respectively, after a step-by-step surgical approach was trained with pig cadavers. Electrophysiological measurements were performed before, during and after implantation for as long as 56 days after surgery. Auditory brainstem responses, electrocochleography as well as electrically and acoustically evoked compound action potentials were recorded. Selected cochleae were further analyzed histologically or with micro-CT imaging. A surgical approach was established using a retroauricular single incision. Baseline auditory thresholds were 27 ± 3 dB sound pressure level (SPL; auditory brainstem click responses, mean ± standard error of the mean) and ranged between 30 and 80 dB SPL in frequency-specific responses (0.5 - 32 kHz). Follow-up measurements revealed deafness within the first two weeks after surgery, but some animals partially recovered to a hearing threshold of 80 dB SPL in certain frequencies as well as in click responses. Electrically evoked compound action potential thresholds increased within the first week after surgery, which led to lower stimulation responses or increase of necessary charge input. Immune reactions and consecutive scalar fibrosis following implantation were confirmed with histological analysis of implanted cochleae and may result in increased impedances. A three-dimensional minipig micro-CT segmentation revealed cochlear volumetric data similar to human inner ear dimensions. This study underlines the feasibility of cochlear implantation with clinically used cochlear implants in a large animal model with representative inner ear dimensions comparable to humans. To bridge the gap between small animal models and humans in translational research and to account for the structural and size differences, we recommend the minipig as a valuable animal model for hearing research. First insights into the induced trauma in minipigs after cochlear implant surgery and a partial hearing recovery present important data of the cochlear health changes in large animal cochleae.


Commentary on the Current Guidelines for the Diagnosis of Lupus Nephritis Flare.
Lupus nephritis flare is a frequent complication in patients with systemic lupus erythematosus. Recognizing disease activity is crucial in lupus nephritis management. Proteinuria magnitude and urine sediment change are major clinical indicators of lupus nephritis activity. This work updates these insights in light of recent findings regarding proteinuria quantification and urine sediment analyses. Currently, BILAG and SLEDAI estimate proteinuria magnitude based on the protein/creatinine ratio of "spot" (single void collections) or "intended" 24-h urine collections without specifying the extent to which the collection approaches a 24-h collection. As discussed here, and based on our recently published work, these approaches often incur serious errors that can adversely affect SLE patient management. Also incorporated into this work is a new analysis of the clinical significance of urine sediment hematuria and pyuria changes with regard to recent-onset SLE glomerulonephritis (GN) flare. This analysis is based on a prospective study of urine sediment changes in the Ohio SLE Study, which was an NIH-sponsored prospective observational study of SLE GN patients with SLE flare of recent onset. We propose that BILAG and SLEDAI renal flare criteria can be made more rigorous by incorporating recently published insights into proteinuria quantification using the protein/creatinine ratio of an intended 24-h urine collection that is at least 50% complete based on its creatinine content. Also proposed are new insights into the interpretation of urine sediment hematuria and pyuria based on findings from the Ohio SLE Study.


Disclosure of sexual orientation by medical students and residency applicants.
The authors report on sexual orientation disclosure issues considered by lesbian, gay, and bisexual students and physicians during their medical school and residency selection process.


Extracellular Signal-Regulated Kinase 5 in the Cerebrospinal Fluid-Contacting Nucleus Contributes to Neuropathic Pain in Rats.
The activation of mitogen-activated protein kinases (MAPKs) have been observed in synaptic plasticity processes of learning and memory in neuropathic pain. Cerebrospinal fluid-contacting nucleus (CSF-CN) has been identified with the onset and persistence of neuropathic pain. However, whether extracellular signal-regulated protein kinase 5 (ERK5), a member of MAPKs, in CSF-CN participates in neuropathic pain has not been studied yet. The aim of the present study was to identify the role of ERK5 in CSF-CN on the formation and development of neuropathic pain, and to investigate its possible mechanism. Controlled animal study. University laboratory. After a chronic constriction injury (CCI) model was produced, BIX02188 was dissolved in 1% DMSO and injected into the lateral ventricles LV in a volume of 3 μl with different doses (0.1 μg, 1 μg, 10 μg). Mechanical allodynia and thermal hypersensitivity behavioral test, immunofluorescence, and western blot technique were used in this research. Following CCI, mechanical allodynia and thermal hypersensitivity were developed within a day, peaked at 14 days, and persisted for 21 days. ERK5 was remarkably activated by CCI in CSF-CN. Moreover, selective inhibiting of p-ERK5 expression in CSF-CN by BIX02188 could significantly relieve CCI-induced mechanical allodynia and thermal hypersensitivity, accompanying with the decreased phosphorylation of cAMP response-element binding protein (CREB) in CSF-CN. More underlying mechanism(s) of the role of ERK5 in CSF-CN on the formation and development of neuropathic pain will be needed to explore in future research. These findings suggest activation of ERK5 in CSF-CN might contribute to the onset and development of neuropathic pain and its role might be partly accomplished by p-CREB.


Relationship between meconium staining and amniotic fluid volume in term pregnancies.
Our purpose was to evaluate the relationship between meconium-stained amniotic fluid (MEC-AF) and amniotic fluid volume (AFV) and their impact on the risk of cesarean delivery for fetal indications in term pregnancies. 1,655 live-born singleton gestations delivering at > or = 37 weeks within 7 days of sonographic assessment of the amniotic fluid index (AFI) were studied. AFI was categorized as: oligohydramnios (< or = 5.0 cm); decreased (5.1-8.0 cm); normal (8.1-18.0 cm); increased (18.1-23.9 cm), and polyhydramnios (> or = 24.0 cm). Frequencies of MEC-AF for each AFV category were stratified by gestational age (GA) and rates of cesarean delivery for fetal indications compared between patients with clear amniotic fluid and those with MEC-AF. Stepwise logistic regression analyses were performed for determinants of MEC-AF and the need for cesarean delivery for fetal indications. The frequency of MEC-AF at birth in term pregnancies was not related to AFV: oligohydramnios (16.7%); decreased (16.7%); normal (20.1%); increased (24.4%), and polyhydramnios (22.1%). The only factor associated with the occurrence of MEC-AF was increasing GA at delivery (p < 0.01). Both MEC-AF (p < 0.02) and decreasing neonatal ponderal index (p < 0.02) were independently associated with cesarean delivery for fetal distress. MEC-AF does not appear to be related to AFV in term pregnancies, and its presence increases the risk of cesarean delivery for fetal distress independent of AFV and neonatal ponderal index.


Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells.
RBP-J is a key mediator of Notch signaling that regulates cell fate determination in various lineages. To investigate the function of Notch-RBP-J in mature B cell differentiation, we generated mice that selectively lacked B cell RBP-J expression using conditional mutagenesis. Absence of RBP-J led to the loss of marginal zone B (MZB) cells with a concomitant increase in follicular B cells; in contrast, B1 cells in the peritoneal cavity were unaffected. Lack of RBP-J caused no defects in B cells maintenance, survival, plasma cell differentiation or activation. It is therefore likely that Notch-RBP-J signaling regulates the lineage commitment of mature B cells into follicular versus MZB cells. In addition, in mice with RBP-J-deficient B cells, had no obvious changes in immunoglobulin production in response to Ficoll, lipopolysaccharide or chicken gammaglobulin. In contrast, these mice exhibited increased mortality rates after blood-borne bacterial infection, which indicates that MZB cells play pivotal roles in the clearance of these bacteria.


Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heart.
Compared with younger patients, myocardial infarction in the elderly has been associated with less favorable clinical outcomes, which may be attributable to a decline in angiogenic capacity in the aging heart. To test the hypothesis that the functional phenotype of cardiac microvascular endothelial cells is maintained partly by a cardiac myocyte platelet-derived growth factor (PDGF)-B-induced paracrine pathway, we conducted in vitro studies with murine cardiac cells. These studies demonstrated that unlike young endothelial cells, endothelial cells of the aging heart do not express PDGF-B when cultured in the presence of cardiac myocytes. The functional significance of this endothelial dysregulation was assessed with an ex vivo pinnal cardiac allograft model to demonstrate that senescent cardiac angiogenic activity was depressed (2 of 17 allografts were viable in 18-month-old mice versus 19 of 20 in 3-month-old mice; P<0.01). PDGF-AB pretreatment specifically restored the viability of the cardiac allografts in the aging hosts (13 of 13 allografts were viable; P<0.01 versus 18-month-old controls). Finally, in vivo studies in rat hearts demonstrated that pretreatment by intramyocardial delivery of PDGF-AB promotes angiogenesis and minimizes the extent of myocardial infarction in the aging hearts after coronary ligation (myocardial infarction size: 10.0 +/- 7.0% of left ventricular area in PDGF pretreatment [n=7] versus 17.6 +/- 5.6% in control [n=5] groups; P<0.03). Aging hearts have impaired angiogenic function as a result of depressed PDGF-B production. Restoration of the dysregulated endothelial PDGF-mediated angiogenic pathway in the aging heart reverses the senescent impairment in cardioprotective angiogenic function and offers a foundation for developing novel therapies for cardiovascular disease in older individuals.


Challenges in the Multivariate Analysis of Mass Cytometry Data: The Effect of Randomization.
Cytometry by time-of-flight (CyTOF) has emerged as a high-throughput single cell technology able to provide large samples of protein readouts. Already, there exists a large pool of advanced high-dimensional analysis algorithms that explore the observed heterogeneous distributions making intriguing biological inferences. A fact largely overlooked by these methods, however, is the effect of the established data preprocessing pipeline to the distributions of the measured quantities. In this article, we focus on randomization, a transformation used for improving data visualization, which can negatively affect multivariate data analysis methods such as dimensionality reduction, clustering, and network reconstruction algorithms. Our results indicate that randomization should be used only for visualization purposes, but not in conjunction with high-dimensional analytical tools. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.


Total transcriptome analysis of Candida auris planktonic cells exposed to tyrosol.
Tyrosol, a secondary metabolite of Candida species, regulates fungal morphogenesis, and its application may represent a novel innovative therapy against emerging multi-resistant fungal superbug such as Candida auris. In the current study, the effects of tyrosol on growth, redox homeostasis, intracellular microelement contents and activities of virulence-related enzymes released by C. auris were examined. To gain further information about the effect of tyrosol exposure, we revealed gene transcriptional changes using total transcriptome sequencing (RNA-Seq). At a concentration of 15 mM, tyrosol significantly decrease the growth of fungal cells within 2 h of its addition (5.6 × 107±1.2 × 107 and 2.5 × 107±0.6 × 107 colony forming unit/mL for control and tyrosol-treated cells, respectively). Furthermore, it enhanced the release of reactive oxygen species as confirmed by a dichlorofluorescein (DCF) assay (7.3 ± 1.8 [nmol DCF (OD640)-1] versus 16.8 ± 3.9 [nmol DCF (OD640)-1]), which was coincided with elevated superoxide dismutase, catalase and glutathione peroxidase activities. Tyrosol exerted in a 37%, 25%, 34% and 55% decrease in intracellular manganese, iron, zinc and copper contents, respectively, compared to control cells. The tyrosol treatment led to a 142 and 108 differentially transcripted genes with at least a 1.5-fold increase or decrease in transcription, respectively. Genes related to iron and fatty acid metabolism as well as nucleic acid synthesis were down-regulated, whereas those related to the antioxidative defence, adhesion and oxoacid metabolic processes were up-regulated. This study shows that tyrosol significantly influences growth, intracellular physiological processes and gene transcription in C. auris, which could highly support the development of novel treatment approaches against this important pathogen.


Radiation enhancement of radiolabelled antibody deposition in tumors.
Recent clinical observations led to the use of external radiation to increase tumor targeting by radiolabelled 131-I antiferritin. Examination of increased uptake of 131-I labelled antiferritin following external radiation was carried out in syngeneic implanted hepatomas (H4IIE, 3924A, 7800, and 7777). Exposure to 10 Gy increased the tumor: liver uptake ratio from 1.55 to 1.86 for H4IIE; from 1.56 to 2.0 for 7800; from 1.34 to 1.97 for 7777; and from 1.05 to 1.19 for 3924A. The pattern of uptake varied among the different tumor types, reflecting their inherent differences in vascularity, tumor permeability, antigen density and growth rate, all of which influence antibody targeting of the tumors. When tumor and liver were irradiated, the tumor showed increased differential uptake of labelled antibody compared to normal liver. 51-Cr labelled erythrocytes were used to study the relative vascularity and blood pooling in H4IIE hepatoma and normal tissue. External radiation to the tumor did not increase the uptake of 51-Cr labelled erythrocytes in any site. These studies provide an insight into the role of external radiation as a modality that increases radiolabelled antibody targeting in hepatoma.


A dynamic block-randomization algorithm for group-randomized clinical trials when the composition of blocking factors is not known in advance.
We present an algorithm for randomizing units in blocks for controlled trials when the composition of blocking factors is not known in advance. For example, suppose the desired goal of an intervention study is to randomize units to one of two interventions while blocking on a dichotomous factor (e.g., gender), but the total number of units, and therefore number or composition, of males and females among those units assembled for randomization cannot be determined in advance. This situation arises in randomized trials when subjects are scheduled to be randomized as a group, but not all of the subjects show up for the visit. Since investigators do not know which of the scheduled subjects will or will not show up, a dynamic randomization scheme is required to accommodate the unknown composition of the blocking factor once a group of subjects (units) is assembled for randomization. These settings are further complicated when there is more than one blocking factor. In this paper, we present an algorithm that ensures the integrity of the randomization process in these settings.


Evaluation of workers exposed to elemental mercury using quantitative tests of tremor and neuromuscular functions.
Workers exposed to metallic mercury vapor were subjects for tremor, EMG, and psychomotor tests. Regression analysis revealed statistically significant trends in these test results related to workers' urine mercury histories. Effects were subclinical, functionally insignificant and most associated with those workers whose urine mercury had exceeded 0.5 mg/L in the previous year. In agreement with previous reports, effects were reversible upon reduction of mercury exposure.


The liver and right atrium-hepatic cyst as a cause of arrhythmia.
Simple hepatic cysts are a relatively common radiological finding. These cysts may be classified as parasitic and non-parasitic. They are usually asymptomatic, but may cause symptoms due to local compression. These compressive complications include: portal hypertension, edema due to caval compression, extrinsic gastric compression and duodenal compression with obstruction.However, no reports in the literature exist describing atrial compression by hepatic cysts.In this case report a simple hepatic cyst causing slight right atrial compression is described. This slight compression is the cause of atrial premature beats.It is proposed that simple hepatic cysts may be the cause of atrial premature beats.


Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study.
DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs; composite endpoint of painful crisis or acute chest syndrome (ACS, Beijing, China)), serious adverse events (SAEs, Florence, Italy), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA). Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA; reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics; approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions. Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting.


H-ras dependent estrogenic effects of epidermal growth factor in the estrogen-independent breast cancer cell line MDA-MB-231.
A crosstalk between cellular estrogen response and receptor tyrosine kinase signaling has been shown in a variety of estrogen receptor (ER)-positive cell lines. We intended to examine the presence of estrogenic growth factor effects in an ER alpha-negative breast cancer cell line. By means of reporter gene assays, we investigated the activation of estrogen response elements (EREs) by epidermal growth factor (EGF) in the estrogen-unresponsive cell line MDA-MB-231. Our results demonstrate the H-ras-dependent activation of EREs after EGF treatment in this estrogen-unresponsive cell line, an effect which was not observed in the ERalpha/beta-positive breast cancer cell line MCF-7. In MDA-MB-231 cells, the transcriptional activity of an ERE-containing promotor was enhanced dose dependently by all tested EGF concentrations. This effect could be blocked by co-treatment with the epidermal growth factor receptor (EGFR) inhibitors AG1478 and ZD1839, as well as by co-transfection with a vector coding for a dominant negative H-ras mutant, but not by co-treatment with the pure antiestrogen ICI182,780. Furthermore, expression of constitutively active H-ras was shown to be sufficient to activate EREs in MDA-MB-231 cells. Our results suggest alternative utilization of ERE-mediated gene regulation in an estradiol-unresponsive breast cancer cell line in response to an EGF stimulus. This mechanism was shown to be dependent on EGFR and H-ras activity, but independent of the presence of functional ERalpha.


Superelastic Multifunctional Aminosilane-Crosslinked Graphene Aerogels for High Thermal Insulation, Three-Component Separation, and Strain/Pressure-Sensing Arrays.
Aerogels have attracted great interest for their unique properties, but their mechanical brittleness and poor functionality highly limit their practical applications. Herein, we report unprecedented superelastic multifunctional aminosilane-crosslinked reduced graphene oxide (AC-rGO) aerogels that are prepared via a facile and scalable strategy involving simultaneous crosslinking and reducing of graphene oxide nanosheets with different kinds of aminosilanes via C-N coupling and hydrolytic polycondensation reactions. It is found that 3-aminopropyl(diethoxy)methylsilane (APDEMS) is the better choice to enhance hydrophobicity, elasticity, and other properties of the resulting aerogels compared with (3-aminopropyl)triethoxysilane. One APDEMS molecule plays three roles as a crosslinker, a reductant, and a hydrophobizing agent. An outstanding combination of high surface area, ultralow density, superhydrophobicity, supercompressibility, superelasticity, low thermal conductivity, ultrahigh absorption capacity for organic liquids, efficient three-component separation, and strain/pressure sensing has been achieved in a single APDEMS-crosslinked rGO aerogel for the first time. In addition, a flexible, highly sensitive, and moisture-resistant AC-rGO aerogel-based strain/pressure-sensing array for the effective detection of strain (0-80%)/pressure (10 Pa to 10 kPa) distributions and object shapes has been demonstrated.


Assessing reliability and validity of the Chinese version of the stroke scale: scale development.
The National Institutes of Health Stroke Scale (NIHSS) is a systematic, 15-point evaluation tool, designed to assess neurological deficit in acute stroke patients and written in English. It is used to support important medical and nursing decisions. To translate the NIHSS into Chinese and establish its psychometric properties using Chinese evaluators. Methodological research design. One medical centre. Using convenience sampling, 48 subjects admitted with acute ischemic stroke were selected. In this study, six clinicians from the Department of Neurology (3 nurses, 3 doctors) assessed the 48 patients using the C-NIHSS, the Glasgow Coma Scale and the Barthel index. The C-NIHSS content validity index reached 1.00, and the Cronbach's alpha coefficient for internal consistency was 0.92. Of the 15 scale items, two (facial palsy and limb ataxia) had low inter-rater values (k values below 0.39). Kappa (kappa) values were substantial (over 0.60) for all other items. The C-NIHSS has a significantly negative correlation with both Glasgow Coma Scale (r = -0.824, p < 0.01), and Barthel index (r = -0.683, p < 0.01) scores. The C-NIHSS is a reliable and valid scale for the clinical assessment of neurological deficit in acute stroke patients.


The role of calcium in macrophage chemotaxis to the phorbol ester tumor promoter TPA.
The significance of the macrophage in the inflammatory response that occurs concurrently with phorbol ester induced tumor promotion has not yet been determined. Biologically active phorbol ester tumor promoters modify several functional responses of macrophages including chemotaxis, cytotoxicity, secretion and prostaglandin synthesis and release. The present study examines calcium metabolism as a possible underlying biochemical mechanism through which 12-0-tetradecanoyl-phorbol-13-acetate (TPA) exerts its effects on macrophage chemotaxis. The chemotaxis of mouse resident peritoneal macrophages was evaluated in the presence of pharmacological agents known to alter cellular calcium metabolism. The calcium ionophore A23187 in microM concentrations enhanced macrophage chemotaxis to TPA by approximately 41%. This enhancement was dependent on the presence of extracellular calcium. TPA-induced chemotaxis was also enhanced by the histological dye ruthenium red (RR), an agent known to modify mitochondrial calcium fluxes and calcium-dependent neuronal transmission. Ruthenium red (0.1 and 1.0 microM) produced a maximal stimulation of macrophage chemotaxis to TPA of approximately 62%. An intracellular calcium antagonist, 8-(N,N-diethylamino) octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) inhibited macrophage chemotaxis to TPA in a dose related fashion (1.0 to 100 microM). Varying extracellular calcium concentrations (0-3.6 mM) had no effect on macrophage chemotaxis in response to TPA. In drug combination studies neither A23187 nor RR was able to overcome the inhibitory effects of TMB-8 on macrophage chemotaxis to TPA. These results indicate that intracellular calcium metabolism may be playing a significant role in modulating TPA's effect on macrophage chemotaxis, while extracellular calcium may be of little import. A possible mode of TPA's effect on the macrophage via mobilization of calcium from cellular storage sites is discussed.


DNA methylating and demethylating treatments modify phenotype and cell wall differentiation state in sugarbeet cell lines.
In plants organogenesis, cell differentiation and dedifferentiation are fundamental processes allowing high developmental plasticity. Such plasticity involved epigenetic mechanisms but limited knowledge is available concerning quantitative aspects. Three sugarbeet (Beta vulgaris L. altissima) cell lines originating from the same mother plant and exhibiting graduate states of morphogenesis were used to assess whether these differences could be related or not to changes in DNA methylation levels. Methylcytosine percentages from 18.3 to 28.8% and distinct levels of DNA methyltransferase (EC 22.214.171.124) activities were shown in the three cell lines. The lowest methylcytosine percentage was associated to organogenesis. In order to test the plasticity of these cell lines, various treatments causing DNA hypo or hypermethylation were performed at different times and concentrations. In this collection of treated lines with+/-10% of methylcytosine percentages, loss of organogenic properties and cell dedifferentiation were observed. As cell wall formation fits well with cell differentiation state, the lignification process was further investigated in treated and untreated lines as a biochemical marker of the phenotypic changes. For example, peroxidase specific activities (EC 188.8.131.52) varied from 0.7 to 0.02 pkat mg(-1) of protein in organogenic and dedifferentiated lines, respectively. A negative relationship between peroxidase activities, incorporation of cell wall-bound phenolic compounds as ferulate and sinapate derivatives and methylcytosine percentages was obtained. This is the first biochemical evidence that phenotypic changes in plant cells induced by DNA hypo- or hypermethylating treatments are correlated in a linear relationship to modifications of the cell wall differentiation state.


Population-based door-to-door survey of migraine in Japan: the Daisen study.
To determine prevalence and characteristics of migraine in Japan, and to investigate use of medical care and whether food preference is associated with risk of migraine. Structured questionnaires were given to all adult residents (N = 5758; 2681 men and 3077 women) in Daisen, a rural community in western Japan. Second questionnaires, specific to headache, were given to 1628 residents with headache. A telephone survey was also carried out. Statistical Packages for the Social Sciences analyzed the data. The 1-year prevalence of migraine was 2.3% (migraine with aura, 0.4% and without aura, 1.9%) in men and 9.1% (migraine with aura, 1.0% and migraine without aura, 8.1%) in women. Overall prevalence of migraine in Daisen was 6.0% (95% confidence interval [CI], 5.4% to 6.6%). Women observed a 5.9-fold higher risk of migraine than men (odds ratio, 5.9; 95% CI, 4.5 to 8.0; P <.0001, after age adjustment, by logistic analysis). Fatigue and loss of vigor were predominant premonitory symptoms of migraine. Fatigue, mental stress, and lack of sleep were the main headache triggers. Over a 3-month period, 20.3% of migraineurs experienced time or days off work due to headache. Only 7.3% of those with migraine with aura and 5.3% of those with migraine without aura had consulted a physician, and of those with migraine, 61.0% with aura and 71.8% without aura had never visited a medical doctor for their headache. Consumption of alcohol and cigarette smoking did not influence the risk for migraine or tension-type headache, after age and gender adjustment (logistic analysis). Migraineurs consume significantly more fatty/oily foods, coffee, and tea than nonheadache subjects of the same community. Migraineurs consume significantly fewer fish than nonheadache residents. Only a few Japanese migraineurs receive benefits of medical services and recent advances of headache medicine. Public education concerning headaches is one of the most urgent issues in Japan.


Clinical Case Discussion: Primary Treatment for Prostate Cancer in an Elderly Man-Treatment of the Primary Tumor is Necessary.
The decision-making process for treatment of prostate cancer should not be based on a single parameter such as patient age but should account for cancer characteristics, life expectancy, comorbidities, and patient expectation. Local treatment might be beneficial in selected elderly men with aggressive disease and a long life expectancy.


[Effect of triton X-100 on preparing porcine thoracic aortas acellular matrix].
To investigate the method of preparing porcine thoracic aortas acellular tissue matrix (ACTM) by trypsin, EDTA and Triton X-100 and to find the best concentration of X-100. A total of 56 roots of fresh thoracic aortas (without adventitial tissue) from 80 kg-100 kg tame pigs were divided randomly into > groups, each containing 8 roots. Every vessel was put into a 50 ml centrifugal tube with a solution of 0.1% trypsin + 0.02EDTA in PBS for 24 h. After that, each group was separately immerged into a solution of 0.1%, 0.2%, 0.5%, 1.0%, 2.0%, 5.0%, 10.0% Triton X-100 for 144 h-240 h. Specimens were taken every 6 h. Specimens were stained with haematoxylin-eosin and observed grossly under the light and transmission electron microscopy. Light and transmission electron microscopy revealed that ACTM was composed of insoluble collagen, elastin, and some insoluble metamorphic organelles. The best concentration of Triton X-100 was 1% at the time of 176.25 h +/- 5.5 h. Porcine thoracic aortas ACTM can be obtained successfully through this procedure. Triton X-100 is a good reagent for preparing vessel ACTM.


Transcription factors and drug resistance.
Intrinsic or acquired resistance to anticancer agents is a major obstacle to the success of chemotherapy. Anticancer agents are known to modulate signal transduction pathways and alter expression of genes that play an important role in drug resistance. Emerging evidence suggests that the complexity of genomic response against anticancer agents arise from elaborate gene expression by multiple transcription factors. Here, we briefly describe the development of solid tumours and the appearance of drug-resistant cells. We also review what is known of the transcription factors that are involved in resistance to drugs, particularly cisplatin.


Comparative expression of the pC194 cat gene in Streptococcus pneumoniae, Bacillus subtilis and Escherichia coli.
The expression of the cat gene of the staphylococcal plasmid pC194 present in the pLS1-pC194 composite plasmid pJS37 was lower in Streptococcus pneumoniae and Escherichia coli than in Bacillus subtilis. Different transcription start points (and, by inference, different promoter utilization) of the cat mRNA synthesized in S. pneumoniae or B. subtilis were detected. Plasmid pJS37 is prone to deletion formation when host cells are grown in the presence of chloramphenicol (Cm). The analysis of the expression of the cat gene carried by the deleted derivatives of pJS37 has shown that a new promoter for the synthesis of cat mRNA is involved in the selective advantage conferred to the host by those deleted plasmids. Characterization of either in vivo or in vitro deleted plasmids has shown that the nucleotide sequence that could encode for a putative leader peptide is required for the Cm-induced pC194 cat gene expression.


Establishing an ultrasound-assisted activated peroxide system for efficient and sustainable scouring-bleaching of cotton/spandex fabric.
This study presents a high-efficient and cost-effective ultrasound-assisted strategy for one-bath one-step scouring and bleaching of cotton/spandex fabric using sodium percarbonate (SPC) and tetraacetylenediamine (TAED) couple. SPC plays both roles of pH regulator and H2O2 donor to initiate the peracetic acid (PAA) release from TAED. The significance and interaction effects of operating parameters (TAED concentration, temperature and time) on the WI (Whiteness Index) of fabrics were investigated through a central composite design. The bleaching mechanism was studied by exploring the relationship between WI and PAA and hydroxyl radical (HO·) concentrations. The mechanical and dyeing performances of treated fabrics were also evaluated. Results show that temperature exerted a significant impact on WI followed by TAED concentration and time. The PAA concentration decreased and HO· concentration increased upon the temperature rise. Both PAA and HO· were significant to upgrade WI and ultrasound was effective in enhancing their bleaching efficiency. The fabric treated only with 15 mmol/L TAED and 10 mmol/L SPC at 40 °C for 40 min under ultrasound could achieve a WI of 68.6 (43% higher than greige fabric), which was almost equivalent to that of the fabric treated at 60 °C without ultrasound. This verifies the contribution of ultrasound technology in reducing bleaching temperature for energy-saving purpose. Moreover, the treated fabric displayed less than 5% tensile strength loss, having a marginal impact on the apparel performance. The wettability of fabric was greatly improved leading to a good dyeing performance. Encouraging results demonstrate the high efficiency of the ultrasound-assisted pre-treatment process of cotton/spandex fabric, which contributes to the sustainable production of textiles.


Analysis of Risk Factors for a Low Immune Response to Messenger RNA COVID-19 Vaccine in Kidney Transplant Recipients and Differences Between Second and Third Dose.
The efficacy of the response to SARS-CoV-2 vaccination in kidney transplant recipients is low. The aim of our study was to evaluate the risk factors correlated with the low antibody response and whether there was an improvement between the second and the third dose. A prospective study was conducted on 176 kidney transplant recipients who received the second and the third dose of the anti-SARS-CoV-2 mRNA Comirnaty vaccine. We evaluated the seroconversion process after administration of the second and the third dose and assessed a possible correlation with age, time between transplant and vaccination, and type of immunosuppressive therapy. A total of 98 of the 176 patients (55.7%) responded positively after the inoculation of the second dose and according to the multivariable logistic regression analysis the lack of seroconversion was independently associated with patient age ≥60 (P = .025; odds ratio [OR], 2.094), time since transplant of 1 to 3 months (P = .032; OR, 2.118), and triple therapy (P = .044; OR, 2.327). After the vaccine third dose, the seroconversion increased to 62.5%, and it was negatively influenced by calcineurin inhibitor use (12/21, 57.1% vs 71/78, 91.0%, P = .0006) and triple therapy (13/21, 61.9% vs 72/78, 92.3%, P = .0014). The median of antispike antibody response significantly increased from 18.5 IU/mL after the second dose to 316.9 IU after the third dose (P < .0001). We demonstrated a correlation between older age and shorter distance from the transplant and triple immunosuppressive therapy with the lack of seroconversion. We noticed a significant improvement in antibody response by a third dose of messenger RNA vaccine.


The MAP4 Kinase SIK1 Ensures Robust Extracellular ROS Burst and Antibacterial Immunity in Plants.
Microbial patterns are recognized by cell-surface receptors to initiate pattern-triggered immunity (PTI) in plants. Receptor-like cytoplasmic kinases (RLCKs), such as BIK1, and calcium-dependent protein kinases (CPKs) are engaged during PTI to activate the NADPH oxidase RBOHD for reactive oxygen species (ROS) production. It is unknown whether protein kinases besides CPKs and RLCKs participate in RBOHD regulation. We screened mutants in all ten Arabidopsis MAP4 kinases (MAP4Ks) and identified the conserved MAP4K SIK1 as a positive regulator of PTI. sik1 mutants were compromised in their ability to elicit the ROS burst in response to microbial features and exhibited compromised PTI to bacterial infection. SIK1 directly interacts with, phosphorylates, and stabilizes BIK1 in a kinase activity-dependent manner. Furthermore, SIK1 directly interacts with and phosphorylates RBOHD upon flagellin perception. Thus, SIK1 positively regulates immunity by stabilizing BIK1 and activating RBOHD to promote the extracellular ROS burst.


Prenatal Diagnosis of Chromosomal Mosaicism in Over 18,000 Pregnancies: A Five-Year Single-Tertiary-Center Retrospective Analysis.
Background: Chromosomal mosaicism (CM) is a common biological phenomenon observed in humans. It is one of the main challenges in prenatal diagnosis due to uncertain outcomes, especially when fetal ultrasonographic features appear normal. This study aimed to assess the phenotypic features of CM detected during prenatal diagnosis and the risk factors affecting parents' pregnancy decisions. Materials and methods: A retrospective cohort study involving 18,374 consecutive pregnancies that underwent prenatal diagnosis by karyotyping, fluorescence in situ hybridization (FISH), or chromosome microarray analysis (CMA) was conducted. The association of risk factors with malformations detected by ultrasound and pregnancy outcomes was assessed using the chi-square test and binary logistic regression. Discordant results between the different methods were identified and further analyzed. Results: During this five-year period, 118 (0.6%) patients were diagnosed with CM. The incidences of CM in the chorionic villus, amniotic fluid, and umbilical cord blood were 3.2, 0.5, and 0.7%, respectively. The frequency of ultrasound malformations in individuals with a high fraction of autosomal CM was significantly higher than that in other groups (62.5% vs. 21.4-33.3%, all p <0.05). Inconsistent results between karyotyping and CMA/FISH were observed in 23 cases (19.5%). The risk of pregnancy termination in cases with ultrasound malformations, consistent results, autosomal CM, or a high CM fraction increased with an odds ratio of 3.09, 8.35, 2.30, and 7.62 (all p <0.05). Multiple regression analysis revealed that all four factors were independent risk factors for the termination of pregnancy. Conclusion: Patients with a high fraction of autosomal CM are more likely to have ultrasound malformations. Inconsistent results between different methods in CM are not rare. Ultrasound malformations, consistent results between different methods, autosomal CM, and a high CM fraction were independent risk factors for the choice to terminate pregnancies.


Wide dynamic range and real-time reagent identification and imaging using multi-wavelength terahertz parametric generation and machine learning.
In this study, we propose a technique for identifying and imaging reagents through shielding over a wide dynamic range using a real-time terahertz (THz) spectroscopy system with multi-wavelength THz parametric generation/detection and machine learning. To quickly identify reagents through shielding, the spectral information of the "detection Stokes beam" is used for reagent recognition via machine learning. In general THz wave-based reagent identification, continuous spectra are acquired and analyzed quantitatively by post-processing. In actual applications, however, such as testing for illicit drugs in mail, the technology must be able to quickly identify reagents as opposed to quantifying the amount present. In multi-wavelength THz parametric generation/detection, THz spectral information can be measured instantly using a "multi-wavelength detection Stokes beam" and near-infrared (NIR) camera. Moreover, machine learning enables reagent identification in real-time and over a wide dynamic range. Furthermore, by plotting the identification results as pixel values, the spatial distribution of reagents can be imaged at high speed without the need for post-processing.


Psychiatric comorbidities of children with elimination disorders.
Enuresis and encopresis can be stressful for children and parents. We investigated the comorbid psychiatric disorders and the emotional and behavioral symptoms associated with elimination disorders. A total of 97 children and adolescents (aged 4-17 years) with an elimination disorder participated in this study. The elimination disorder group consisted of three subgroups: 50 subjects with enuresis nocturna, 26 with encopresis, and 21 subjects with enuresis+encopresis. The control group with no elimination disorder comprised 50 healthy subjects. All children were interviewed by a child and adolescent psychiatrist. Comorbid psychiatric disorders were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). Parents completed the Strengths and Difficulties Questionnaire. The most common diagnosis was attention-deficit/hyperactivity disorder, followed by oppositional defiant disorder. The highest rate of psychiatric comorbidity was observed in the enuresis+encopresis subgroup, followed by the enuresis nocturna and encopresis subgroups. All the subgroups had higher total difficulties scores than the control group. Screening for psychiatric disorders should be performed for all children with incontinence.


Periorbital cellulitis.
Sixty-seven cases of orbital cellulitis from BGSM are reported and 247 cases from the literature reviewed. Staphylococcus aureus was the predominant pathogen except in the age group from three months to three years where a significant number of cases yielded Hemophilus influenzae and Diplococcus pneumoniae. The frequent association of paranasal sinus involvement and orbital cellulitis has been confirmed. Orbital cellulitis is a multifaceted disease which, for proper management, requires close cooperation among pediatricians, ophthalmologists, and nursing service as a multidisciplinary approach for optimal therapy and decreased frequency of complications and sequelae.


Primary psoas abscess complicating a normal vaginal delivery.
Psoas abscess is a rare and potentially dangerous complication of normal delivery. We describe a case of primary psoas abscess after normal vaginal delivery. A young woman presented with fever, left back pain, left lower abdominal pain, and hip pain starting on postpartum day 2. Computed tomography demonstrated a large retroperitoneal collection. Aspiration drainage of the abscess under computed tomography guidance isolated Streptococcus viridans, which responded to antibiotic therapy and percutaneous drainage with complete resolution. A high index of suspicion is necessary for diagnosis of psoas abscess, which should be considered in postpartum patients with pyrexia, back and hip pain, and a normal neurologic examination. Computed tomography is effective for diagnosis and allows percutaneous drainage of the abscess.


Is There an Obesity Paradox in Critical Illness? Epidemiologic and Metabolic Considerations.
Obesity represents a global epidemic with serious implications in public health due to its increasing prevalence and its known association with a high morbidity and mortality burden. However, a growing number of data support a survival benefit of obesity in critical illness. This review summarizes current evidence regarding the obesity paradox in critical illness, discusses methodological issues and metabolic implications, and presents potential pathophysiologic mechanisms. Data from meta-analyses and recent studies corroborate the obesity-related survival benefit in critically ill patients as well as in selected populations such as patients with sepsis and acute respiratory distress syndrome, but not trauma. However, this finding warrants a cautious interpretation due to certain methodological limitations of these studies, such as the retrospective design, possible selection bias, the use of BMI as an obesity index, and inadequate adjustment for confounding variables. Main pathophysiologic mechanisms related to obesity that could explain this phenomenon include higher energy reserves, inflammatory preconditioning, anti-inflammatory immune profile, endotoxin neutralization, adrenal steroid synthesis, renin-angiotensin system activation, cardioprotective metabolic effects, and prevention of muscle wasting. The survival benefit of obesity in critical illness is supported from large meta-analyses and recent studies. Due to important methodological limitations, more prospective studies are needed to further elucidate this finding, while future research should focus on the pathophysiologic role of adipose tissue in critical illness.


Protective effect of sophocarpine on lipopolysaccharide-induced acute lung injury in mice.
Sophocarpine (SOP) is a tetracyclic quinolizidine alkaloid isolated from Sophora alopecuroides L. A number of studies have shown that SOP has anti-inflammatory actions and protects against a variety of tissue and organ injuries. The purpose of this study was to investigate the protective effects of SOP on LPS-induced acute lung injury (ALI) in mice. Lung histological alterations, edema, and MPO activity were measured in this study. Furthermore, the production of inflammatory cytokines and the expression of NF-κB and MAPKs signaling pathways were measured. The results showed that the LPS-induced lung histological alterations, edema, protein concentration, inflammatory cell level in BALF, MDA content, and MPO activity were significantly attenuated by SOP. The LPS-induced inflammatory cytokine TNF-α, IL-1β, and IL-6 were also inhibited by SOP. SOP also inhibited the LPS-induced IL-6 and IL-8 production in A549 cells. Western blot analysis demonstrated that SOP remarkably inhibited the phosphorylation of IκBα and NF-κB. LPS-induced MAPKs activation and TLR4 expression were also suppressed by treatment with SOP. In conclusion, the results indicate that SOP protects against LPS-induced ALI by inhibiting TLR4 signaling pathway.


The age-related neuroinflammatory environment promotes macrophage activation, which negatively impacts synaptic function.
The impact of infiltration of macrophages into the brain is debatable with evidence of both beneficial and detrimental effects. Recent work suggests that inflammatory macrophages, with an inflammatory phenotype that resembles the M1 activation state, may be detrimental, whereas anti-inflammatory M2-like macrophages may be beneficial. We set up a model to examine the response of bone marrow-derived macrophages to the inflammatory milieu that occurs in the aged brain. Expression of MHCII and CD40 was increased in macrophages incubated with soluble brain extract prepared from aged, compared with young, mice and this was accompanied by increased production of tumor necrosis factor-α and interleukin-6. Analysis of soluble brain extract indicated that it contained increased concentrations of several inflammatory mediators and, importantly, when bone marrow-derived macrophages were incubated in the inflammatory cytokines that were increased and applied to hippocampal slices, long-term potentiation was inhibited. The data suggest that infiltrating macrophages respond to local conditions and, in the case of aging, adopt an inflammatory phenotype that ultimately has a neurodetrimental effect.


Congenital absence of the nose: a case report.
Congenital absence of the nose (arhinia, congenital nasal atresia) is a rare anomaly which is infrequently described in the literature. Herein we present a case of congenital absence of the nose recently evaluated and treated at Children's Hospital Medical Center (CHMC), Cincinnati, OH. CT and MRI studies were obtained. To our knowledge, no such radiographic evaluations have been described in patients with congenital absence of the nose. In addition to complete absence of the anterior soft tissues of the nose, thin anterior and thick posterior atretic plates were present. MRI was useful in defining the nature of the soft tissue mass which filled the single hypoplastic nasal cavity. The lip, alveolus, and palate were remarkably well developed. A thorough investigation revealed no other congenital defects. At 15 days of life, because of the airway support required and the associated feeding difficulties, a nasal airway was created using a combination of sublabial, transpalatal and percutaneous approaches. Frequent home dilation of the surgically created opening has been successful in maintaining nasal patency thus allowing the patient to go without continuous stenting.


Prediction and evaluation of combination pharmacotherapy using natural language processing, machine learning and patient electronic health records.
Combination pharmacotherapy targets key disease pathways in a synergistic or additive manner and has high potential in treating complex diseases. Computational methods have been developed to identifying combination pharmacotherapy by analyzing large amounts of biomedical data. Existing computational approaches are often underpowered due to their reliance on our limited understanding of disease mechanisms. On the other hand, observable phenotypic inter-relationships among thousands of diseases often reflect their underlying shared genetic and molecular underpinnings, therefore can offer unique opportunities to design computational models to discover novel combinational therapies by automatically transferring knowledge among phenotypically related diseases. We developed a novel phenome-driven drug discovery system, named TuSDC, which leverages knowledge of existing drug combinations, disease comorbidities, and disease treatments of thousands of disease and drug entities extracted from over 31.5 million biomedical research articles using natural language processing techniques. TuSDC predicts combination pharmacotherapy by extracting representations of diseases and drugs using tensor factorization approaches. In external validation, TuSDC achieved an average precision of 0.77 for top ranked candidates, outperforming a state of art mechanism-based method for discovering drug combinations in treating hypertension. We evaluated top ranked anti-hypertension drug combinations using electronic health records of 84.7 million unique patients and showed that a novel drug combination hydrochlorothiazide-digoxin was associated with significantly lower hazards of subsequent hypertension as compared to the monotherapy hydrochlorothiazide alone (HR: 0.769, 95% CI [0.732, 0.807]) and digoxin alone (0.857, 95% CI [0.785, 0.936]). Data-driven informatics analyses reveal that the renin-angiotensin system is involved in the synergistical interactions of hydrochlorothiazide and digoxin on regulating hypertension. The prediction model's code with PyTorch version 1.5 is available at http://nlp.case.edu/public/data/TuSDC/.


Correlation of chronological age and bone age with the correction of ankle valgus by surface epiphysiodesis of the distal medial tibial physis.
A review of the results of medial distal tibial surface epiphysiodesis to correct valgus deformity in the growing child indicates that the bone age can be used to predict correction. When performed at the appropriate bone age, it may have some advantage over the use of staples or screws.


Osteopontin, a transformation-associated cell adhesion phosphoprotein, is induced by 12-O-tetradecanoylphorbol 13-acetate in mouse epidermis.
A murine mRNA (provisionally called 2ar) is described whose abundance is greatly increased by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate both in JB6 epidermal cells in vitro and in epidermis in vivo. We have previously shown induction of 2ar in epidermal or fibroblast cell lines by tumor promoters, growth factors, and transformation with H-ras. The 2ar mRNA appears to be derived from a single copy gene. It encodes the mouse homolog of rat osteopontin, a 41.5-kDa glycosylated bone phosphoprotein that binds to fibroblasts and osteosarcoma cells and to hydroxylapatite (bone matrix). The rat and mouse sequences are 84% identical at the amino acid level and 87% identical at the nucleotide level. Many of the primary structural features are conserved, including a run of 9-10 aspartic residues and a Gly-Arg-Gly-Asp-Ser cell adhesion sequence. Antiserum raised against portions of the predicted polypeptide immunoprecipitated proteins of apparent Mr 55,000-70,000 both from reticulocyte lysates containing the translation products of hybrid-selected mRNA and from cell culture medium containing metabolically labeled proteins secreted by JB6 cells. The results presented here demonstrate that osteopontin is identical to a transformation-associated phosphoprotein whose level of expression by cultured cells and abundance in human sera has been correlated with tumorigenicity. These results suggest a role for osteopontin in carcinogenesis. The murine version of osteopontin has been given the formal name "secreted phosphoprotein 1" and the designation spp.


Developing techniques for determining sperm morphology in today's andrology laboratory.
To investigate three areas: the staining of spermatozoa; the Computer Assisted Semen Analysis (CASA); and the variability of technicians. Staining experiment: sperm from 15 beef bulls were randomized to one of three staining protocols. CASA experiment: slides were evaluated using the Integrated Visual Optical System and compared to technician results. Variability of technicians: five laboratorians analyzed the same set of 20 slides six different times. Staining experiment: the size of the sperm increased in proportion to increased time and heat associated with each successive protocol. CASA experiment: coefficient of variation ranged from 18.3 to 101.7% (12 slides). Variability of technicians: the mean sperm morphology results ranged from 7.3 to 15% normal forms. Until laboratories adhere to the universal standard set by the World Health Organization to evaluate sperm morphology, a laboratory must rely on its own quality control to insure repeatable results.


Fc receptor-mediated signal transduction.
Receptors for the Fc domain of IgG (Fc gamma Rs) on leukocytes mediate a pleiotropic response following cross-linking by immune complexes. Signaling events following cross-linking of B and T cell antigen receptors, Fc epsilon RI, and Fc gamma Rs share common elements. In each, signaling is initiated by receptor cross-linking by antigen or immune complexes and results in the activation of src family kinases and ZAP-70-related tyrosine kinases, which associate with members of the receptor complex. Subsequent events include phosphorylation on tyrosine of multiple cellular substrates including phospholipase C gamma 1 and PI3-kinase. The [Ca2+]i flux is an event secondary to phospholipase C gamma 1 activation. Protein tyrosine kinase inhibitors block both early events such as [Ca2+]i flux and the later effects of cytokine release and cellular proliferation.


Inhibitory effect of pirfenidone on pulmonary fibrosis in patients with acute paraquat poisoning.
To study the efficacy of pirfenidone (PFD) on patients with pulmonary fibrosis caused by acute paraquat (PQ) poisoning. A total of 86 patients with pulmonary fibrosis caused by acute PQ poisoning admitted to our hospital were analyzed retrospectively. All of them successfully received the standard 21-day treatment based on "Taishan Consensus", and they were assigned to the PFD group or the NO-PFD group according to whether they received PFD treatment (at 200 mg/time, 3 times/day) for 6 months after discharge. The two groups were compared in effective treatment rate, mortality and incidence of adverse reactions such as liver and kidney function damage, pulmonary fibrosis-associated indexes, pulmonary function-associated indexes, and arterial blood gas indexes before and after therapy. The PFD group showed a notably higher effective treatment rate than the NO-PFD group (P<0.05). Additionally, the PFD group showed notably lower levels of serum hyaluronic acid (HA), laminin (LN), type IV collagen (CIV), and type III procollagen (PCIII), and notably higher levels of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC than the NO-PFD group (all P<0.001), and the PFD group also showed significantly higher levels of arterial blood gas indexes including arterial partial pressure of oxygen (PaO2) and PaO2/inspired oxygen (FIO2) than the NO-PFD group (both P<0.001). Moreover, the Kaplan-Meier survival curves showed that the survival rate of the patients in PFD group was significantly higher than that in the NO-PFD group (P<0.05). With a high safety, PFD can effectively improve the treatment efficacy in patients with pulmonary fibrosis caused by acute PQ poisoning. PFD can improve the pulmonary function and arterial blood gas status of patients, without causing obvious liver and kidney damage.


Vasopressin decreases sepsis-induced pulmonary inflammation through the V2R.
The early use of vasopressors in sepsis has been associated with a decrease in immune activation independent of hemodynamic effects, although the mechanism behind this remains unclear. We hypothesize that low dose vasopressin will reduce the pulmonary inflammation associated with sepsis. Our aims were to (1) determine whether vasopressin reduces lipopolysaccharide (LPS)-induced pulmonary inflammation and (2) determine which vasopressin receptor is responsible for pulmonary immune modulation. Mice were treated with intraperitoneal LPS to induce both systemic and pulmonary inflammation. Vasopressin or saline was infused via peritoneal pump and interleukin 6 (IL-6) in lung and serum was measured at 6h. NF-kappaB activation as was determined in the lung through immunoblotting total and phospho-IkappaB. Hemodynamic data was also obtained at the 6h mark. In a separate series of experiments mice received both LPS and vasopressin infusion following pretreatment with vasopressin receptor antagonists to V1R, V2R and OTR. Low dose LPS dramatically raises both serum IL-6 and pulmonary levels of IL-6 and phospho-IkappaB despite no significant changes in mean arterial pressure at 6h. Compared to saline, vasopressin infusion significantly decreases both the pulmonary IL-6 levels and phospho-IkappaB in LPS treated mice without raising arterial pressure. Pretreatment with V2R antagonist results in complete attenuation of vasopressin's immunosuppressive effects, with restoration of pulmonary IL-6 and phospho-IkappaB levels to those seen with LPS alone. Vasopressin exerts a local anti-inflammatory effect on the lung through the V2R in a model of sepsis.


Immunohistologic diagnosis of 2 cases of metastatic prostate cancer to breast.
We report 2 cases of primary prostatic carcinoma with subsequent carcinomatous lesions in the breast. Prostatic origin of these carcinomas was confirmed by immunocytochemical demonstration of prostatic acid phosphatase and prostate specific antigen within paraffin sections. Previously, only 20 cases of prostatic carcinoma metastatic to the breast have been reported in the literature. In most of these cases the designation of the breast lesion as prostatic carcinoma has been made on morphologic and clinical grounds only.