Insulin in the rat fetus. A new form of circulating insulin.
The apparent hyperinsulinemia seen in the fetal rat in late gestation (day 20) is shown to be due to an immunoreactive insulin (IRI) species peculiar to the fetal rat, and not monomeric insulin. This species disappears within 12 h after birth and only insulin as found in the adult can then be detected. The fetal serum IRI has a molecular weight of approximately 11,000 and differs from monomeric insulin and proinsulin in its behavior on gel filtration and anion-exchange chromatography. The activity of fetal serum in an insulin bioassay based on the incorporation of glucose into lipid was half that expected on the basis of the serum IRI concentration. The addition of fetal serum to purified insulin or proinsulin caused an increase in the apparent molecular weight of both hormones by 2000. In the case of insulin, the generated species of mol wt 8000 was clearly differentiated from the endogenous species (11,000) on Sephadex G50. The fetal pancreas at this age was found to contain predominantly monomeric insulin that had full biologic activity in the insulin bioassay. It is postulated that the fetal pancreas secretes monomeric insulin, which is then modified in the circulation to a complex with reduced biologic activity. This process appears to have two steps in that in vitro fetal serum increases the apparent molecular weight of added insulin to 8000, whereas in vivo an additional component of approximately 3000 mol wt is involved to produce the endogenous insulin complex.


Administration of N-Acyl-Phosphatidylethanolamine Expressing Bacteria to Low Density Lipoprotein Receptor-/- Mice Improves Indices of Cardiometabolic Disease.
Obesity increases the risk for cardiometabolic diseases. N-acyl phosphatidylethanolamines (NAPEs) are precursors of N-acylethanolamides, which are endogenous lipid satiety factors. Incorporating engineered bacteria expressing NAPEs into the gut microbiota retards development of diet induced obesity in wild-type mice. Because NAPEs can also exert anti-inflammatory effects, we hypothesized that administering NAPE-expressing bacteria to low-density lipoprotein receptor (Ldlr)-/- mice fed a Western diet would improve various indices of cardiometabolic disease manifested by these mice. NAPE-expressing E. coli Nissle 1917 (pNAPE-EcN), control Nissle 1917 (pEcN), or vehicle (veh) were given via drinking water to Ldlr-/- mice for 12 weeks. Compared to pEcN or veh treatment, pNAPE-EcN significantly reduced body weight and adiposity, hepatic triglycerides, fatty acid synthesis genes, and increased expression of fatty acid oxidation genes. pNAPE-EcN also significantly reduced markers for hepatic inflammation and early signs of fibrotic development. Serum cholesterol was reduced with pNAPE-EcN, but atherosclerotic lesion size showed only a non-significant trend for reduction. However, pNAPE-EcN treatment reduced lesion necrosis by 69% indicating an effect on preventing macrophage inflammatory death. Our results suggest that incorporation of NAPE expressing bacteria into the gut microbiota can potentially serve as an adjuvant therapy to retard development of cardiometabolic disease.


[A method for assessing the morphological status of the maxillodental system].
The authors propose a device for measuring plaster models of patients' jaws with normal occlusion in order to evaluate the distance from the coordinate point to the point between the incisors (i), points of contact of the canines (p) and of contact of the first molars of the maxilla and mandible (m). It is possible to assess the position of the upper and lower dentition in the skull space in relation to the universal parameter--the coordinate point common for both dentitions and parameters of the skull.


ARR1 directly activates cytokinin response genes that encode proteins with diverse regulatory functions.
Plant cells respond to cytokinins by changing their gene expression patterns. The histidyl-aspartyl (His-Asp) phosphorelay mediates the signal from cytokinin receptors to type-B response regulators including ARR1, which transactivate cytokinin primary response genes. However, the overall architecture of the signal cascade leading to cytokinin-responsive phenomena is still unclear, mainly because it is not known how the His-Asp phosphorelay is connected to downstream phenomena. To reveal events immediately downstream from the phosphorelay-mediated transcriptional activation, we searched for direct-target genes of ARR1 by exploiting ARR1DeltaDDK-GR, a chimeric transcription factor that transactivates ARR1 direct-target genes in transgenic plants by glucocorticoid induction. We identified 23 direct-target genes, most of which were found to be cytokinin primary response genes. The arr1-1 mutation clearly affected the primary response in at least 17 genes, meaning that they respond primarily to cytokinins through the function of ARR1. The 17 genes encode proteins with diverse functions, including type-A response regulators, cytokinin metabolic enzymes and putative disease resistance response proteins. These results provide novel evidence indicating that the His-Asp phosphorelay is connected to diverse regulatory levels of cytokinin-responsive phenomena through ARR1 direct-target genes.


A Cross-Talk about Radioresistance in Lung Cancer-How to Improve Radiosensitivity According to Chinese Medicine and Medicaments That Commonly Occur in Pharmacies.
Lung cancer is one of the most common cancers in the population and is characterized by non-specific symptoms that delay the diagnosis and reduce the effectiveness of oncological treatment. Due to the difficult placement of the tumor, one of the main methods of lung cancer treatment is radiotherapy, which damages the DNA of cancer cells, inducing their apoptosis. However, resistance to ionizing radiation may develop during radiotherapy cycles, leading to an increase in the number of DNA points of control that protect cells from apoptosis. Cancer stem cells are essential for radioresistance, and due to their ability to undergo epithelial-mesenchymal transition, they modify the phenotype, bypassing the genotoxic effect of radiotherapy. It is therefore necessary to search for new methods that could improve the cytotoxic effect of cells through new mechanisms of action. Chinese medicine, with several thousand years of tradition, offers a wide range of possibilities in the search for compounds that could be used in conventional medicine. This review introduces the potential candidates that may present a radiosensitizing effect on lung cancer cells, breaking their radioresistance. Additionally, it includes candidates taken from conventional medicine-drugs commonly available in pharmacies, which may also be significant candidates.


Maternal antihypertensive drugs may influence cerebral oxygen extraction in preterm infants during the first days after birth.
To determine whether maternal antihypertensive drugs influenced cerebral oxygenation in preterm infants during the first days after birth. We included 49 preterm infants (median gestational age 30.3 weeks, (range 26.0-31.9), birth weight 1250 g (560-2250)). Regional cerebral oxygen saturation (rcSO2) was measured by near-infrared spectroscopy on postnatal days 1, 2, 3, 4 and 5. Fractional tissue oxygen extraction (FTOE) was calculated using rcSO2 and arterial oxygen saturation (SpO2) values:(SpO2 - rcSO2)/SpO2. Nine mothers were treated with labetalol and/or MgSO4 during pregnancy, three mothers with labetalol, MgSO4 and nifedipine, and 19 mothers with nifedipine only. Eighteen infants served as controls. Multivariate linear regression analysis showed that exposure to labetalol and/or MgSO4 during pregnancy decreased FTOE on day 1 after birth, while nifedipine did not. Treating pregnant women with labetalol and/or MgSO4 may influence cerebral oxygen extraction in their offspring shortly after birth.


Ping pong ball in the hefty heart: a case report.
We describe here a very unusual case of a large free floating left atrial thrombus due to critical mitral stenosis detected by incidental echocardiography, in whom peculiar symptoms and complications of ball thrombus were absent. The patent's only symptom was mild dyspnoea attributed to smoking. She had no syncope or arrhythmia induced embolic event. Owing to non-availability of cardiothoracic facility, she was given anticoagulant therapy which resulted in intracerebral haemorrhage and death.


Is there a role for high resolution manometry in GERD diagnosis?
Gastroesophageal reflux disease (GERD) is a condition, which develops when the reflux of stomach contents causes troublesome symptoms and/or complications. In patients with alarm symptoms or signs or in those refractory to antiacid therapy, it is indicated to perform instrumental tests to correctly diagnose GERD presence. Esophageal manometry is currently considered the gold standard test for the diagnosis of esophageal dysmotility. However, it has shown limited capability in diagnosing GERD. With the advent of high resolution manometry (HRM), more accurate evaluations of esophageal motility are now possible. Furthermore, new metrics have been developed to investigate esophagogastric junction (EGJ) morphology and function. In particular, the antireflux barrier function of EGJ can now be assessed evaluating the contraction integral of the junction. Also, transient lower esophageal relaxations can be defined more precisely with HRM. Provocative tests with multiple swallows can give additional information on peristaltic reserve. Finally, adding impedance measurement to HRM allows to detect retrograde movements (e.g. reflux) in the esophagus and to measure the baseline impedance, a novel promising metric associated to esophageal mucosal integrity. The present review will discuss the recent progresses made in evaluation of GERD patients with HRM and its potential role in diagnosing pathological reflux presence.


Functional significance of CD14 promoter polymorphisms and their clinical relevance in a Chinese Han population.
Several polymorphisms in the CD14 promoter have been reported to be associated with various inflammatory diseases. However, conflicting results have been shown in association studies in different populations. This study aimed to investigate the possible functional significance of both the G-1145A and T-159C polymorphisms in the CD14 promoter and their association with organ dysfunction and sepsis in adult trauma patients. Genetic, functional, and association studies. National Key Laboratory of Trauma and Departments of Traumatic Surgery in two teaching hospitals. Three hundred twenty-five healthy volunteers and 105 patients with major trauma. None. Among the five single nucleotide polymorphisms identified within CD14 promoter in a Chinese Han population, two single nucleotide polymorphisms (G-1145A and T-159C) were selected according to bioinformatics analysis. Promoter activity of polymorphisms was determined using the reporter gene assay. Plasma sCD14 and tumor necrosis factor-alpha levels were measured by enzyme-linked immunosorbent assay. Both single nucleotide polymorphisms significantly reduced transcriptional activity of the promoter, and were significantly associated with a decrease of inducible sCD14 and tumor necrosis factor-alpha production in an allele-dose effect. Moreover, trauma patients carrying the -1145 A or -159 C allele appeared to have a decreased risk of multiple organ dysfunction and sepsis. In addition, both polymorphisms had a marked synergistic effect. The CD14/-1145 and -159 polymorphisms are functional variants, which may function in a synergistic fashion, and could be used as biological risk predictors of multiorgan dysfunction and sepsis in trauma patients.


Induction of detoxifying enzyme by sesquiterpenes present in Inula helenium.
Our previous study showed that the methanolic extract of Inula helenium (elecampane) had the potential to induce detoxifying enzymes such as quinine reductase (QR) and glutathione S-transferase. In this study we further fractionated the methanolic extract into hexane-, dichloromethane-, butanol-, and water-soluble fractions according to polarity. The hexane fraction showed the highest QR-inducing activity and also induced glutathione S-transferase in a dose-dependent manner. Its potential to induce the reporter activity suggested an antioxidant response element-mediated mechanism of action in the induction of phase II detoxifying enzymes. Intraperitoneal injection of the hexane fraction of I. helenium into ICR mice caused a significant increase of QR activity in liver, kidney, small intestine, and stomach. Sesquiterpenes, isolated from the hexane fraction, appeared to be major components responsible for QR induction. Among the seven compounds tested in this study, alantolactone, isoalantolactone, and 5alpha-epoxyalantolactone significantly induced QR activity in both Hepa1c1c7 and BPRc1 cells. In conclusion, sesquiterpenes, including alantolactone, isoalantolactone and 5-epoxyalantolactone, present in I. helenium merit further evaluation as chemopreventive agents.


How to improve bilio-stasis in liver surgery.
One of the most fearful complications following hepatic resection is the onset of a biliary fistula. We have attempted to improve intraoperative bilio-stasis to minimize the risk of postoperative fistula development by testing different materials. In the early 2005 we began employing a collagen sponge coated with fibrinogen and thrombin (Tachosil) In our clinical experience, prior to sponge use, a biliary fistula developed in 3.9% of elective resections and 5.1% of surgical procedures for liver trauma. Until now there were no postoperative bile leaks in the patients treated with Tachosil.


Gastric Cancer Mortality Trends in China (2006-2013) Reveal Increasing Mortality in Young Subjects.
Although the advent of Helicobacter pylori eradication and global societal changes are widely assumed to impact on gastric cancer (GC)-related mortality, there is remarkable little quantitative and qualitative insight into the nature of its effects. Here, we exploited a nationwide reporting system to investigate the epidemiological features of GC-related mortality in China between 2006 and 2013. GC mortality data between 2006 and 2013 were obtained from the National Disease Surveillance System published by the China Center for Disease Control and Prevention (CDC). GC mortality increased by 8.2% (from 18.87/100,000 to 20.41/100,000), while GC mortality standardized by the age scale of the population in 2010 decreased by 17.8% (from 21.87/100,000 to 17.98/100,000). Standardized GC mortality in males (25.66/100,000 to 33.89/100,000) was higher compared to females (10.72/100,000 to 14.79/100,000), while standardized GC mortality in rural areas (19.17/100,000 to 26.46/100,000) was higher than in urban areas (15.48/100,000 to 20.04/100,000). Both crude and standardized rates in the 0- to 29-year-old group increased by 22.3% and 16.2%, respectively; while these rates declined in the 30- to 59-year-old group and over 60-year-old group. The proportion of GC deaths that accounts for all cancer deaths declined from 15.99% (2006) to 13.6% (2013); however, the proportion in the 0- to 29-year-old group revealed an increasing trend from 2006 (3.20%) to 2013 (3.87%). Our results reveal a remarkable increase in GC-related mortality in subjects under the age of 30 calling for further measures to prevent the increase in the incidence of GC in young patients.


Uncoupling primer and releaser responses to pheromone in honey bees.
Pheromones produce dramatic behavioral and physiological responses in a wide variety of species. Releaser pheromones elicit rapid responses within seconds or minutes, while primer pheromones produce long-term changes which may take days to manifest. Honeybee queen mandibular pheromone (QMP) elicits multiple distinct behavioral and physiological responses in worker bees, as both a releaser and primer, and thus produces responses on vastly different time scales. In this study, we demonstrate that releaser and primer responses to QMP can be uncoupled. First, treatment with the juvenile hormone analog methoprene leaves a releaser response (attraction to QMP) intact, but modulates QMP's primer effects on sucrose responsiveness. Secondly, two components of QMP (9-ODA and 9-HDA) do not elicit a releaser response (attraction) but are as effective as QMP at modulating a primer response, downregulation of foraging-related brain gene expression. These results suggest that different responses to a single pheromone may be produced via distinct pathways.


Exposure to Cadmium Telluride Quantum Dots and Gene Expression Profile of Huh-7 Hepatocellular Carcinoma Cell Line.
Nanoparticles have shown promising potential for efficient drug delivery, circumventing biological interferences like immunological and renal clearance and mechanical and enzymatic destruction. However, a handful of research papers have questioned the biomedical use of metal-based nanoparticles like cadmium telluride quantum dots (CdTe-QDs) for their cytotoxic, genotoxic, and carcinogenic potential. Herein, we examined the effects of CdTe-QD NPs on gene expression profile of hepatocellular carcinoma (Huh-7) cell line. Huh-7 cells were treated with CdTe-QD NPs (10 μg/ml for 6, 12, and 24 hours, and 25 μg/ml for 6 and 12 hours), and transcriptomic analysis was performed using microarray to evaluate the global gene expression profile. Differential expressed genes (DEGs) were observed for both the doses (10 and 25 μg/ml) of CdTe-QD NPs at different time points. Gene ontology (GO) analysis revealed that genes involved in molecular function of cell cycle, organizational injury and abnormalities, cell death and survival, gene expression, cancer, organismal survival, and cellular development were differentially expressed. Overall, we have demonstrated differential expression of several genes, involved in maintaining cell survival, metabolism, and genome integrity. These findings were confirmed by RT-qPCR study for some canonical pathway genes signifying possible implication in NP toxicity-mediated cell survival and inhibition of cell death.


Age and the dexamethasone suppression test in depression.
The authors examined the effects of age on plasma cortisol concentrations of 81 depressed men after dexamethasone administration. Dexamethasone nonsuppression was significantly more frequent in patients older than age 55 than those younger. Similarly, older patients had significantly higher postdexamethasone cortisol concentrations than younger patients at all time points sampled. These differences could not be attributed to severity or to the prevalence of psychosis in older and younger depressed patients.


Implant Surface Options and Biofilm Mitigation Strategies.
Two important topics in breast augmentation and reconstruction relate to device surface texture and practices to mitigate biofilm contamination of implants. Breast augmentation can be considered a manufacturing process where planning concepts of process engineering and quality can be used to produce great outcomes. This article reviews the options available for surgeons with regards to device surface texture selection and practices to mitigate biofilm contamination of implants at the time of surgery.


Minimally invasive resection of choledochal cyst: a feasible and safe surgical option.
The use of minimally invasive surgery (MIS) for choledochal cyst (CC) has not been well documented. We sought to define the overall utilization and outcomes associated with the use of the open versus MIS approach for CC. We examined the factors associated with receipt of MIS for CC, as well as characterized perioperative and long-term outcomes following open versus MIS for CC. Between 1972 and 2014, a total of 368 patients who underwent resection for CC were identified from an international, multicenter database. A 2:1 propensity score matching was used to create comparable cohorts of patients to assess the effect of MIS on short-term outcomes. Three hundred thirty-two patients had an open procedure, whereas 36 patients underwent an MIS approach. Children were more likely to be treated with a MIS approach (children, 24.0 % vs. adults, 2.1 %; P<0.001). Conversely, patients who had any medical comorbidity were less likely to undergo MIS surgery (open, 26.2 % vs. MIS, 2.8 %; P=0.002). In the propensity-matched cohort, MIS resection was associated with decreased length of stay (open, 7 days vs. MIS, 5 days), lower estimated blood loss (open, 50 mL vs. MIS, 17.5 mL), and longer operative time (open, 237 min vs. MIS, 301 min) compared with open surgery (all P<0.05). The overall and degree of complication did not differ between the open (grades I-II, n=13; grades III-IV, n=15) versus MIS (grades I-II, n=5; grades III-IV, n=5) cohorts (P=0.85). Five-year overall survival was 98.6 % (open, 98.0 % vs. MIS, 100.0 %; P=0.45); no patient who underwent MIS developed a subsequent cholangiocarcinoma. MIS resection of CC was demonstrated to be a feasible and safe approach with acceptable short-term outcomes in the pediatric population. MIS for benign CC disease was associated with similar perioperative morbidity but a shorter length of stay and a lower blood loss when compared with open resection.


Rat plasma proteomics: effects of abundant protein depletion on proteomic analysis.
The proteomic analysis of plasma and serum samples represents a formidable challenge due to the presence of a few highly abundant proteins such as albumin and immunoglobulins. Detection of low abundance protein biomarkers requires therefore either the specific depletion of high abundance proteins with immunoaffinity columns and/or optimized protein fractionation methods based on charge, size or hydrophobicity. Here we describe the depletion of seven abundant rat plasma proteins with an immunoaffinity column with coupled antibodies directed against albumin, IgG, transferrin, IgM, haptoglobin, fibrinogen and alpha1-anti-trypsin. The IgY-R7-LC2 (Beckman Coulter) column showed high specificity for the targeted proteins and was able to efficiently remove most of the albumin, IgG and transferrin from rat plasma samples as judged by Western blot analysis. Depleted rat plasma protein samples were analyzed by SELDI-TOF MS, 2D SDS-PAGE and 2D-LC and compared to non-depleted plasma samples as well as to the abundant protein fraction that was eluted from the immunoaffinity column. Analysis of the depleted plasma protein fraction revealed improved signal to noise ratios, regardless of which proteomic method was applied. However, only a small number of new proteins were observed in the depleted protein fraction. Immunoaffinity depletion of abundant plasma proteins results in the significant dilution of the original sample which complicates subsequent analysis. Most proteomic approaches require specialized sample preparation procedures during which significant losses of less abundant proteins and potential biomarkers can occur. Even though abundant protein depletion reduces the dynamic range of the plasma proteome by about 2-3 orders of magnitude, the difference between medium-abundant and low abundant plasma proteins is still in the range of 7-8 orders of magnitude and beyond the dynamic range of current proteomic technologies. Thus, exploring the plasma proteome in greater detail remains a daunting task.


Septosones A-C, in Vivo Anti-inflammatory Meroterpenoids with Rearranged Carbon Skeletons from the Marine Sponge Dysidea septosa.
Three unusual meroterpenoids, septosones A-C (1-3), were isolated from the marine sponge Dysidea septosa. The structures were determined by analysis of spectroscopic data combined with single-crystal X-ray diffraction and ECD calculations. Septosone A (1) features an unprecedented "septosane" carbon skeleton, whereas septosones B (2) and C (3) share a rare spiro[4.5]decane motif. Septosone A showed in vivo anti-inflammatory activity in CuSO4-induced transgenic fluorescent zebrafish likely through inactivation of the NF-κB signaling pathway.


Paclitaxel (Taxol) efficacy in patients with advanced breast cancer resistant to anthracyclines.
We assessed the efficacy of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when administered by 3-hour intravenous infusion in 15 patients with advanced breast cancer resistant to anthracyclines. Paclitaxel was administered at 175 mg/m2. In the event of severe toxicity, dose reductions to 150 or 125 mg/m2 could be made; otherwise, the dose was subsequently increased to 200 mg/m2. Patients received a median of five cycles of treatment (range, one to nine cycles). Paclitaxel induced three complete responses and four partial responses, for an overall response rate of 47%. The most frequently observed toxicities associated with paclitaxel administration were neutropenia and alopecia, which occurred in all patients. The frequency and severity of the observed toxicities were never of clinical concern. We conclude that paclitaxel is active in breast cancer patients clinically resistant to anthracyclines and that it can be safely administered by 3-hour infusion with standard premedication. Considering the good tolerability, higher doses of paclitaxel in advanced breast cancer should be explored.


[Isolation and characterization of a sulfate reducing Citrobacter sp. strain SR3].
A sulfate reducing bacterium, designated strain 'SR3', was isolated from sludge of a sulfate-reducing up-flow anaerobic sludge bed (UASB) reactor for treating high concentration sulfate wastewater. It was identified as Citrobacter sp. based upon the phenotypic-characteristics and physiological properties as well as the analysis of the sequence of 16S rDNA. The strain could reduce sulfate under anaerobic and micro-aerobic conditions. The dissimilatory sulphite reductase gene (dsr) was also amplified from this strain's genomic DNA using specific dsr gene primers. In aerobic conditions, the strain couldn't reduce sulfate, but exhibited a highest growth rate. In anaerobic conditions, the optimal growth conditions for this stain were temperature 37 degrees C and initial pH 8.0. Under this conditions,the strain could reduced both SO4(2-) and Cr(VI) at initial Cr(VI) concentrations of 0.4-0.8 mmol synchronously. Its tolerance ability to Cr(VI) concentrations reaches 1.0 mmol. This is the first report about an facultative anaerobe with sulfate reducing function and dissimilatory sulphite reductase gene (dsr).


Stereotactic Body Radiation Therapy for Liver Tumors: Current Status and Perspectives.
Surgical resection is the standard therapy for solitary primary or metastatic liver tumors. However, liver tumors are often unresectable at diagnosis and hepatectomy is invasive. Local therapies, such as radiofrequency ablation, are used instead, which can be challenging. Recent advances in modern radiotherapy, including stereotactic body radiation therapy (SBRT), have increased the use of radiotherapy as a curative modality. SBRT delivers ablative high doses of irradiation in small volumes. SBRT for liver tumors provided local control with potential survival benefits in patients with inoperable status. However, the following issues remain: primary vs. metastatic liver cancers; SBRT-related toxicity and prevention; pathological features of liver cancers; and potential SBRT strategies. We summarized a literature review to summarize the effectiveness of SBRT and patient tolerance and present the current status and future perspective of SBRT for liver tumors. SBRT is a potential game changer for multimodal therapy.


A New Potential Predictor of Coronary Artery Disease: The Ratio of Mitral Peak Filling Velocity to Mitral Annular Velocity in Early Diastole.
BACKGROUND The aim of this study was to explore the value of the ratio of mitral peak filling velocity (E) to mitral annular velocity (e') in early diastole as a predictor of coronary artery disease (CAD). MATERIAL AND METHODS The study population consisted of 83 consecutive patients (aged 38-77 years, 22 women and 61 men) who received coronary angiography. The E/e' ratio was estimated by echocardiographic examination. Statistical significance was determined by receiver operating characteristic (ROC) curve and multiple logistic regression analyses. RESULTS ROC curve analysis showed that the optimal E/e' ratio cut-off for predicting CAD was 8.153 with a specificity of 72.4% and sensitivity of 57.4%. The area under the ROC curve was 0.635 with a 95% confidence interval (CI) for normal distribution of 0.515-0.755 (p=0.043). Multivariate logistic regression analysis demonstrated that the E/e' ratio was closely associated with CAD (odds ratio [OR], 1.350; 95% CI, 1.087-1.676, p=0.007). CONCLUSIONS The E/e' ratio is a simple and practical predictor of CAD and may be an independent risk factor for CAD. Large-cohort and multi-center studies are required to confirm these observations.


Description of the larva of Orthemis ferruginea (Fabricius, 1775) (Odonata: Libellulidae).
The last larval stadium of Orthemis ferruginea (Fabricius, 1775) is described and illustrated in detail based on reared material collected in the municipality of Paso de Ovejas, Veracruz, Mexico. It is compared with larvae of other species of the genus previously described. The main structural features are the number of setae on palp, prementum and palp crenations, the size proportion of cerci respect to epi- and paraprocts, and the number of sclerites on abdominal sternum 5.


One-step cross-genogroup multiplex RT-qPCR with an internal control system for the detection of infectious pancreatic necrosis virus (IPNV).
Infectious pancreatic necrosis virus (IPNV) causes great losses in fish hatcheries world-wide. The detection of IPNV can be challenging in certain circumstances, particularly due to low viral load and the genetic variability of this RNA virus. For the first time, this project created a quantitative triplex real-time reverse transcription PCR (RT-qPCR), including an endogenous control system, for specific, sensitive and rapid detection of IPNV in routine diagnostics. Multiple sequence alignment of 46 nucleotide sequences of the segment A genome obtained from the NCBI database allowed the design of two RT-qPCR systems covering the IPNV genogroup 1 and genogroups 2-5, respectively. The completed triplex RT-qPCR including a salmonid-specific endogenous control showed high specificity and an analytical sensitivity of 20-40 oligonucleotide copies. Testing of dilution series of virus-loaded cell culture suspensions proved equality of the triplex RT-qPCR with virus detection in cell culture and a higher sensitivity than conventional RT-PCR in field samples. In comparative studies of a total of 77 field samples tested, 51 showed identical positive and 19 identical negative results in cell culture and the triplex RT-qPCR. However, seven other samples yielded positive results in the triplex RT-qPCR, but negative results in cell culture.


Hydroquinone and its analogues in dermatology - a risk-benefit viewpoint.
Hydroquinone (HQ) has been used since the 1950s in commercially available over-the-counter skin lightener products and since the 1960s as a commercially available medical product. It is also used in cosmetic products such as hair dyes and products for coating finger nails. Beginning in 2001, HQ is no longer authorized for use in cosmetic skin lightening formulations in European Union countries, although products containing arbutin, an analogue of HQ, and botanicals, including plants that naturally contain HQ and arbutin, continue to remain available in European countries. The potential toxicity of HQ is dependent on the route of exposure, and toxicity in rodents is highly sex-, species-, and strain-specific. Subchronic and chronic toxicity in experimental animals is primarily limited to nephrotoxicity in male F-344 rats. Dermal toxicity studies, even those conducted in the sensitive male F-344 rat, are essentially devoid of systemic toxicity. Developmental and reproductive toxicity studies with HQ in rats and rabbits have not demonstrated significant effects. Cancer bioassay data for HQ demonstrate limited effects and are not sufficient to classify HQ for human carcinogenicity. Epidemiology and occupational studies of workers with extensive exposure to HQ have not reported any evidence of adverse systemic health effects or carcinogenicity. A risk-benefit approach is recommended for assessing the available data for HQ, arbutin, and other materials in use as, or proposed for use as, skin lighteners to provide optimal therapeutic benefits to patients with pigmentary changes of the skin.


[Comparative study of factors associated with the progression of primary open-angle and angle-closure glaucoma].
To compare the factors associated with the progression of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). This prospective study analyses clinical data of POAG and PACG patients followed up for 6 years. The progression of glaucomatous optic neuropathy (GON) was determined using perimetry and spectral optical coherence tomography (OCT). The value of each diagnostic indicator (z-value) was calculated using the Wilcoxon-Mann-Whitney test and the area under the ROC-curve (AUC) to identify the parameters reliably associated with the progression in both groups of patients. According to OCT, 47.3% of PACG patients and 52.46% of POAG patients had GON progressing, while according to perimetry, these figures were 21.8% and 23%, respectively. The common factors associated with progression of these glaucoma forms were age (AUC 0.7, z -1.9 in PACG and AUC 0.7, z -2.9 in POAG) and maximum IOP (0.7; -2.7 in PACG and 0.79; -5.4 in POAG). The progression of PACG is associated with lens size (0.7; -2.4), subfoveal choroidal thickness (AUC 0.8, z -3.3) and peripapillary choroidal thickness (0.79; -3.2), resistive index in the vortex veins (0.81; -3.3) and their end diastolic blood flow velocity (0.83; 3.2). The progression of POAG is associated with a thin peripapillary (0.75; 2.6) and subfoveal choroid (0.74; 2.5), increased resistive index in the posterior short ciliary arteries (0.8; -2.3), and initial retinal nerve fiber layer (RNFL) thickness: 0.69; 2.9. The progression of POAG and PACG has only two common factors - age and maximum IOP. The progression of PACG is mainly related to the lens size, venous dysfunction and the choroid expansion, while the progression of POAG is related to the initial RNFL thickness, reduced arterial blood flow and choroid thinning.


Choroidal neovascularization secondary to ocular penetration during retrobulbar anesthesia and its treatment.
Retrobulbar anesthesia is still used before ocular surgery; however, it has various complications including ocular penetration. The penetration/perforation of the globe can cause complications such as endophthalmitis, retinal detachment, and scotoma. Choroidal neovascularization (CNV) is rarely seen, following choroidal rupture in penetrating eye injuries. Here, we present a patient who underwent a pars plana vitrectomy for vitreous hemorrhage secondary to ocular penetration during a retrobulbar injection for cataract surgery. This patient later developed CNV at the penetration site during follow-up. Physicians should remember that CNV can occur as an unusual late complication of ocular penetration during retrobulbar anesthesia.


Precise characterization of nanometer-scale systems using interferometric scattering microscopy and Bayesian analysis.
Interferometric scattering microscopy can image the dynamics of nanometer-scale systems. The typical approach to analyzing interferometric images involves intensive processing, which discards data and limits the precision of measurements. We demonstrate an alternative approach: modeling the interferometric point spread function and fitting this model to data within a Bayesian framework. This approach yields best-fit parameters, including the particle's three-dimensional position and polarizability, as well as uncertainties and correlations between these parameters. Building on recent work, we develop a model that is parameterized for rapid fitting. The model is designed to work with Hamiltonian Monte Carlo techniques that leverage automatic differentiation. We validate this approach by fitting the model to interferometric images of colloidal nanoparticles. We apply the method to track a diffusing particle in three dimensions, to directly infer the diffusion coefficient of a nanoparticle without calculating a mean-square displacement, and to quantify the ejection of DNA from an individual lambda phage virus, demonstrating that the approach can be used to infer both static and dynamic properties of nanoscale systems.


Inorganic arsenic-mediated upregulation of TUG1 promotes apoptosis in human bronchial epithelial cells by activating the p53 signaling pathway.
Exposure to arsenic, an environmental contaminant, is known to cause arsenicosis and cancer. Although considerable research has been conducted to understand the underlying mechanism responsible for arsenic-induced cancers, the precise molecular mechanisms remain unknown, especially at the epigenetic regulation level. Long non-coding RNAs (LncRNAs) that have been shown to mediate various biological processes, including proliferation, apoptosis, necrosis, and mutagenesis. There are few studies on LncRNAs and biological damage caused by environmental pollutants. The LncRNAs taurine upregulated gene 1 (TUG1) regulates cell growth both in vitro and in vivo, and contributes its oncogenic role. However, the precise roles and related mechanisms of arsenic-induced cell apoptosis are still not fully understood owing to controversial findings in the literature. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed higher expression levels of TUG1 in people occupationally exposed to arsenic than in individuals living away from the source of arsenic exosure (N = 25). In addition, the results suggested that TUG1 was involved in arsenic-induced apoptosis. Furthermore, knockdown experiments showed that silencing of TUG1 markedly inhibited proliferation, whereas depletion of TUG1 led to increased apoptosis. The TUG1-small interfering RNA (siRNA) combination with arsenic (3 μM/L) slightly increased apoptosis compared with the TUG1-siRNA. Additionally, the knockdown experiments showed that the silencing of TUG1 by siRNA inhibited proliferation and promoted apoptosis by inducing p53, p-p53 (ser392), FAS, BCL2, MDM2, cleaved-caspase7 proteins in 16HBE cells. These results indicated that arsenic mediates the upregulation of TUG1 and induces cell apoptosis via activating the p53 signaling pathway.


Fascicular Ventricular Tachycardia Originating From Papillary Muscles: Purkinje Network Involvement in the Reentrant Circuit.
Verapamil-sensitive fascicular ventricular tachycardia (FVT) has been demonstrated to be a reentrant mechanism using the Purkinje network as a part of its reentrant circuit. Although the papillary muscles (PMs) are implicated in arrhythmogenic structure, reentrant FVT originating from the PMs has not been well defined. We studied 13 patients in whom FVT was successfully eliminated by ablation at the posterior PMs (n=8; PPM-FVT) and anterior PMs (n=5; APM-FVT). Although intravenous administration of verapamil (5 mg) terminated ventricular tachycardia (VT) in 6 patients, VT was only slowed in the remaining 7 patients. PPM-FVT exhibited right bundle branch block and superior right axis (extreme right axis) or horizontal axis deviation. APM-FVT exhibited right bundle branch block configuration and right axis deviation with deep S wave in leads I, V5, and V6. VT was reproducibly induced by programmed atrial or ventricular stimulation. His-ventricular interval during VT was shorter than that during sinus rhythm. Ablation at the left posterior or anterior fascicular regions often changed the QRS morphology but did not completely eliminate it. Mid-diastolic Purkinje potentials were recorded during VT around the PMs, where ablation successfully eliminated the tachycardia. All patients have been free from recurrent VT after ablation. Reentrant circuit of verapamil-sensitive FVT can involve the Purkinje network lying around the PMs. PM-FVT is a distinct entity that is characterized by distinctive electrocardiographic characteristics and less sensitivity to verapamil administration compared with common type FVT. Ablation targeting the mid-diastolic Purkinje potentials around the PMs during tachycardia can be effective in suppressing this arrhythmia.


Early leg blood flow adjustment during dynamic foot plantarflexions in upright and supine body position.
The time courses of leg blood flow, systolic peak velocity, heart rate and blood pressure have been studied in nine health volunteers during dynamic exercise in upright sitting and in a tilted sitting body position. In both positions the subjects performed single and repeated foot plantarflexions against light and moderate forces corresponding to 5%-10% and 25%-30% of maximal voluntary contraction. The following measurement techniques were used: Doppler ultrasound method (blood flow parameters), FINAPRES device (arterial blood pressure) and standard ECG chest leads (heart rate). At rest the supine blood flow parameters measured in the arteria femoralis were significantly higher than in the upright sitting position. In both positions, even one single plantarflexion at the light exercise intensity caused significant increases in blood flow for almost 20s. The major part of the blood flow response to repeated contractions always occurred within the first 10s at virtually unchanged blood pressures. During this initial phase upright leg blood flow increased by factors of 2.5 (light exercise) and 3.1 (moderate exercise). The corresponding values in the tilted sitting posture were 1.7 and 1.9, respectively. The initial increases in the upright position were too large to be attributed only to the increase of the perfusion pressure caused by the withdrawal of the hydrostatic pressure on the venous side ("muscle pump"). Additional, fast decreases in local resistance have to be considered. In the supine posture effects on local resistance have to be taken into account for the early increases in blood flow since hydrostatic effects on arterio-venous pressure differences are too small. The present findings indicate that the effects of repeated contraction-relaxation cycles on the early adjustment of muscle blood flow are not sufficiently described by a "muscle pump" that induces only venous volume shifts and hydrostatic pressure changes. Additional fast effects on local resistance have to be taken into account.


Endoscope- and video-assisted endodontic surgery.
Since the introduction of microsurgical principles in the 1990s, the field of endodontic surgery has made continuous and substantial progress. Particularly, root-end cavity preparation has been simplified and optimized by means of newly developed surgical microinstruments. However, the successful outcome of endodontic surgery depends to a large extent on accurate intraoperative diagnostics. Conventionally, micromirrors (retromirrors) and microprobes have been used for this purpose. Recently, the surgical microscope has been used to enhance visibility during dental procedures. In addition, endoscopy has been reported to provide the surgeon with outstanding vision and ease of use. This article describes the technical specifications and the diagnostic application of the endoscope during endodontic surgery.


Concurrent IgA Nephropathy and Membranous Nephropathy, Is It an Overlap Syndrome?
IgA nephropathy (IgAN) and membranous nephropathy (MN) are common glomerulonephritis, the presence of which in the same patient- concurrent of IgAN and MN (cIgAN/MN) has been described occasionally. This study aims to show clinical-pathological features of cIgAN/MN and attempts to suggest underlying pathogenesis using disease-specific biomarkers and a genomics approach. This retrospective cohort study described the clinical and pathological data from 137 patients with cIgAN/MN diagnosed in Peking University First Hospital from 2005 to 2019. One hundred primary IgAN and 100 MN cases were randomly selected as disease controls between the same time interval. Moreover, disease-specific biomarkers and polygenic risk score models were conducted to reveal the underlying pathogenesis. The median age of the cIgAN/MN cases was 45-year-old, and 46% were women. Compared to IgAN, patients with cIgAN/MN had a higher level of 24-hour proteinuria excretion but lower microscopic hematuria. They had a lower median level of galactose-deficient IgA1 (Gd-IgA1, 4.00 versus 5.45 μg/ml, P=0.002) as well as the standardized genetic risk scores of developing IgAN (GRSs: 0.05 versus 0.68, P<0.001). Compared to MN, patients with cIgAN/MN had a lower proportion of nephrotic syndrome and a lower level of albumin-to-creatinine ratio. However, the 24-hour proteinuria levels, serum lipid profiles, proportion of hypertension, and pathology classification were similar. Patients with cIgAN/MN had lower levels of plasma autoantibodies against the M-type transmembrane phospholipase A2 receptor (PLA2R) (11.23 versus 36.59 U/ml, P=0.005). Intriguingly, there were no statistical differences in standardized GRSs of developing MN between them (2.77 versus 3.02, P=0.326). Compared to IgAN, cIgAN/MN may lean towards MN more according to clinical-pathological features, disease-specific biomarker levels, and disease-specific genetic risk scores.


Effects of external iron concentration upon seedling growth and uptake of Fe and phosphate by the common reed, Phragmites australis (Cav.) Trin ex. Steudel.
The objectives of this study were to determine whether, and to what degree, the aqueous iron concentration in the growing medium affects the growth of, and Fe uptake by, Phragmites australis, and whether the presence of iron in the growing environment affects the uptake of the essential element phosphate. The wetland macrophyte P. australis was grown under laboratory conditions in nutrient solution (0.31 mg L(-1) phosphate) containing a range of iron concentrations (0-50 mg L(-1) Fe). A threshold of iron concentration (1 mg L(-1)) was found, above which growth of P. australis was significantly inhibited. No direct causal relationship between iron content in aerial tissues and growth inhibition was found, which strongly suggests that iron toxicity cannot explain these results. Phosphate concentrations in aerial tissues were consistently sufficient for growth and development (2-3 % d. wt) despite significant variation in concentration of phosphate associated with roots. External Fe concentration had a significant effect on the growth of P. australis and on both Fe and phosphate concentrations associated with roots. However, neither direct toxicity nor phosphate deficiency could explain the reduction in growth above 1 mg L(-1) external Fe concentration


Eradication of Plasmodium falciparum from Erythrocytes by Controlled Reactive Oxygen Species via Photodynamic Inactivation Coupled with Photofunctional Nanoparticles.
We investigated the antimalarial effect of photodynamic inactivation (PDI) coupled with magnetic nanoparticles (MNPs) as a potential strategy to combat the emergence of drug-resistant malaria and resurgence of malaria after treatment. Because the malarial parasite proliferates within erythrocytes, PDI agents need to be taken up by erythrocytes to eradicate the parasite. We used photofunctional MNPs as the PDI agent because nanosized particles were selectively taken up by Plasmodium-infected erythrocytes and remained within the intracellular space due to the enhanced permeability and retention effect. Also, the magnetism of Fe3O4 nanoparticles can easily be utilized for the collection of photofunctional nanoparticles (PFNs), and the uptaken PFNs infected the erythrocytes after photodynamic treatment with external magnetics. Photofunctionality was provided by a photosensitizer, namely, pheophorbide A, which generates reactive oxygen species (ROS) under irradiation. PAs were covalently bonded to the surface of the MNPs. The morphology and structural characteristics of the MNPs were investigated by scanning electron microscopy and X-ray diffraction (XRD), whereas the photophysical properties of the PFNs were studied with Fourier transform infrared, absorption, and emission spectroscopies. Generation of singlet oxygen, a major ROS, was directly confirmed with time-resolved phosphorescence spectroscopy. To evaluate the ability of PFNs to kill malarial parasites, the PDI effect of PFNs was evaluated within the infected erythrocytes. Furthermore, malarial parasites were completely eradicated from the erythrocytes after PDI treatment using PFNs on the basis of an 8 day erythrocyte culture test.


Occurrence, seasonal variation and removal efficiency of antibiotics and their metabolites in wastewater treatment plants, Jiulongjiang River Basin, South China.
Wastewater treatment plants (WWTPs) are regarded as one of the most important sources of antibiotics in the environment. The occurrence, seasonal variation and removal efficiency of 21 antibiotics and 10 metabolites, including five sulfonamides and three of their metabolites, six quinolones, two macrolides, two β-Lactams and five tetracyclines and seven of their metabolites, were investigated in five WWTPs in different seasons in the Jiulongjiang River Region, South China. 16 antibiotics and 6 metabolites in summer and 14 antibiotics and 6 metabolites in winter were found, respectively. The most frequently detected antibiotics were sulfamethazine, sulfamethoxazole, n-acetyl sulfamethazine, n-acetyl sulfamethoxazole, ofloxacin, cephalexin monohydrate and cephradine; of these, the concentration of cephradine was the highest in most of the influent and effluent samples. The highest level of total antibiotics was found in Longyan City WWTPs, where there are more population and swine farms. Seasonal variation of the antibiotics in wastewater samples was also studied. The concentrations of antibiotics in winter were higher than those in summer. The antibiotics could not be removed completely by the WWTPs, and the mean removal efficiency ranged from -71.6 to 56.3%. Of all the antibiotics, the tetracyclines were removed comparatively more efficiently, probably due to their adsorption to sludge. The low removal efficiency of antibiotics in WWTPs could be one of the important reasons for the presence of antibiotics in the environment in Jiulongjiang Region.


An AnteOwl WR intravascular ultrasound-guided parallel wiring technique for chronic total occlusion of below-the-knee arteries.
Although endovascular therapy is used to treat chronic limb-threatening ischemia, long chronic total occlusion (CTO) is still challenging to treat. Especially in patients with poor run-off below-the-knee (BTK) arteries, it is difficult to perform a retrograde approach, and even guidewire passage may be difficult. We treated two cases of chronic limb-threatening ischemia using our novel extreme antegrade guidewire crossing technique by AnteOwl WR intravascular ultrasound (IVUS)-guided parallel wiring to a BTK artery (EXCAVATOR technique). Case 1 was a 70-year-old man with ulceration of the right toe. The AnteOwl WR IVUS was intentionally advanced into the subintimal space of the posterior tibial artery, and the totally intraplaque route was advanced by IVUS-guided parallel wiring that was successfully passed from the lateral plantar aspect to the true lumen of the digital artery. Case 2 was a 76-year-old woman with rest pain and cyanosis of the right lower limb. Angiography showed total occlusion from the superficial femoral artery to BTK arteries. AnteOwl WR IVUS-guided parallel wiring was repeatedly performed until the distal true lumen of the peroneal artery was reached, and revascularization was successfully achieved via the antegrade approach alone. With its excellent crossable performance, good image quality, and high navigational ability within the CTO, the AnteOwl WR can be used to pass parallel wiring into the distal true lumen for BTK CTO.


The Tick Microbiota Dysbiosis Promote Tick-Borne Pathogen Transstadial Transmission in a Babesia microti-Infected Mouse Model.
Ticks are obligate hematophagous ectoparasites. They are important vectors for many pathogens, of both medical and veterinary importance. Antibiotic residues in animal food are known, but very little is known about the effects of antibiotic residues in animals on the microbiome diversity of ticks and tick-borne pathogen transmission. We used a Haemaphysalis longicornis-infested mouse model to evaluate the effect of antibiotic usage on tick microbiome. Nymphal ticks were fed on an antibiotic cocktail-treated or water control mice. Adult ticks molted from nymphs fed on the antibiotic cocktail-treated mouse had a dysbiosed microbiota. Nymphal ticks were also fed on a B. microti-infected mice that had been treated with antibiotic cocktail or water. We found that the B. microti infection in adult ticks with a dysbiosed microbiota (44.7%) was increased compared with the control adult ticks (24.2%) by using qPCR targeting 18S rRNA gene. This may increase the risk of tick-borne pathogens (TBPs) transmission from adult ticks to a vertebrate host. These results show that an antibiotic-treated mouse can induce tick microbiota dysbiosis. Antibiotic treatment of B. microti-infected mouse poses the possibility of increasing transstadial transmission of B. microti from the nymph to the adult H. longicornis. These findings suggest that B. microti transmission may be exacerbated in high antibiotic usage areas.


Bidirectional Soliton Rain Dynamics Induced by Casimir-Like Interactions in a Graphene Mode-Locked Fiber Laser.
We study experimentally and theoretically the interactions among ultrashort optical pulses in the soliton rain multiple-pulse dynamics of a fiber laser. The laser is mode locked by a graphene saturable absorber fabricated using the mechanical transfer technique. Dissipative optical solitons aggregate into pulse bunches that exhibit complex behavior, which includes acceleration and bidirectional motion in the moving reference frame. The drift speed and direction depend on the bunch size and relative location in the cavity, punctuated by abrupt changes under bunch collisions. We model the main effects using the recently proposed noise-mediated pulse interaction mechanism, and obtain a good agreement with experiments. This highlights the major role of long-range Casimir-like interactions over dynamical pattern formations within ultrafast lasers.


The BH3 only Bcl-2 family member BNIP3 regulates cellular proliferation.
The BH3-only family member BNIP3 has been described as either promoting cell survival or cell death. This depends upon the level of BNIP3 expression and its cellular localization. Increased BNIP3 expression under hypoxia contributes to cell death through increased mitochondrial dysfunction. Furthermore, mice lacking BNIP3 show inhibition of ischemic cardiomyocyte apoptosis. In contrast, nuclear localization of BNIP3 contributes to blockage of apoptosis in glioma cells through repression of pro-apoptotic genes. We have discovered that mouse embryonic fibroblasts (MEFs) lacking BNIP3 expression show increased proliferation and cell number compared to wild-type cells. Furthermore, the cells lacking BNIP3 showed increased MAPK activation. Increased proliferation was not due to decreased cell death as oxidative stress induced cell death in BNIP3 null MEFs. In addition, we isolated astrocytes from wild-type or embryonic mice lacking expression of BNIP3. There was increased density and cell number in the astrocytes lacking BNIP3 expression. To confirm these results in human cells, we inducibly expressed BNIP3 in human embryonic kidney (HEK293) cells and found that induced BNIP3 reduced cell proliferation and failed to change background cell death levels. Transient over-expression of BNIP3 in the nucleus of HEK293 cells also reduced DNA synthesis. Finally, to determine whether this increased proliferation occurs in mice lacking BNIP3, we isolated brains from wild-type mice or those lacking BNIP3 expression. The mice lacking BNIP3 had increased cellularity in the brain of embryonic and adult mice. Taken together, our study describes a new function for BNIP3 in the regulation of cellular proliferation.


[Changes in the energy status of synchronous Escherichia coli cultures during aerobic-anaerobic transitions].
The behaviour of energy and growth parameters for a synchronous Escherichia coli culture was studied in the course of aerobic-anaerobic transitions induced by either reversible or constant cessation of aeration at different phases of the cell cycle. The intracellular concentrations of ATP, ADP and AMP were assayed using a technique developed by the authors and based on thin-layer chromatography of adenyl nucleotide dansyl derivatives. Prolonged anaerobiosis led to profound alterations in the energy status which diminished the energy flux in constructional processes and preserved the energy resources for maintenance needs. The response of the energy parameters to a transitory anaerobic shock depended on the phase of synchronous growth and, apparently, on the ratio between the rates of reactions supplying and consuming the energy, which underwent changes in the cell cycle.


Increased Rac1 Activation in the Enhanced Carbachol-Induced Bronchial Smooth Muscle Contraction of Repeatedly Antigen-Challenged Mice.
Recently, we demonstrated that Rac1 upregulation is involved in augmented bronchial smooth muscle (BSM) contractions of antigen-challenged mice. However, change in G protein-coupled receptor (GPCR)-induced Rac1 activation remains unknown in BSMs of repeatedly antigen-challenged (Chal.) mice. We here examined carbachol (CCh)-induced Rac1 activation in BSMs of Chal. mice. Gene expression levels of both Rac1 and Rac-guanine nucleotide exchange factors (GEFs), such as Tiam1 and Trio, were increased in BSMs of Chal. mice. Furthermore, CCh-induced Rac1 activation was inhibited by pretreatment with Rac1-GEF inhibitor NSC23766 and Rac1 inhibitor EHT1864 in BSMs of sensitized-control (S.C.) and Chal. mice. Compared with S.C. mice, CCh-induced Rac1 activation was increased in BSMs of Chal. mice. In conclusion, we reported that increased CCh-induced Rac1 activation via Tiam1 and Trio upregulation, in addition to upregulate Rac1, may be involved in increased CCh-induced BSM contractions in Chal. mice.


Clinical evaluation of serodiagnosis of active tuberculosis by multiple-antigen ELISA using lipids from Mycobacterium bovis BCG Tokyo 172.
The humoral immune responses of 69 active tuberculosis (TB) patients against three major mycobacterial lipid antigens, monoacyl phosphatidylinositol dimannoside (Ac-PIM2), trehalose 6,6'-dimycolate (TDM-T) and trehalose 6-monomycolate (TMM-T) from Mycobacterium bovis BCG Tokyo 172, were examined by ELISA. IgG antibodies from active TB patients were reactive against each of the three lipid antigens (Ac-PIM2, TDM-T and TMM-T), giving positive results of 42.0-59.4%. If tests were combined and an overall positive was scored when any of the three tests was positive, sensitivity was 71.0%, showing better discrimination between patients and normal subjects. Although this value is not satisfactory for the clinical diagnosis of active TB, it is still higher than values for Determinar TBGL (56.5%) and MycoDot (31.9%) test results, both of which are commercially available. IgG antibody responses to particular lipid antigens in an individual patient differed diversely between patients. Positive IgG antibody rates and IgG antibody levels to lipid antigens were mostly paralleled by the amount of mycobacteria excreted and by the severity of pathological lesions (size and cavity formation). Serologically positive responsiveness was shown in 60.0% of tuberculin skin test (TST)-negative TB patients. Furthermore, seropositivity for multiple-antigen ELISA in active TB patients was demonstrated in other possible immune-suppressed cases, such as senile, diabetes mellitus and fulminant TB patients. Therefore, in contrast to tests based on cellular immune responses such as the TST, the humoral immune responses of TB patients against mycobacterial lipid antigens were disease-specific and were shown to be useful for the early diagnosis of active TB disease in conjunction with smear and cultivation tests, even if cellular immune responses are decreased.


Effects of somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonists on the growth of human small-cell and non-small-cell lung carcinomas in nude mice.
We investigated the effects of our synthetic bombesin/gastrin-releasing peptide (GRP) antagonists and somatostatin analogue RC-160 on the growth of human small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (non-SCLC) lines in nude mice. Athymic nude mice bearing xenografts of the SCLC NCl-H69 line or non-SCLC NCl-H157 line were treated for 5 and 4 weeks, respectively, with somatostatin analogue RC-160 or various bombesin/GRP antagonists. RC-160, administered s.c. peritumorally at a dose of 100 micrograms per animal per day, inhibited the growth of H69 SCLC xenografts as shown by more than 70% reduction in tumour volumes and weights, as compared with the control group. Bombesin/GRP antagonists, RC-3440, RC-3095 and RC-3950-II, given s.c. peritumorally at a dose of 20 micrograms per animal per day, also inhibited the growth of H69 SCLC tumours. RC-3950-II had the greatest inhibitory effect and decreased tumour volume and weights by more than 80%. The growth of H-157 non-SCLC xenografts was significantly reduced by treatment with RC-160, but not with bombesin/GRP antagonist RC-3095. In mice bearing either tumour model, administration of RC-160 significantly decreased serum growth hormone and gastrin levels. Specific high-affinity receptors for bombesin and somatostatin were found on membranes of SCLC H69 tumours, but not on non-SCLC H157 tumours. Receptor analyses demonstrated high-affinity binding sites for epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on the membranes of H69 and H157 tumours. EGF receptors were down-regulated on H69 tumours after treatment with RC-160 and bombesin/GRP antagonists. The concentration of binding sites for EGF and IGF-I on the H157 tumours was decreased after treatment with RC-160, but bombesin/GRP antagonist RC-3095 had no effect. These results demonstrate that bombesin/GRP antagonists inhibit the growth of H-69 SCLC, but not of H-157 non-SCLC xenografts in nude mice, whereas somatostatin analogue RC-160 is effective in both tumour models. This raises the possibility that these peptide analogues could be used selectively in the treatment of various subclasses of lung cancer.


Neuroprotective effect of sodium ferulate and signal transduction mechanisms in the aged rat hippocampus.
To investigate whether the age-related increase in interleukin-1beta (IL-1beta) and c-Jun N-terminal kinases (JNK) pathway was coupled with a decrease in cell survival signaling pathways and whether sodium ferulate (SF) treatment was effective in preventing these age-associated changes. Groups of young and aged rats were fed for 4 weeks on a diet enriched in SF (100 mg/kg and 200 mg/kg per day). At the end of the period of dietary manipulation, Western blotting analysis was used to determine the expressions of IL-1beta, phosphorylated mitogen-activated protein kinase kinase (MKK)4, phospho-JNK, phospho-c-Jun, phosphorylated extracellular signal-regulated kinase (ERK1/2), phospho-MEK, phospho-Akt, phosphorylated ribosomal protein S6 protein kinase (p70S6K), and activated caspase-3 and caspase-7. Nissl staining was used to observe the morphological change in hippocampal CA1 regions. Immunohistochemical techniques for glial fibrillary acidic protein (GFAP) and integrin alphaM (OX-42) were used to determine the astrocyte and microglia activation. IL-1beta protein levels, and phospho-MKK4, phospho-JNK1/2, and phospho-c-Jun were significantly enhanced in hippocampus prepared from age-matched control rats. Increased IL-1beta production and JNK1/2 activation was accompanied by downregulation of MEK/ERK1/2 pathway and Akt/p70S6K pathway, leading to cell apoptosis assessed by activation of caspase-3. Significantly, treatment of aged rats with SF (100 mg/kg and 200 mg/kg per day) for 4 weeks prevented the agerelated increase in IL-1beta and IL-1beta-induced JNK signaling pathway and also the age-related changes in ERK and Akt kinase. SF plays neuroprotective roles through suppression of IL-1beta and IL-1beta-induced JNK signaling and upregulation of MEK/ERK1/2 and Akt/p70S6K survival pathways.


[Alternative therapy concept for the treatment of psychosomatic disorders. Controlled double-blind evaluation of fluspirilene versus bromazepam].
Today, Fluspirilene 1.5 mg i.m. (Imap 1,5 mg), is used to treat psychosomatic conditions, anxiety states and psychogenic disorders. The present article reports on clinical studies involving these indications. The efficacy of Fluspirilene 1.5 mg i.m. was demonstrated in patients with functional organic complaints, autonomic emotional symptom complexes, patients with anxiety, patients with functional heart complaints, and patients with functional gynaecological disorders. The results of a controlled study of 1.5 mg Fluspirilene i.m. and 6 mg Bromazepam are discussed. Forty-five patients from a neurologist's practice participated, all of whom had been classified as treatment-requiring patients with neurotic anxiety, on the basis of the physician's diagnosis and psychometric examination. Treatment lasted 42 days. The clinical assessment by the physician revealed that 1.5 mg Fluspirilene i.m. is significantly more effective than Bromazepam. The psychometric findings showed that patients with marked somatic anxiety treated with Fluspirilene showed greater improvement as expressed in a reduction in anxiety, lightening of mood, and increased activity, as compared with Bromazepam.


Effect of nanoparticle clustering on the effective thermal conductivity of concentrated silica colloids.
Recent research on nanofluids has offered particle clustering as a possible mechanism for the abnormal enhancement of the effective thermal conductivity (k) when nanoparticles are dispersed in liquids. This paper was devoted to verify experimentally and theoretically the significance of the effect by altering the cluster structure, size distribution, and thermal conductivity of solid particles in water. Starting with well dispersed SiO2 sols in water as a reference system, we control the aggregation kinetics by adjusting pH. Contrary to previous model predictions, the present experiment showed that clustering did not show any discernable enhancement in the thermal conductivity even at high volume loading. A series of fractal model calculations not only suggested that the conductive benefit due to clustering might be completely compensated by the reduced convective contribution due to particle growth, but also recommended the need for higher thermal conductivity and optimized fractal dimension of particles for maximizing the clustering effect.


Interaction of hydrogen with cerium oxide surfaces: a quantum mechanical computational study.
The interaction of the (110) and (111) surfaces of ceria (CeO(2)) with atomic hydrogen is studied with ab initio calculations based on density functional theory. A Hubbard U term added to the standard density functional allows to accurately describe the electronic structure of the two surfaces. The minimum energy configuration for the adsorbed H on each of the two surfaces is obtained. An O-H-O bridge is formed on the (110) surface, whereas an axial tricoordinated OH group results on the (111) surface. For both surfaces, the adsorption of an H atom is accompanied by the reduction of a single Ce ion (which is one of the nearest neighbors of the adsorbed atom) and by a substantial outward protrusion of the O atom(s) directly bound to H. The adsorption of atomic H on the (110) and (111) surfaces is energetically favored by -150.8 and -128.3 kJ/mol, respectively, with respect to free molecular H(2). The calculated frequencies for the OH stretching vibrational mode are 3100 cm(-1) for the (110) surface and 3627 cm(-1) for the (111) surface. The latter value is in excellent agreement with experimental data reported in the literature.


Safety and Feasibility of Direct Magnetic Resonance Imaging-guided Transperineal Prostate Biopsy Using a Novel Magnetic Resonance Imaging-safe Robotic Device.
To evaluate safety and feasibility in a first-in-human trial of a direct magnetic resonance imaging (MRI)-guided prostate biopsy using a novel robotic device. MrBot is an MRI-safe robotic device constructed entirely with nonconductive, nonmetallic, and nonmagnetic materials and developed by our group. A safety and feasibility clinical trial was designed to assess the safety and feasibility of a direct MRI-guided biopsy with MrBot and to determine its targeting accuracy. Men with elevated prostate-specific antigen levels, prior negative prostate biopsies, and cancer-suspicious regions (CSRs) on MRI were enrolled in the study. Biopsies targeting CSRs, in addition to sextant locations, were performed. Five men underwent biopsy with MrBot. Two men required Foley catheter insertion after the procedure, with no other complications or adverse events. Even though this was not a study designed to detect prostate cancer, biopsies confirmed the presence of a clinically significant cancer in 2 patients. On a total of 30 biopsy sites, the robot achieved an MRI-based targeting accuracy of 2.55 mm and a precision of 1.59 mm normal to the needle, with no trajectory corrections and no unsuccessful attempts to target a site. Robot-assisted MRI-guided prostate biopsy appears safe and feasible. This study confirms that a clinically significant prostate cancer (≥5-mm radius, 0.5 cm3) depicted in MRI may be accurately targeted. Direct confirmation of needle placement in the CSR may present an advantage over fusion-based technology and gives more confidence in a negative biopsy result. Additional study is warranted to evaluate the efficacy of this approach.


A glycine-rich RNA-binding protein mediating cold-inducible suppression of mammalian cell growth.
In response to low ambient temperature, mammalian cells as well as microorganisms change various physiological functions, but the molecular mechanisms underlying these adaptations are just beginning to be understood. We report here the isolation of a mouse cold-inducible RNA-binding protein (cirp) cDNA and investigation of its role in cold-stress response of mammalian cells. The cirp cDNA encoded an 18-kD protein consisting of an amino-terminal RNAbinding domain and a carboxyl-terminal glycine-rich domain and exhibited structural similarity to a class of stress-induced RNA-binding proteins found in plants. Immunofluorescence microscopy showed that CIRP was localized in the nucleoplasm of BALB/3T3 mouse fibroblasts. When the culture temperature was lowered from 37 to 32 degrees C, expression of CIRP was induced and growth of BALB/3T3 cells was impaired as compared with that at 37 degrees C. By suppressing the induction of CIRP with antisense oligodeoxynucleotides, this impairment was alleviated, while overexpression of CIRP resulted in impaired growth at 37 degrees C with prolongation of G1 phase of the cell cycle. These results indicate that CIRP plays an essential role in cold-induced growth suppression of mouse fibroblasts. Identification of CIRP may provide a clue to the regulatory mechanisms of cold responses in mammalian cells.


Healthcare workers' behaviors and personal determinants associated with providing adequate sexual and reproductive healthcare services in sub-Saharan Africa: a systematic review.
Healthcare workers may affect the utilization of sexual and reproductive healthcare (SRH) services, and quality of care thereof, for example by their behaviours or attitudes they hold. This can become a hindrance to accessing and utilizing SRH services, particularly by young people, and thus a better understanding of these behaviours and associated factors is needed to improve access to and utilization of SRH services. A systematic review of literature was conducted to identify studies focusing on healthcare workers' behaviors and personal determinants associated with providing adequate SRH services in sub-Saharan Africa (January 1990 - October 2015). Five databases were searched until 30th October 2015, using a search strategy that was adapted based on the technical requirements of each specific database. Articles were independently screened for eligibility by two researchers. Of the 125-screened full-text articles, 35 studies met all the inclusion criteria. Negative behaviours and attitudes of healthcare workers, as well as other personal determinants, such as poor knowledge and skills of SRH services, and related factors, like availability of essential drugs and equipment are associated with provision of inadequate SRH services. Some healthcare workers still have negative attitudes towards young people using contraceptives and are more likely to limit access to and utilization of SRH by adolescents especially. Knowledge of and implementation of specific SRH components are below optimum levels according to the WHO recommended guidelines. Healthcare workers' negative behaviours and attitudes are unlikely to encourage women in general to access and utilize SRH services, but more specifically young women. Knowledge of SRH services, including basic emergency obstetric care (EmOC) is insufficient among healthcare workers in SSA. A protocol for this systematic review was registered with PROSPERO and the registration number is: CRD42015017509 .


Behavioral interventions to improve asthma outcomes: a systematic review of recent publications.
Asthma outcomes are influenced by factors at multiple ecological levels: the individual and his/her family, home, medical care, and community. This systematic review describes recently published single-level and multilevel behavioral interventions to improve asthma outcomes. Of the 23 total title/abstracts reviewed in the original systematic search of PubMed, Ovid, Scopus, PsychINFO, and CIHAHL reference review databases, six met inclusion criteria. Five of the studies focused on low-income and/or minority populations. Promising interventions include culturally tailored online asthma self-management programs and family-centered asthma education delivered at the bedside during hospitalization for an acute asthma exacerbation. Culturally, tailored online self-management programs offer difficult-to-reach populations asthma support that can be completed at the time and pace most convenient for the individual user. Family-focused asthma education, delivered at the bedside during an acute asthma hospitalization by highly motivated lay volunteers, is an efficacious and low-cost approach to improving pediatric asthma self-management.


Characteristics of adherence of enteroaggregative Escherichia coli to human and animal mucosa.
An Escherichia coli strain (serotype O127a:H2) that had been isolated from a child with diarrhea in Thailand and that was negative for the virulence factors of the four categories of diarrheagenic E. coli (enterotoxigenic, enteropathogenic, enteroinvasive, and enterohemorrhagic) and that showed an aggregative pattern of adherence to HeLa cells was investigated for adherence to native or Formalin-fixed human and animal mucosa. The hemagglutinating activity and adherence ability of the bacteria were resistant to D-mannose and were strictly regulated by environmental conditions. Genetic data supported the close relation between the hemagglutinating activity and adherence ability. In accordance with the adherence pattern on tissue-cultured cells, the bacteria adhered to human and animal mucosa, as evidenced by a direct gold-labeling analysis. In human intestines, Formalin-fixed mucous coatings, epithelial cells of colonic mucosa, epithelial cells of ileal single lymphoid follicles and Peyer's patches, and the absorptive cells of jejunal or ileal villi provided adherence targets. Adherence to M cells in the Peyer's patch-associated epithelium was also confirmed. The adherence levels to native jejunal or ileal human villi were low, as was the case with the corresponding Formalin-fixed villi. In human urinary tract, the superficial epithelial cells of both native and Formalin-fixed ureter provided striking adherence targets. In animal (porcine and rabbit) small intestines, the bacteria adhered to the native villi to a lesser extent than to the Formalin-fixed villi. The adherence levels were compared with those of enterotoxigenic E. coli with colonization factor antigen (CFA)/I pili or CFA/II pili. The data suggested unique mucosa adherence characteristics of the enteroaggregative E. coli strain. The possibility of the adherence ability as a virulence factor was discussed.


Identification of peptide:N-glycanase activity in mammalian-derived cultured cells.
The recent finding of peptide:N-glycanase (PNGase) in medaka embryos (Seko, A., Kitajima, K., Inoue, Y., & Inoue, S., J.Biol. Chem. 266, 22110 (1991)) raised the question of how widespread is the occurrence of this type of de-N-glycosylating enzyme. In experiments designed to identify PNGase in the mammalian system, we searched for its activity in some cultured cell lines. Incubation of a 14C-labeled N-glycopeptide with extracts prepared from cultured cells resulted in producing the free glycan and the peptide. Detailed characterizations of the products, formed upon incubation of a 14C-labeled N-glycopeptide substrate with the enzyme preparation from C3H mouse loose connective tissue-derived L-929 cells, by HPLC, amino acid and carbohydrate composition analyses, and peptide sequence analysis unequivocally established the reaction products to be the free glycan having di-N-acetylchitobiosyl sequence at its reducing end and free peptide in which the originally glycan-linked Asn residue was converted to the Asp residue. This represents the first demonstration of PNGase in mammalian cells and thus PNGase appears to be a very common enzyme expressed in not only plants and bacteria but also a wide range of animals although its functional significance remains to be clarified.


Career dreams among health care students: I want to make a difference.
There is a continuous increase in demand for health services in most countries because people who are older are living longer. Health care for people who are older is not, generally, an attractive career option for undergraduate health professionals. This study investigated career dreams among undergraduates studying a variety of health care subjects to understand what motivates them. Eighteen focus groups were conducted with 90 students, and template analysis was performed within a sociological framework. Four themes emerged from the analysis: no plans to work with people who are older, dreaming of making a difference, seeking variety, and the impact of clinical placements on stimulating or reducing interest in working with people who are older. Geriatrics and gerontology do not offer the opportunities that students are looking for in their future careers. There is a need to change the way we talk about adults who are older everywhere, not just in health care training. However, health care educators should also help students to understand the value of care provided to adults who are older.


Isolated Extranodal Natural Killer T-Cell Lymphoma of the Orbit in a Young Patient: Complete Regression with the SMILE Regimen.
Natural killer T-cell lymphoma (NKTL) is a highly malignant tumor that typically arises in the nose and/or paranasal sinuses. Isolated orbital involvement by NKTL is extremely rare, and only few case reports exist in the literature. Herein, we report a case of primary orbital NKTL in a young patient who showed very good response to chemotherapy with the SMILE regimen. A 28-year-old healthy female presented to us with epiphora and fullness of the lower eyelid. She had previously been diagnosed as orbital pseudotumor and was prescribed oral steroids. However, there was no response to the treatment. She also had a history of recurrent sinusitis. An incision biopsy revealed NKTL. A systemic workup did not reveal any other site of involvement. The patient received 6 cycles of chemotherapy (SMILE) and external beam radiotherapy. The tumor showed complete regression after 2 cycles of chemotherapy. The patient is disease free at 24 months of follow-up. Reported median survival for primary orbital NKTL is extremely poor. This is perhaps the first report of a primary orbital NKTL demonstrating a remarkable treatment response to a newer chemotherapy regimen (SMILE) in combination with radiotherapy.


[Encephalopathy and acute renal failure during acyclovir treatment].
Adverse neurological and renal effects can occur in patients taking acyclovir. Neurotoxicity of acyclovir results from an accumulation of the antiviral and its metabolites in the bloodstream. This can be observed in the elderly or in patients with chronic renal failure, generally in dialysis patients. Acute renal failure results from intratubular crystallization of acyclovir. A 78-year-old right-handed woman was admitted in an emergency setting for aphasia. Analysis of the cerebrospinal fluid was normal, but herpetic meningo-encephalitis was suspected and intravenous treatment was initiated with acyclovir. After the second infusion, the patient began to suffer from visual hallucinations, confusion and acute renal failure. Herpes PCR was negative in the cerebrospinal fluid, and the adverse drug reactions regressed completely after 72 hours. Renal function has to be checked often in patients given acyclovir for appropriate dose titration. Patients recover prompt from the adverse effects at drug withdrawal.


Immunoperoxidase versus immunofluorescence in the assessment of human renal biopsies.
For half a century, immunofluorescence (IF) on frozen sections has been the gold standard for immunohistochemical evaluation of renal biopsy specimens. In routine diagnostic immunohistopathologic evaluation, traditional IF has been replaced to a large extent by immunoperoxidase (IP) methods applied to paraffin sections of formaldehyde-fixed tissue. This is caused in part by the practical disadvantages inherent in the IF method, eg, separate tissue specimen and handling, UV microscopy, fading and impermanence of the label-making archiving, and difficult later investigation. Our aim for the present study is to evaluate IP as an alternative to IF in the diagnostic assessment of renal biopsy specimens. Proteolytic antigen retrieval, antibodies effective on deparaffinized sections, a sensitive detection system (Dako EnVision HRP; Dako, Copenhagen, Denmark), and a standardized and rigorously controlled procedure were applied to a series of renal biopsy specimens (n = 81) previously classified by means of light microscopy (LM) and IF. Staining for immunoglobulin G (IgG), IgA, IgM, C1q, and C3c were recorded as positive or negative for IF and IP in paired proportions, presuming that IF was the test standard. Concordant observations were 71% for all (282 of 398 observations), 82% for IgG (65 of 79 observations), and 89% for IgA (72 of 81 observations). The majority of discordant observations (74 of 116 observations) were positive by means of IP, with mesangial deposits of IgM and C1q that were not found by IF. Statistically, there was no significant difference in outcomes between IF and IP for IgG, IgA, and C3c ( P > 0.2). In addition, IP staining allowed simultaneous evaluation of tissue by LM and therefore correlation between tissue structure and immune deposits not readily attained by IF. In the present study, it is documented that for the detection of IgG, IgA, and C3c, IP applied to protease-digested deparaffinized sections of formaldehyde-fixed renal tissue is, with few exceptions, equal to IF on frozen sections. The EnVision HRP method used here is several times more effective in terms of primary antibody dilution than earlier existing IP methods, and because the avidin-biotin system is not involved, very little nonspecific background staining will occur. Discordant observations (116 of 398 observations; 29%) were in the majority (91 of 116 observations) due to positive IP findings of IgM and C1q, which deserve additional investigation.


Do neuroglobin and myoglobin protect Toxoplasma gondii from nitrosative stress?
Toxoplasma gondii is a Apicomplexa obligate intracellular protozoan parasite that infects up to a third of the world's population. In most humans infected with T. gondii, the disease toxoplasmosis is asymptomatic. However, T. gondii causes blindness, severe neurological disorders, hepatitis, and pneumonia in immunocompromised patients, and severe damage to the fetus. Here, we postulate that the colonization of the retina, heart, and skeletal muscle by T. gondii may reflect the role of neuroglobin (Ngb) and myoglobin (Mb) to protect the parasite from the toxoplasmacidal effects of nitric oxide (NO). This is based on the knowledge that Ngb and Mb catalyzes NO oxidation yielding the harmless nitrate. The postulated protective role of Ngb and Mb on the viability of T. gondii is reminiscent of that postulated for hemoglobin (Hb) and Mb in protecting intraerythrocytic Plasmodia and T. cruzi in cardiomyocytes, respectively, from the parasiticidal effect of NO. Therefore, undesirable pathogen protection by pseudo-enzymatic NO scavenging may represent a new unexpected function of members of the Hb superfamily.


Assessment of left atrial appendage function during sinus rhythm in patients with obstructive sleep apnea.
Obstructive sleep apnea (OSA) is associated with thromboembolic events. Compromised left atrial appendage (LAA) function due to left ventricular (LV) performance abnormality, often present in patients with OSA, may play an important role. The purpose of this study is to evaluate LV and LAA mechanical functions during sinus rhythm (SR) in patients with OSA. LV and LAA functions were assessed in 43 OSA patients and compared with that of 20 control patients in SR. Tissue Doppler velocities of the LAA apex and emptying velocities (EV) of LAA were obtained on parasternal short-axis view. The baseline clinical characteristics were similar except for AHI (apnea-hypopnea index), minimal SaO2, mean SaO2, hypertension, and body-surface area. Most of the LV echocardiographic parameters significantly deteriorated in OSA patients in comparison with those in the control group. LAA EV, LAA systolic relaxation velocity (SM), LAA early-diastolic velocity (EM), LAA contraction velocity (AM), left atrial (LA) minimum volume index, LA ejection fraction, LA conduit volume index, and LA reservoir volume index were lower in OSA patients compared with those in the control group (p<0.05). LAA AM was negatively correlated with AHI and the ratio of peak early diastolic flow velocity (E) to early-diastolic (E') and positively correlated with LA conduit volume (p<0.05). Multiple predictors for LAA AM were AHI, presence of diastolic dysfunction, and E/E' values (p<0.05). LAA mechanical function is significantly depressed in patients with OSA and SR. LAA dysfunction may predispose these patients to thromboembolic events. The evaluation of LAA mechanical function by tissue Doppler study using transthoracic echocardiography (TTE) may become an alternative for routine work-up in OSA patients.


Describing complex disease progression using joint latent class models for multivariate longitudinal markers and clinical endpoints.
Neurodegenerative diseases are characterized by numerous markers of progression and clinical endpoints. For instance, multiple system atrophy (MSA), a rare neurodegenerative synucleinopathy, is characterized by various combinations of progressive autonomic failure and motor dysfunction, and a very poor prognosis. Describing the progression of such complex and multi-dimensional diseases is particularly difficult. One has to simultaneously account for the assessment of multivariate markers over time, the occurrence of clinical endpoints, and a highly suspected heterogeneity between patients. Yet, such description is crucial for understanding the natural history of the disease, staging patients diagnosed with the disease, unravelling subphenotypes, and predicting the prognosis. Through the example of MSA progression, we show how a latent class approach modeling multiple repeated markers and clinical endpoints can help describe complex disease progression and identify subphenotypes for exploring new pathological hypotheses. The proposed joint latent class model includes class-specific multivariate mixed models to handle multivariate repeated biomarkers possibly summarized into latent dimensions and class-and-cause-specific proportional hazard models to handle time-to-event data. Maximum likelihood estimation procedure, validated through simulations is available in the lcmm R package. In the French MSA cohort comprising data of 598 patients during up to 13 years, five subphenotypes of MSA were identified that differ by the sequence and shape of biomarkers degradation, and the associated risk of death. In posterior analyses, the five subphenotypes were used to explore the association between clinical progression and external imaging and fluid biomarkers, while properly accounting for the uncertainty in the subphenotypes membership.


Evidence against a role of prolactin in the timing of ovulation in the turkey.
Two separate experiments in which blood was sampled at 2-h intervals from turkeys hens failed to show a significant change in plasma prolactin (Prl) concentrations in relation to the preovulatory surge of luteinizing hormone (LH) for the first (C1) ovulation of a sequence. Intravenous injection of 125 IU of ovine Prl (NIH-P-S10) or of 1 or 2 ml of antiserum to turkey Prl at varying intervals before C1 ovulation had no effect on the timing or incidence of C1 ovulation. However, injection of Prl before C1 ovulation tended to inhibit ovulation of the second (C2) egg of the sequence, while injection of antiserum to Prl before C1 ovulation tended to either advance or inhibit C2 ovulation. Possibly, the effects of Prl and Prl antiserum on C2 ovulation reflect interference with maturation of the C2 ovarian follicle rather than interference with neuroendocrine processes that regulate the timing of the preovulatory surge of LH. The data for C1 ovulation argue against a change in circulating levels of Prl as a factor in the timing of the preovulatory surge of LH.


Some actual aspects of ischemic heart disease.
The 59th annual conference of the German Society for Heart and Vessel Research was held from 15th to 17th April 1993 in Mannheim. More than six hundred lectures and posters were presented (including those invited from abroad) introducing the topics of current experimental and clinical cardiology. The primary lectures dealt with problems of etiology and pathogenesis of atherosclerosis and its complications. Also the principles of treatment of ischemic heart disease were discussed. Moreover, insights into confusing problems of reperfusion injury, hibernating myocardium and stunned myocardium were introduced. The presented data have shown that myocardial ischemia, its etiology, pathogenesis, manifestations and treatment form a bulk of challenging problems of present cardiology. Many such phenomena were described, which provoke more questions than give answers. Only close interdisciplined cooperation can help to solve some of them in the near future. (Ref. 35.)


The Prognostic Biomarkers of Plasma Trimethylamine N-Oxide and Short-Chain Fatty Acids for Recanalization Therapy in Acute Ischemic Stroke.
Bidirectional communication of the microbiota-gut-brain axis is crucial in stroke. Recanalization therapy, namely intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), are recommended for eligible patients with acute ischemic stroke (AIS). It remains unclear whether gut microbiota metabolites, namely trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), can predict the prognosis after recanalization therapy. This prospective study recruited patients with AIS receiving IVT, EVT, or both. The National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) scores were used to assess the severity and functional outcomes of AIS, respectively. A functional outcome of mild-to-moderate disability was defined as a mRS score of 0-3 at discharge. Plasma TMAO and SCFA levels were measured through liquid chromatography with triple-quadrupole mass spectrometry. Fifty-six adults undergoing recanalization therapy for AIS were enrolled. Results showed that TMAO levels were not associated with stroke severity and functional outcomes, while isovalerate levels (one of the SCFAs) were negatively correlated with NIHSS scores at admission and discharge. In addition, high isovalerate levels were independently associated with a decreased likelihood of severe disability. The study concluded that an elevated plasma isovalerate level was correlated with mild stroke severity and disability after recanalization therapy for AIS.


Microhardness and anisotropy of the vital osseous interface and endosseous implant supporting bone.
Limited information is available on the mechanical properties of the rapidly remodeling bone that surrounds endosseous implants. Fifteen implant-bone blocks were obtained from the mid-femoral diaphyses of three mature male hounds 12 weeks after placement of the implants. To evaluate the microhardness and cortical anisotropy of bone, the implants were sectioned along their long axes. In this process, the femurs were sectioned transversely. Knoop microhardness measurements (HK) were made with a 50 g force on cortical bone and a 25 g force on periosteal callus, endocortical callus, and circumferential lamellar bone. The long diagonal of the indenter was placed parallel to the implant (in the radial bone direction). Measurements were made in cortical bone at 200, 400, 600, 800, 1,000, 1,500, 2,000, and 2,500 microm from both sides of the implant. To detect cortical anisotropy in the radial compared with the tangential direction, a second set of indentations was made perpendicular to the first. Microhardness of periosteal callus and endocortical callus and anisotropy of circumferential lamellar bone near the endocortical surfaces of the femur were also evaluated. Repeated measures analysis of variance showed significantly (p < 0.05) lower microhardness values (30.6 +/- 0.8 HK [mean +/- SEM]) for cortical bone at 200 microm than at any other location (range: 40.3-46.6 HK). Microhardness anisotropy was not detected in cortical bone. Furthermore, within 200 microm of the implant surface, the Knoop microhardness values were significantly lower for periosteal and endocortical calluses than for cortical bone. These data provide information about the mechanical properties of bone adjacent to endosseous implants at a microstructural level. The results are consistent with the high rate of remodeling seen adjacent to endosseous implants at 12 weeks after implantation.


Immunofluorescence mapping of antigenic determinants within the dermal-epidermal junction in the mechanobullous diseases.
The classification of mechanobullous diseases often depends on the electron microscopic distinction of intradermal (dermolytic), junctional and intraepidermal sites of cleavage. Electron microscopy is tedious and time consuming. In this report we describe a different approach to the determination of the cleavage plane by using a method which recognizes subtle differences in the localization of antigenic structures relative to the cleavage plane. Cryostat sections of lesional and extralesional skin of 3 patients with dermolytic epidermolysis bullosa, 3 with epidermolytic epidermolysis bullosa and 8 with junctional epidermolysis bullosa were examined by immunofluorescence, with specific antisera against type IV collagen (localized within the basal lamina); against laminin (noncollagenous protein, localized in the lamina lucida); and with bullous pemphigoid antibodies (directed against the bullous pemphigoid antigen localized in the lamina lucida). All specimens were also examined by electron microscopy. In dermolytic epidermolysis bullosa (where cleft formation occurs intradermally) type IV collagen, laminin and the bullous pemphigoid antigen were consistently found in the roof of the blister, whereas in junctional epidermolysis bullosa (where the cleft occurs in the lamina lucida) type IV collagen and laminin were found on the floor of the blister whereas bullous pemphigoid antigen was present mainly on the roof, but focally also on the floor, of the blister. In epidermolytic epidermolysis bullosa (where the cleft is intraepidermal) all antigens were localized below the cleavage plane. In all cases electron microscopy confirmed the level of cleft formation predicted from the immunofluorescence mapping of the antigenic sites. The described method equals electron microscopy in accuracy but it is more rapid and simpler to perform.


Degenerative disc disease, active component, U.S. Armed Forces, 2001-2011.
Degeneration of intervertebral discs is a common disorder that often leads to pain syndromes and mechanical dysfunction of the spine. Between 2001 and 2010, 131,986 active component service members received diagnoses of degenerative disc disease (DDD) during a hospitalization or at least two ambulatory visits (overall crude incidence rate: 951.4 per 100,000 person-years). Annual crude incidence rates more than doubled during the surveillance period (2001: 614.9 per 100,000 p-yrs; 2010: 1347.8 per 100,000 p-yrs). An estimated 68,247 days of lost duty time were attributed to DDD-specific diagnoses. Among service members diagnosed with DDD who subsequently deployed in support of overseas combat operations, more than two-thirds experienced exacerbations of their condition while deployed, although only 1.7 percent were medically evacuated. Deployed service members with DDD were more likely than a deployed comparison group to be medically evacuated for any cause.


[Causes of spontaneous pneumothorax from the pathologic-anatomic viewpoint].
The symptomatic spontaneous pneumothorax is an illness of the middle-aged and elderly. In former times the main cause was a rupture of a tuberculous cavity. Nowadays it is usually due to a rupture of an emphysematous bulla. The so-called idiopathic spontaneous pneumothorax is predominantly found in young adults. The main cause is a pleura defect within the vicinity of the apical scars due to emphysematous changes. Nevertheless sometimes it can be the first clinical manifestation of interstitial lung fibrosis. In young persons who suffer from multiple spontaneous pneumothoraces the cause may be pulmonary histiocytosis X.