A Narrative Review of the Epidemiology of Congenital Syphilis in the United States From 1980 to 2019.
Congenital syphilis (CS) is the result of antepartum transmission from mother to fetus of the spirochete Treponema pallidum. Although preventable through timely screening and treatment, the incidence of CS in the United States is increasing. This review describes the epidemiological trends in CS in the United States from 1980 to 2019 and characteristics of mothers of infants with CS. We performed a narrative review of epidemiological studies of CS following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting of observational studies in epidemiology. Quality and bias of included studies were assessed using the Newcastle-Ottawa Scale. Studies that described the demographics and characteristics of pregnant women with syphilis or who delivered an infant with CS in the United States were identified from PubMed and Embase. We identified a total of 2771 studies, of which 309 were selected for further review and 27 were included in the final analysis. Substance use during pregnancy was a risk factor for CS in 16 studies. Maternal cocaine use was described in 11 of the 16 studies, 10 of which were published between the years 1980 and 1999. No prenatal care was a risk factor for CS in 17 studies. Evidence of inadequate syphilis testing (i.e., no maternal screen, first screen after the first trimester, or no repeat screen in third trimester) or treatment (i.e., no treatment, treatment <30 days before delivery, or nonpenicillin treatment) was significantly associated with CS in 13 studies. Finally, higher rates of CS were reported among African American women in 11 studies. Infection with and antepartum transmission of syphilis disproportionately affect certain subgroups of women. Women who report substance use during pregnancy are more likely to give birth to an infant with CS. No prenatal care and evidence of inadequate syphilis testing and treatment during pregnancy are also significantly associated with giving birth to an infant with CS. Finally, cases of CS disproportionately affect African American women. Addressing the CS epidemic will require identification and targeted allocation of resources to communities at elevated risk for syphilis, removal of barriers to prenatal care, and ensuring timely treatment and adequate partner notification of identified cases.


Solubilization of brain mitochondrial hexokinase by thiopental.
The control of hexokinase activity probably is accomplished by regulating the partitioning of the enzyme between soluble and particulate forms, the latter being more active. In the present investigation we have examined the thiopental effect on the cerebral hexokinase distribution. In anesthesia, after administration of thiopental to male Sprague Dawley rats, the increase of the soluble fraction of hexokinase was dose dependent. The change in the intracellular hexokinase distribution was reversible and lasted as long as general anesthesia existed. Also in experiments in vitro a solubilization of the mitochondrial hexokinase by thiopental (0.1--1 mM) occurred; it was depending on drug concentration. An inhibition of hexokinase was found neither in the total brain extract, nor in the soluble or the particulate fraction. The results suggest that phosphorylation of glucose in brain may be suppressed in anesthesia by shifting hexokinase activity from a more active mitochondrial form to its less active soluble form. This effect seems to be caused by a direct action of thiopental and is obviously correlated with anesthesia.


An arabinogalactan extracted with alkali from Portulaca oleracea L. used as an immunopotentiator and a vaccine carrier in its conjugate to BSA.
A neutral polysaccharide (POPAN) from Portulaca oleracea L. was isolated with alkali and purified to obtain. HPLC analysis suggested POPAN (40.9 kDa) was mainly composed of Ara and Gal with traces of Glc and Man. GC-MS and 1D/2D NMR analysis confirmed POPAN was an arabinogalactan possessing a backbone mainly composing of (1 → 3)-α-l-Araf-linked arabinan and (1 → 4)-β-d-Galp-linked galactan, which was different from structure characterization of typical arabinogalactan reported previously. Importantly, we conjugated POPAN to BSA (POPAN-BSA), and detected the potential and mechanism of POPAN as an adjuvant in POPAN-BSA. The results indicated, in contrast to BSA, POPAN-BSA induced the robust and persistent humoral response in addition to the cellular response with Th2-biased immunity response in mice. Further investigations of mechanism revealed effects of POPAN-BSA were a result of POPAN as the adjuvant to: 1) significantly activate DCs in vitro or in vivo including the upgraded expressions of costimulators, MHCs and cytokines; 2) greatly facilitated the capture of BSA. Overall, present studies demonstrated POPAN can be a potential adjuvant as an immunopotentiator and an antigen delivery vehicle in its conjugate to recombinant protein vaccines.


Failure to demonstrate resistance in goats, sheep and cattle to Fasciola hepatica after infection with Cysticercus tenuicollis.
Goats, sheep and cattle given 1000--1500 eggs of Taenia hydatigena and challenged orally 12 weeks later with 400 Fasciola hepatica metacercariae, showed no evidence of resistance. The fluke burdens were not significantly different from those in control animals.


The patient-doctor relationship and metabolic control in patients with type 1 (insulin-dependent) diabetes mellitus.
Our hypothesis was that patient-doctor relationship experienced positively by the patient is associated with adequate compliance behavior and thus to the long-term metabolic control of diabetes. Cross-sectional study of 100 consecutive adult patients with Type 1 diabetes treated in a diabetes out-patient department. From a questionnaire, four scores (direct estimate of physician, satisfaction with the place of treatment, self-esteem score, security with the patient-doctor relationship) determining the patient-doctor relationship were formed. In score 3 (self-esteem score) the impact of the patient-doctor relationship to the patients' self-esteem was indirectly estimated. The anonymous data taken from diabetes register including information about treatment of diabetes, metabolic control and end-organ complications were returned together with the questionnaire. On the basis of GHbA1c diabetic patients were divided into two groups: with adequate metabolic control (GHbA1c < or = 8.0%) or with poor/moderate control (GHbA1c > 8.0%). In univariate analyses the score 3 associated with metabolic control (p < 0.001). In logistic regression analyses the nephropathy (t = 2.80, p < 0.05) and score 3 (t = 3.98, p < 0.001) were associated with metabolic control. Patient's positively-experienced patient-doctor relationship was associated with good metabolic control of diabetes.


'I'd rather just go on as I am'--pelvic floor care preferences of frail, elderly women in residential care.
Little is known about how frail, elderly women in assisted living and long-term care facilities view pelvic floor dysfunctions and treatments. Twenty-five residents reflect on these issues, and quality of life.


Computed tomographic demonstration of hemobilia.
A patient with hemobilia presumably due to a small hemangioma in the liver is presented. The condition was diagnosed by computed tomography (CT) done immediately following hepatic arteriography and confirmed by hem-positive duodenal aspirates on two occasions.


Spatial distributions of strontium isotope ratios in human hair and tap water from South Korea.
Natural variations of 87Sr/86Sr ratios in biological samples, such as human hair, provide a biological record of provenance. Spatial distribution maps reflecting heterogeneity in isotopic signatures across large geographical regions are helpful for discerning the provenance and mobility of organisms. In this national-scale study conducted across South Korea, we investigated the spatial distribution patterns of 87Sr/86Sr ratios in human hair and tap water samples to determine their spatial variabilities and the relationships of isotopic signatures between hair and tap water. The strontium isoscapes of tap water and hair showed similar spatial distribution patterns. Non-parametric comparison indicated no significant differences in isotopic ratios between the two sample types. The 87Sr/86Sr ratios in human hair showed a significant and strong correlation with the ratios in tap water in eastern Korea, suggesting potential use of 87Sr/86Sr ratios in provenance studies. However, tap water and hair samples from western Korea did not show significant correlation between them, overall reducing the predictive power of the hair 87Sr/86Sr ratios for provenance studies. The deviation between 87Sr/86Srtap water and 87Sr/86Srhair was much larger in western coastal areas than in eastern Korea. Relatively high utilization of groundwater or exogenous materials, such as Asian dust, may have been responsible for this pattern. To fully utilize the potential of the strontium isotope signature as a biorecorder in provenance studies, it is essential to evaluate the effects of groundwater and other exogenous materials on the isotope signatures of hair and other biological samples. In this study, only hair samples from males were used to develop 87Sr/86Sr isoscapes. Therefore, further studies are required to examine the applicability of 87Sr/86Sr hair isoscapes based solely on human hair samples from males to forensic and provenance studies of human hair samples from females.


Quantitative assessment of tolerance development to diisopropylfluorophosphate.
Rats were treated with diisopropylfluorophosphate (DFP) acutely or daily for 14 days. The quantitative assessment of tolerance development after a challenge dose of DFP, 2 mg/kg, was studied. The subacutely-treated rats developed tolerance to DFP-induced tremors. However, the severity of tremors in DFP-tolerant animals was not significantly different from that of the controls after the challenge dose of DFP was administered. Hind-limb abduction was significantly lower in the subacutely-treated group than in the acutely-treated group. The recovery of body weights in subacutely-treated rats (3.5%/day) was significantly higher than that in acutely-treated rats (2.0%/day). The consummatory behaviors (food and water consumption) recovered faster in subacutely-treated rats than in the acutely-treated group. Body temperatures were decreased to the same extent in both groups, but the subacutely-treated group recovered faster. The total mortality was significantly lower in subacutely-treated rats (10%) than in acutely-treated rats (35%). The results further substantiate the finding that tolerance develops to various DFP-induced signs of toxicity.


Estimating a worker entry interval for the carbamate pesticide furadan 4F insecticide.
Existing methods for the calculation of worker entry intervals by the use of kinetic data have focused on the anticholinesteratic organic phosphates. As carbamate pesticides share with these materials a common site for inhibition, the kinetic method was applied in estimating an entry interval for the carbamate, carbofuran, applied to citrus and grapes as Furadan 4F. No allowance was made for the more transient carbamylation of cholinesterase attributed to N-methyl carbamates, compared with the phosphorylation of the enzyme by organic phosphates. Thus, a measure of safety was built into the calculations which can then be used to establish safe reentry intervals to insure residue levels below the physiological threshold for cholinesterase inhibition.


Predictive Factors and Intracytoplasmic Sperm Injection Results for Sperm Retrieval by Microdissection Testicular Sperm Extraction (micro-TESE) in Patients with Klinefelter Syndrome.
To determine the predictive factors for successful retrieval of sperm from testicles before microdissection-testicular sperm extraction (micro-TESE) in patients with Klinefelter syndrome (KS) in order to counsel these patients regarding the likelihood of findings sperm. The study is a retrospective analysis of the records of 67 men with KS between April 2016 and August 2020. Serum luteinizing hormone, follicle stimulating hormone, testosterone, prolactin, and estradiol levels were investigated. Testicular volumes were measured by ultrasonography. TESE was noted as positive or negative. There were 32 (47.8%) micro-TESE-negative patients and 35 (52.2%) m-TESE positive patients. The age of the micro-TESE-negative (34.9 ± 5.1 years) patient group was significantly higher than the micro-TESE-positive (32.3 ± 4.7 years) group (P = .035).The left testicular volume values were significantly higher in the micro-TESE-positive group (P = .019). Follicle stimulating hormone, luteinizing hormone, and prolactin levels were higher in m-TESE-negative patients compared to micro-TESE-positive patients, and testosterone levels and testicular volume were lower in micro-TESE-negative patients compared to micro-TESE-positive patients. However, these differences were not significant. As a result of intracytoplasmic sperm injection (ICSI) performed on 31 couples, 20 pregnancies and 16 live births were obtained (51.06%). Among the parameters examined in this study, the age of the patient with KS may be predictive for micro-TESE success. Counseling should be given that some patients with KS may have a child via micro-TESE-ICSI.


Hubs of long-distance co-alteration characterize brain pathology.
It is becoming clearer that the impact of brain diseases is more convincingly represented in terms of co-alterations rather than in terms of localization of alterations. In this context, areas characterized by a long mean distance of co-alteration may be considered as hubs with a crucial role in the pathology. We calculated meta-analytic transdiagnostic networks of co-alteration for the gray matter decreases and increases, and we evaluated the mean Euclidean, fiber-length, and topological distance of its nodes. We also examined the proportion of co-alterations between canonical networks, and the transdiagnostic variance of the Euclidean distance. Furthermore, disease-specific analyses were conducted on schizophrenia and Alzheimer's disease. The anterodorsal prefrontal cortices appeared to be a transdiagnostic hub of long-distance co-alterations. Also, the disease-specific analyses showed that long-distance co-alterations are more able than classic meta-analyses to identify areas involved in pathology and symptomatology. Moreover, the distance maps were correlated with the normative connectivity. Our findings substantiate the network degeneration hypothesis in brain pathology. At the same time, they suggest that the concept of co-alteration might be a useful tool for clinical neuroscience.


Non-invasive assessment of lower extremity muscle composition after incomplete spinal cord injury.
Cross-sectional study. (1) To quantify intramyocellular lipid (IMCL) content of the soleus muscle. (2) To assess the T(2) relaxation rates in the lower extremity skeletal muscles in persons with incomplete spinal cord injury (SCI). Academic Institution, Florida. Eight subjects (42+/-10 years old; 70+/-12 kg; 176+/-10 cm) with chronic (17+/-9 months post injury) motor SCI (C4-T12; ASIA C or D) and eight matched healthy controls were tested. Localized unsuppressed proton spectroscopy (H-MRS) was performed to estimate total lipid content and individual lipid components; IMCL and extramyocellular lipid (EMCL) from the soleus muscle. T(2)-weighted imaging of lower extremity muscles yielded muscle T(2) rates. The IMCL content of the soleus muscle was 3.3 times higher in the patient group as compared to controls (P=0.002; 0.0401 (0.0234-0.0849) versus 0.0123 (0.0090-0.0175)). Similarly, EMCL measures were 4.5 times higher as compared to the controls (P=0.002). Significant differences were observed in the T(2) relaxation times of the soleus and gastrocnemius muscles (P<0.05). The increased levels of IMCL might interfere with the glucose uptake in skeletal muscle; potentially predisposing persons with incomplete SCI to the development of peripheral insulin resistance. Marked elevations in the T(2) relaxation times of the locomotor muscles are reflective of an altered muscle composition.


Frequencies of the CC chemokine receptor 5 delta 32 allele in various populations of defined racial background.
The 32-nucleotide deletion (delta 32) within the chemokine co-receptor CCR5 gene was studied in 1,031 DNA samples from various racial origins. The mutation is absent in 48 Vietnamese living in Paris, and we confirm that delta 32 allele is very rare in a sample of 302 individuals originating from sub-Saharan Africa. The mean delta 32 allelic frequency in unrelated non-HIV-1 infected blood donors is 0.113 in France, as calculated in a sample of 620 individuals. A slight decrease in allelic frequencies was noticed in the southern part of the country compared to the Paris region. In a population of 71 North African people the delta 32 frequency is 0.063, a value significantly lower than the mean frequency observed in France.


Visual recovery in combined central retinal artery and central retinal vein occlusion.
We observed two patients who had combined central retinal artery occlusion and central retinal vein occlusion with severely reduced visual acuity and characteristic retinal changes. Over the course of several months, visual acuity and ophthalmoscopic appearance returned to normal. Both patients had a transient visual loss before their occlusive events and a mild nonconcurrent central retinal vein occlusion in their fellow eye. There was no evidence of inflammatory, vascular, or myeloproliferative disease.


Cloning of whiG, a gene critical for sporulation of Streptomyces coelicolor A3(2).
In whiG mutants of Streptomyces coelicolor A3(2), aerial hyphae do not show any sign of sporulation. A library of S. coelicolor DNA was prepared in a phi C31 temperate phage vector (KC516), and one recombinant phage (KC750) that could restore the wild-type phenotype to a collection of whiG mutants when integrated into their genomes was found. Subcloning experiments with low- and high-copy-number Streptomyces plasmid vectors allowed partial localization of whiG in the cloned DNA and revealed that hypersporulation was associated with the presence of extra copies of whiG.


MR imaging of cardiac masses.
Cardiac MR imaging is the preferred method for assessment of cardiac masses. A comprehensive cardiac MR imaging examination for a cardiac mass consists of static morphologic images using fast spin-echo sequences, including single-shot techniques, with T1 and T2 weighting and fat suppression pulses as well as dynamic imaging with cine steady-state free precession techniques. Further tissue characterization is provided with perfusion and delayed enhancement imaging. Specific cardiac tumoral characterization is possible in many cases. When specific tumor characterization is not possible, MR imaging often can demonstrate aggressive versus nonaggressive features that help in differentiating malignant from benign tumors.


Translocations are infrequent among couples having repeated spontaneous abortions but no other abnormal pregnancies.
During the years 1977 to 1986, cytogenetic studies were performed on 342 women and 297 men whose reproductive history included one or more first trimester spontaneous abortions. Thirty-nine women and 35 men experienced not only early fetal losses but also one or more stillborn infants, liveborn anomalous infants, or early neonatal deaths. Among the 303 women and 262 men evaluated solely because of repetitive abortions, only 1 woman and 1 man showed a translocation. Two translocations were detected among the 39 women and 35 men having not only repetitive abortions but also a stillborn infant, anomalous liveborn, or unexplained neonatal death. Only among the 25 women having abortions and other abnormal perinatal events was the frequency of translocations high (2/25 or 8%). Our data continue to indicate that balanced chromosomal translocations are relatively infrequent in individuals having repeated abortions but no other adverse perinatal outcome.


Magnetic Three-Phase Single-Drop Microextraction for Rapid Amplification of the Signals of DNA and MicroRNA Analysis.
The detection of nucleic acids usually suffers from a lengthy amplification process. To obtain an enhanced signal within several seconds, a magnetic three-phase single-drop microextraction (MTP-SDME) approach was developed for the quantification of nucleic acids. First, a target-triggered recycling amplification strategy was used to constitute magnetic branched DNA/Fe3O4 networks, which displayed peroxidase-like catalytic activity toward the 3,3',5,5'-tetramethylbenzidine colorimetric reaction. The networks were separated and enriched by rapid (6 s) MTP-SDME (with only 6 μL of solvent required), thereby producing highly sensitive signals for the quantification of nucleic acids. The signals were significantly amplified by the triple strategy (network formation, MTP-SDME, and catalytic reaction). The application of magnetic extraction minimized the background signal, avoided sample matrix effects, and enhanced the analyte signals. This assay achieved linear calibration curves of between 0.5 aM and 1 pM for microRNA-122 (miRNA-122) and between 1 aM and 1 pM for HBV-T (a DNA fragment from hepatitis B virus). Limits of detection of 0.15 aM for miRNA-122 and 0.34 aM for HBV-T were attained, with relative standard deviations of <5.0% (n = 3). Furthermore, the procedure was applied to determine miRNA-122 and HBV-T in genuine serum samples from hepatocellular carcinoma patients.


"Normal suppression" to dexamethasone in Cushing's disease: an expression of decreased metabolic clearance for dexamethasone.
The adrenal cortical function of a patient with pituitary-dependent Cushing's syndrome exhibited normal responsiveness to conventional doses of dexamethasone (Dex) over several years of evaluation. "Periodic hormonogenesis" did not seem to explain the phenomenon. Plasma concentrations of Dex were measured to ascertain whether an abnormality in Dex metabolism might explain the apparent discrepancy in Dex responsiveness. Plasma levels of Dex after oral administration of the steroid were higher than normal, suggesting that decreased clearance of Dex accounts for the phenomenon of "normal suppression" in this patient with Cushing's syndrome.


Some comments on interpretations of Viking biological experiments.
Data from Viking experiments are analyzed from a biological viewpoint. The lack of organic matter in Martian soil could be due to the specificity of regions with optimal landing conditions. All data of labeled release experiments may be explained by assuming the existence of psychrophilic organisms, cultivated at temperatures above optimal ones, and other factors of a biological origin. The biological interpretation does not contradict the results of other life search experiments.


Bioelectric regulation of intestinal stem cells.
Proper regulation of ion balance across the intestinal epithelium is essential for physiological functions, while ion imbalance causes intestinal disorders with dire health consequences. Ion channels, pumps, and exchangers are vital for regulating ion movements (i.e., bioelectric currents) that control epithelial absorption and secretion. Recent in vivo studies used the Drosophila gut to identify conserved pathways that link regulators of Ca2+, Na+ and Cl- with intestinal stem cell (ISC) proliferation. These studies laid a foundation for using the Drosophila gut to identify conserved proliferative responses triggered by bioelectric regulators. Here, we review these studies, discuss their significance, as well as the advantages of using Drosophila to unravel conserved bioelectrically induced molecular pathways in the intestinal epithelium under physiological, pathophysiological, and regenerative conditions.


A Mother's Touch: Emerging Roles in Development of the Cutaneous Microbiome.
Skin-associated bacteria constitute a large proportion of the human microbiome and influence host immunity. The healthy cutaneous microbiome adopts site-specific composition, weeks to months postpartum. Zhu et al. (2019) expand the scope of pediatric data, tracking infant skin microflora changes by site, through childhood, and establish new associations with delivery mode and maternal microbiome.


Species-specific lifespans: Can it be a lottery based on the mode of mitochondrial DNA replication?
Accumulating evidence suggests that the aging process is, in part, driven by accumulation of large deletions in mitochondrial DNA (mtDNA). Here, I present a hypothesis that significant variations in lifespans can be explained by species-specific mtDNA sequence features that cause a shift in the mode of mtDNA replication and thus preclude the formation of large deletions.


Changes in integrin expression are associated with altered homing properties of Lin(-/lo)Thy1.1(lo)Sca-1(+)c-kit(+) hematopoietic stem cells following mobilization by cyclophosphamide/granulocyte colony-stimulating factor.
Although migration of hematopoietic stem cells (HSC) is essential for normal hematopoiesis and successful hematopoietic cell transplantation, little is known about the mechanisms that underlie this movement. We have sought to characterize the factors that regulate HSC migration by analyzing changes in expression of particular adhesion receptors associated with cyclophosphamide/granulocyte colony-stimulating factor (Cy/G-CSF)-induced HSC mobilization. Expression by Lineage(-/lo)Thy1.1(lo)Sca-1(+)c-kit(+) HSC of members of the beta1 integrin family of adhesion molecules was assessed in untreated or Cy/G-CSF-treated mice by multiparameter flow cytometry. In parallel, the in vivo homing properties of normal and mobilized HSC were compared following intravenous transfer of fluorescently marked HSC. Normal adult HSC express high levels of several beta1 integrin family members. Following Cy/G treatment, bone marrow HSC selectively downregulate alpha 2 integrin expression and upregulate alpha 5 expression. HSC found in the blood following Cy/G-CSF treatment express significantly lower levels of multiple integrins than their bone marrow and/or splenic counterparts. Changes in integrin expression by blood-borne HSC correlate with a 50% decrease in their ability to home to the bone marrow in short-term assays, and with previously observed defects in competitive engraftment by these HSC. Similar reductions in bone marrow (BM) homing are observed for BM HSC treated with alpha 4 integrin function blocking mAb prior to injection. Modulation of integrin expression induced by mobilization was not associated with cell-cycle progression. Changes in integrin expression and function are associated with HSC mobilization and likely significantly affect the engraftment potential of hematopoietic stem cells.


Digital imaging of colon tissue: method for evaluation of inflammation severity by spatial frequency features of the histological images.
The efficacy of histological analysis of colon sections used for evaluation of inflammation severity can be improved by means of digital imaging giving quantitative estimates of main diagnostic features. The aim of this study was to reveal most valuable diagnostic features reflecting inflammation severity in colon and elaborate the evaluation method for computer-aided diagnostics. Tissue specimens from 24 BALB/c mice and 15 patients were included in the study. Chronic and acute colon inflammation in mice was induced by oral administration of dextran sulphate sodium (DSS) solution, while mice in the control group did not get DSS. Human samples of inflamed colon tissue were obtained from patients with ulcerative colitis (n = 6). Non-inflamed colon tissue of control subjects (n = 9) was obtained from patients with irritable bowel syndrome or functional obstipation. Analysis of morphological changes in mice and human colon mucosa was performed using 4-μm haematoxylin-eosin (HE) sections. The features reflecting morphological changes in the images of colon mucosa were calculated by convolution of Gabor filter bank and array of pixel values. All features were generalized by calculating mean, histogram skewness and entropy of every image response. Principal component analysis was used to construct optimal representation of morphological changes. First principal component (PC1) was representing the major part of features variation (97 % in mice and 71 % in human specimens) and was selected as a measure of inflammation severity. Validation of new measure was performed by means of custom-made software realizing double blind comparison of differences in PC1 with expert's opinion about inflammation severity presented in two compared pictures. Overall accuracy of 80 % for mice and 67 % for human was reached. Principal component analysis of spatial frequency features of histological images may provide continuous scale estimation of inflammation severity of colon tissue.


Vibrational spectroscopic study of the contents of a chest excavated from the wreck of the HMS Pandora.
The FT-IR and Raman spectroscopic analysis of a red powder found in a chest from an officer's cabin during the excavation of the wreck of the 18th Century frigate HMS Pandora have confirmed that the pigment is cinnabar, mercury(II) sulphide. Weaker signals in the Raman spectrum are assignable to a proteinaceous material, such as collagen, typical of a degraded vellum or parchment. Comparison of the Raman spectra with that of a pigmented seal from a 1786 Lieutenant's commission demonstrated that the beeswax component of the seal was not observable.


Computational modeling based on confocal imaging predicts changes in osteocyte and dendrite shear stress due to canalicular loss with aging.
Exercise and physical activity exert mechanical loading on the bones which induces bone formation. However, the relationship between the osteocyte lacunar-canalicular morphology and mechanical stress experienced locally by osteocytes transducing signals for bone formation is not fully understood. In this study, we used computational modeling to predict the effect of canalicular density, the number of fluid inlets, and load direction on fluid flow shear stress (FFSS) and bone strains and how these might change following the microstructural deterioration of the lacunar-canalicular network that occurs with aging. Four distinct computational models were initially generated of osteocytes with either ten or eighteen dendrites using a fluid-structure interaction method with idealized geometries. Next, a young and a simulated aged osteocyte were developed from confocal images after FITC staining of the femur of a 4-month-old C57BL/6 mouse to estimate FFSS using a computational fluid dynamics approach. The models predicted higher fluid velocities in the canaliculi versus the lacunae. Comparison of idealized models with five versus one fluid inlet indicated that with four more inlets, one-half of the dendrites experienced FFSS greater than 0.8 Pa, which has been associated with osteogenic responses. Confocal image-based models of real osteocytes indicated a six times higher ratio of canalicular to lacunar surface area in the young osteocyte model than the simulated aged model and the average FFSS in the young model (FFSS = 0.46 Pa) was three times greater than the aged model (FFSS = 0.15 Pa). Interestingly, the surface area with FFSS values above 0.8 Pa was 23 times greater in the young versus the simulated aged model. These findings may explain the impaired mechano-responsiveness of osteocytes with aging.


Combined Treatment of an Aortoesophageal Fistula After Aortoplasty for Aortic Stenosis.
The aortoesophageal fistula secondary to the rupture of an aneurysm is a rare entity that usually has a fatal outcome. We present the case of a young patient with an aortoesophageal fistula secondary to a thoracic aortic aneurysm successfully treated with a combination of endoscopic and surgical techniques.


Increased GABA release in the human brain cortex as a potential pathogenetic basis of hyperosmolar diabetic coma.
Human cerebral cortical slices preincubated with [3H]GABA, [3H]noradrenaline, or 5-[3H]hydroxytryptamine and superfused with Krebs solution or Mg(2+)-free Krebs solution were used to investigate the influence of increased D-glucose concentrations on the release of these [3H]-neurotransmitters evoked by high K+ content or NMDA receptor activation, respectively. An increase in level of D-glucose (normal content, 11.1 mM) by 32, 60, and/or 100 mM (a range characteristic for hyperosmolar diabetic coma) increased the [3H]GABA release and inhibited the [3H]noradrenaline release evoked by both methods of stimulation. The K(+)-induced 5-[3H]hydroxytryptamine release was also inhibited by high D-glucose content. Blockade of GABAB receptors by p-(3-aminopropyl)-p-diethoxymethylphosphinic acid (CGP 35348) attenuated the inhibitory effect of high D-glucose content on the K(+)-evoked release of [3H]noradrenaline and 5-[3H]hydroxytryptamine, suggesting that the effect on monoamine release is, at least to a major part, the result of the increased GABA release and, as a consequence, of an increased GABA concentration at inhibitory GABAB receptors. The membrane-impermeable sorbitol mimicked the increasing effect of D-glucose on [3H]GABA release and its inhibitory effect on 5-[3H]hydroxytryptamine release. However, dimethyl sulfoxide, which is known to permeate rapidly through biological membranes, had no effect at concentrations equiosmolar to D-glucose. It is concluded that a reduction in brain cell volume caused by increased extracellular, compared with cytoplasmic, osmolarity is crucial for the changes in neuronal function observed at high D-glucose and sorbitol content.(ABSTRACT TRUNCATED AT 250 WORDS)


[Detection of cell-free fetal DNA in the urine of pregnant women by nested polymerase chain reaction].
To investigate the clinical feasibility of fetal sex determination by using nested polymerase chain reaction (PCR) to detect cell-free fetal DNA in the urine of pregnant women. The urine specimens of 40 healthy predelivery women were centrifuged. The DNA in the specimens of supernatant was extracted by using of QIAamp Viral RNA Mini Kits. Nested PCR was used to specifically amplify the SRY gene, 300 bp in length, on Y chromosome in order to detect the fetal DNA from the women bearing male fetuses. One specimen of normal man's urine and one specimen of non-pregnant woman's urine were used as controls for each specimen from pregnant women. The results were confirmed by the sexes of neonates examined after birth. Amplified band of SRY was found in 6 specimens. Sex examination after delivery showed 21 male neonates and 19 female neonates. The positive rate of detection of SRY gene was 28.6% (6/21) and the false negative rate was 71.4%, and false positive rate was 0. Five out of the 6 cases with positive results showed positive 2 times and one out of the 6 cases only showed positive at the second time. There is cell-free fetal DNA in the urine of pregnant women. Nested PCR is useful in detection of fetal sex, however, still with a rather low positive rate.


Pigment epithelium-derived factor expression is down-regulated in bladder tumors and correlates with vascular endothelial growth factor and matrix metalloproteinase-9.
Growth of solid tumor depends on angiogenesis, a process regulated by the balance of pro- and anti-angiogenic factors. We investigated the expression of anti-angiogenic factor pigment epithelium-derived factor (PEDF) and proangiogenic factors vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) with immunohistochemistry in 64 bladder tumor samples and 23 normal controls. Compared with normal urothelium, we identified decreased PEDF expression (P = 0.000) whereas increased expression of VEGF (P = 0.000) and MMP-9 (P = 0.000) in tumorous tissue as well as in papillary urothelial neoplasm of low malignant potential (PUNLMP) (P = 0.009 and P = 0.000 accordingly) but MMP-9 (P = 0.704). Decreased PEDF expression was revealed with higher tumor grade (P = 0.014) but stage (P = 0.687). There was no age or gender preference in PEDF, VEGF or MMP-9 expression. Negative correlation of expression in tumorous and cancerous tissue regarding PEDF and VEGF (P = 0.000, r = -0.56, and P = 0.000, r = -0.50, respectively), PEDF and MMP-9 (P = 0.002, r = -0.39, and P = 0.032, r = -0.30, respectively) was identified. There was a negative correlation of expression between PEDF and VEGF (P = 0.016, r = -0.677) and no correlation between PEDF and MMP-9 (P = 0.147, r = -0.45) in PUNLMP. Decreased PEDF and increased VEGF and MMP-9 expression may play considerable roles in differentiation and invasion of bladder tumor.


Zero incidence of inhibitor development in previously treated haemophilia A, HIV-negative patients upon exposure to a plasma-derived high-purity and double viral inactivated factor VIII concentrate.
Thirty-six haemophilia A, HIV-negative, previously treated patients were changed therapy to a highpurity and double-inactivated (solvent/detergent and dry-heating) previously unused factor VIII concentrate. The mean age of these patients was 27 years at the time of the change. Twenty-three patients were severe haemophiliacs (FVIII:C < 0.02 IU mL-1), seven moderate (FVIII:C between 0.02 and 0.05 IU mL-1) and six mild (FVIII:C > 0.05 IU mL-1). The mean follow-up with this single product was 16 months, with 82 accumulated exposure days and the mean consumption was 117,300 IU of FVIII corresponding to a mean of six batches per patient. No patient developed FVIII inhibitors (upper limit of the CI95: 7.98%), resulting in an incidence rate of 0/48 patient-years (upper limit of the CI95: 77/1000 patient-years). The change in therapy to this new factor VIII concentrate was not associated with the appearance of inhibitors.


Bilateral sixth cranial nerve palsy in infectious mononucleosis.
A 15-year-old girl who presented with a bilateral sixth nerve palsy caused by infectious mononucleosis is described. The neurological presentation of infectious mononucleosis is discussed.


[Pathogenetic aspects of studying clonal properties of bone marrow stromal cells in diseases of the osteoarticular system].
Properties of clonogenic stromal fibroblasts of bone marrow which are precursors of osteo- and chondrogenesis, of patients with different diseases of osteoarticular apparatus have been studied. Peculiarities of their reaction on growth-stimulating influence of nonstromal auto- and xenogeneic cells have been demonstrated. The possibilities of data application for studying of pathogenesis of hereditary osteochondrodysplasias as well as other groups of the skeleton affections are considered.


Mesophilic methane fermentation of chicken manure at a wide range of ammonia concentration: stability, inhibition and recovery.
A 12L mesophilic CSTR of chicken manure fermentation was operated for 400 days to evaluate process stability, inhibition occurrence and the recovery behavior suffering TAN concentrations from 2000 mg/L to 16,000 mg/L. A biogas production of 0.35-0.4 L/gVS(in) and a COD conversion of 68% were achieved when TAN concentration was lower than 5000 mg/L. Ammonia inhibition occurred due to the addition of NH4HCO3 to the substrate. The biogas and COD conversion decreased to 0.3 L/gVS(in) and 20% at TAN 10,000 mg/L and was totally suppressed at TAN 16,000 mg/L. Carbohydrate and protein conversion decreased by 33% and 77% after inhibition. After extreme inhibition, the reactor was diluted and washed, reducing TAN and FA to 4000 mg/L and 300 mg/L respectively, and the recovered biogas production was 0.5 L/gVS(in). The extended Monod model manifested the different sensitivities of hydrolysis, acidogenesis and methanogenesis to inhibition. VFA accumulation accompanied an increase in ammonia and exerted a toxic on microorganism.


The structure of psychosomatic symptoms.
1. According to our findings, a psychosomatic structure is not an alternative to neurosis. The syndrome of alexithymia appears to be, in our cases, a transitional phase, the dynamics of which can be understood and treated by psychotherapy. In the course of psychotherapeutic treatment, alexithymia always disappears. 2. However, a special psychotherapeutic technique is advisable, one different from that applied in classical neurosis. 3. For this reason the term psychosomatic structure can be used as a way of expressing a variation of neurosis. 4. Modern concepts of psychosomatic disease describe pathological personalities that are different from the classic pseudoneurotic type because of their narcissistic and pregenital structures. These structures can be concealed underneath a facade of genital and psychoneurotic defense. 5. The old relationship between psychosomatosis and psychosis can be better understood on the basis of our findings, which reveal a borderline structure and splitting mechanisms in many psychosomatic patients. 6. Psychosomatic pathology can be better understood today by relating it to the structure of the psychosomatic family. 7. It appears that if, on the one hand, psychosomatic diseases of a more hysterical picture are frequent among preindustrial cultures and in low-income classes, on the other hand psychosomatic syndromes of a narcissistic and borderline type are characteristic for our civilization.


Electrochemical immunosensor based on Cu(II)-tetrahydroxy-1,4-benzoquinone amplifier for carcinoembryonic antigen determination.
In order to solve the problems of unstable signal and fast decrease of response signal of traditional electroactive substances, we synthesized a new type of electroactive substances, so that they can cooperatively amplify the response signal of the immune sensor and further improve its sensitivity. The conductive organic ligand tetrahydroxy 1,4-benzoquinone (THQ) and Cu2+ were chelated to form a stable polymeric two-dimensional metal-organic framework material Cu-THQ. Cu-THQ is a new type of electroactive substance. Compared with the traditional electroactive substance, Cu-THQ not only has stronger Redox activity, but also better stability and biocompatibility. We carried out various electrochemical characterizations on Cu-THQ and further proved that the introduction of Cu2+ not only greatly enhanced the stability of THQ electrical signal, but also increased its signal response. The experimental results showed that the prepared immunosensor exhibited good linearity for the detection of carcinoembryonic antigen in the range 1 fg/mL to 40 ng/mL, with detection limits and sensitivity of 0.477 fg/mL and 14.81 µA/(ng/mL)/cm2, respectively.


Complications with Over the Scope Clip: How Can We Prevent It?
The over-the-scope clip is safe and efficacious and has become the preferred device of choice for the treatment of complex gastrointestinal bleeding, perforation, and gastrointestinal leaks. With its widespread adoption in clinical practice, information on complications associated with over-the-scope clip use is emerging. Nonetheless, the overall complication rate is still very low. Most of the reported complications have been related to the technique rather than the actual device and could likely be prevented with proper technique. In this article, the authors summarize the complications associated with over-the-scope clip use and provide guidance on safety measure to mitigate them.


Serial 67Ga-citrate imaging during treatment of acute osteomyelitis in childhood.
To test the hypothesis that abnormalities on 67Ga-citrate scans parallel the clinical course of acute osteomyelitis and revert to normal with successful antibiotic therapy, serial scans were performed in ten children. Scans improved markedly within the first two to four weeks of treatment, but abnormalities persisted at six or more weeks in over 50% of the cases, despite complete clinical resolutions of disease.


Efficacy of nalmefene with noninvasive positive-pressure ventilation on elderly patients with chronic obstructive pulmonary disease combining with type II respiratory failure.
To investigate the therapeutic effect of nalmefene combined with noninvasive positive-pressure mechanical ventilation (NIPPV) on elderly patients with chronic obstructive pulmonary disease (COPD) complicated with type II respiratory failure and to explore its influence on TGF-β1/Smads signaling pathway. In this retrospective study, data of 106 COPD patients with type II respiratory failure were collected and divided into a research group and a control group based on different treatment, with 53 cases in each group. Both groups were given NIPPV. Besides, the control group was treated with conventional therapy and the research group was treated with nalmefene for 7 days. The changes of heart rate, respiratory rate, clinical efficacy, pulmonary arterial pressure (PAP), serum inflammatory parameters, levels of TGF-β1/Smads signaling pathway related molecules and the incidences of adverse reactions of both groups were compared. After treatment, the heart rate, respiratory rate, PAP, IL-6 and TNF-α concentrations in both groups were lower than those before treatment (P<0.05). The levels of PaO2 and SaO2 were higher and the levels of PaCO2 were lower than those before treatment in both groups (P<0.05). The expression levels of TGF-β1 and Smad2 in the research group were significantly lower than those in the control group (P<0.05). And all the above indicators in the research group were better than those in the control group after treatment (P<0.05). Besides, the incidence of adverse reactions in the research group was lower than that in the control group (P<0.05). Nalmefene combined with NIPPV can significantly improve the level of PaO2 and reduce inflammatory response in elderly COPD patients with type II respiratory failure, and the mechanism may be related to the inhibition of TGF-β1 and Smads expressions.


Evaluation of electrophysiological and clinical tests in an exploratory trial of Org 2766 in motor neuron disease.
Twenty four patients with motor neuron disease (MND) participated in a double-blind, placebo-controlled trial with the ACTH 4-9 analog, Org 2766. Patients were examined three times during an 8 week treatment period, using a summated score for several manually and functionally tested muscles (sum score), myometry, jitter, fibre density (FD), macro motor unit potential (MUP), and supramaximal evoked muscle action potentials. No differences were found between Org 2766 and placebo treated patients. In an open 1 yr follow-up study, 5 out of 13 patients treated with Org 2766 died; the others showed continued progression of weakness. The methods used for assessment of muscle function were compared. The highest interest reliability was obtained in the sum score and myometry. Mean differences that might be detectable were relatively small for the sum score and myometry, and large for FD and MUP. We concluded that clinical function testing and myometry are superior to electromyographic measurements for assessment of changes in MND patients.


Influence of patient characteristics on success of ambulatory blood pressure monitoring.
To examine the influence of specific patient characteristics on the success of ambulatory blood pressure monitoring (ABPM). Retrospective analysis. University-affiliated family care center. Five hundred thirty patients (mean age 52.7 yrs, range 14-90 yrs) who were undergoing ABPM between January 1, 2001, and July 1, 2007. Specific patient characteristics were identified through an electronic medical record review and then examined for association with ABPM session success rate. These patient characteristics included age, sex, weight, height, body mass index (BMI), occupation, clinic blood pressure, travel distance to clinic, and presence of diabetes mellitus or renal disease. The percentage of valid readings obtained during an ABPM session was analyzed continuously (0-100%), whereas overall session success was analyzed dichotomously (0-79% or 80-100%). Univariate and multivariate regression analyses were performed to examine the influence of patient characteristics on the percentage of valid readings and the overall likelihood of achieving a successful session. In the 530 patients, the average percentage of valid readings was 90%, and a successful ABPM session (>or= 80% valid readings) was obtained in 84.7% (449 patients). A diagnosis of diabetes was found to negatively predict ABPM session success (continuous variable analysis, p=0.019; dichotomous variable analysis, odds ratio [OR] 0.45, 95% confidence interval [CI] 0.23-0.87, p=0.019), as did renal disease (continuous variable analysis, p=0.006; dichotomous variable analysis, OR 0.39, 95% CI 0.17-0.90, p=0.027) and increasing BMI (continuous variable analysis, p<0.001; dichotomous variable analysis, OR 0.78, 95% CI 0.65-0.93, p=0.005). Renal disease and BMI remained significant predictors in adjusted analyses. For most patients, ABPM was successful; however, elevated BMI and renal disease were associated with less complete ABPM session results. Adaptation and individualization of the ABPM process may be necessary to improve results in these patients.


Inducible HEK293 AAV packaging cell lines expressing Rep proteins.
Packaging or producer cell lines for scalable recombinant adeno-associated virus (rAAV) production have been notoriously difficult to create due in part to the cytostatic nature of the Rep proteins required for AAV production. The most difficult challenge being creating AAV packaging cell lines using HEK293 parental cells, currently the best mammalian platform for rAAV production due to the constitutive expression of E1A in HEK293 cells, a key REP transcription activator. Using suspension and serum-free media adapted HEK293SF carrying a gene expression regulation system induced by addition of cumate and coumermycin, we were able to create REP-expressing AAV packaging cells. This was achieved by carefully choosing two of the AAV Rep proteins (Rep 40 and 68), using two inducible promoters with different expression levels and integrating into the cells through lentiviral vector transduction. Three of our best clones produced rAAV titers comparable to titers obtained by standard triple plasmid transfection of their parental cells. These clones were stable for up to 7 weeks under continuous cultures condition. rAAV production from one clone was also validated at scale of 1 L in a wave bioreactor using serum-free suspension culture.


Production of a novel red pigment, rubrolone, by Streptomyces echinoruber sp. nov. I. Taxonomy, fermentation and partial purification.
A taxonomic study of Streptomyces X-14077 (NRRL 8144), which produces a water-soluble purple-red pigment complex, revealed it to be a new species which has been named Streptomyces echinoruber sp. nov. The pigment complex was produced in deep culture fermentation and isolated by solvent extraction and concentration. The major pigment component, rubrolone, has low toxicity and may have potential as a food coloring agent. It appears to be devoid of antibiotic activity.


Health care provision
On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the French national ESKD register was carried out. On the issue of healthcare provision, the following key messages were retained. France offers diversified, local healthcare that adapts to the patients' needs with several additional players (public, university, lucrative private, solidarity private). However, the spatial distribution of this offer shows differences between territories as regards the distribution of the different treatment modalities. For several years now, the REIN proposes a new way of representing the provision of care using groups of establishments working together, a granularity that seems more suited to the evaluation of practices than isolated dialysis units.


Clinical significance of neurological soft signs in schizophrenia: factor analysis of the Neurological Evaluation Scale.
Nonlocalizing neurologic deficits detectable by clinical evaluation-"soft signs"-are a robust finding in patients diagnosed with schizophrenia, but their conceptual and neuroanatomical correlates remain unclear. The purpose of this study was to evaluate the organization of these deficits and their clinical correlates using the Neurological Evaluation Scale (NES). Ninety-three male veterans with schizophrenia and schizoaffective disorder were evaluated using a detailed clinical assessment that included the NES, the Extrapyramidal Symptom Rating Scale, the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale, the Positive and Negative Syndrome Scale, the Wisconsin Card Sorting Test (WCST), the Schedule for the Deficit Syndrome (SDS), and the Digit Symbol Substitution Task (DSST). Four factors explained 73% of the variance and had distinct clinical and neuropsychological correlates. Factor 1 reflected deficits involved with memory and sensory integration, and was associated with lower PANSS positive and higher AIMS scores. Factor 2 reflected impairments in motor control, and was associated with lower intelligence, more cognitive deficits, and deficit-syndrome schizophrenia. Factor 3 was related to lower intelligence and more perseverative errors on the WCST. Factor 4 was related to increasing age, more extrapyramidal symptoms, more perseverative errors, and worse scores on the DSST. Neurologic deficits in schizophrenia have an intrinsic organization that appears to have clinical significance, highlighting the continued utility of the NES in studies of neurological deficits in schizophrenia patients. The theoretical underpinning of this organization remains unclear.


Providing perinatal loss care: satisfying and dissatisfying aspects for midwives.
There is limited midwifery research that focuses on midwives experiences and attitudes to providing care for women who experience the death of a baby. There is also limited research investigating care components, and evidence to inform the basis of clinical practice in Australia and internationally. This paper presents the qualitative findings of a small study that aimed to investigate midwives experience, confidence and satisfaction with providing care for women who experienced perinatal loss. Eighty-three Western Australian midwives responded to an open ended question asking them to describe the most and least satisfying aspects of their role when providing care to women who experienced a perinatal loss. Thematic analysis was used to analyse the data. The analysis revealed that Australian midwives gained most satisfaction from providing skilled midwifery care that they considered made a difference to women. This was enabled when midwives were afforded the opportunity to provide continuity of midwifery carer to women throughout the labour, birth and early postnatal period. In terms of the least satisfying aspects of care, midwives identified that they struggled with the emotional commitment needed to provide perinatal loss care, as well as with how to communicate openly and share information with women. Within the context of the study setting, midwifery care for women following perinatal loss reflects the care components espoused in the literature. There are, however, organisational issues within health care that require commitment to continuity of care and further education of practitioners to enhance outcomes for clients.


[The investigation of clinical images of 88 hospital staff with SARS].
To investigate the clinical thoracic images of hospital staff with SARS. Thoracic images was analyzed in 88 medical workers with SARS, including 394 chest plain films and 9 CT scans. The typical signs of SARS are multifocal air-space consolidations, and progress over a day from small shadow to becoming generalized. Thoracic plain film was necessary for diagnosis of SARS, CT could detect the pulmonary abnormality of SARS early.


Antibacterial and antioxidant properties of grape stem extract applied as disinfectant in fresh leafy vegetables.
In the present study total phenolic content (TPC), total flavonoid content (TFC), antioxidant activity and antimicrobial properties of grape (Vitis vinifera var. Red Globe) stem extract is reported. Also, the identification of main phenolic compounds was carried out by UPLC-PAD analysis. TPC and TFC of extract were 37.25 g GAE kg-1 and 98.07 g QE kg-1, respectively. Extract showed an antioxidant capacity of 132.60 and 317 g TE kg-1 for DPPH and ABTS radical scavenging capacity, respectively. The main phenolic compounds identified were rutin, gallic acid, chlorogenic acid, caffeic acid, catechin and ferulic acid. Extract inhibited the growth of Listeria monocytogenes, Staphylococcus aureus, Salmonella enterica subsp. enterica serovar Typhimurium, and Escherichia coli O157: H7 at MIC range 16-18 g L-1. Extract affected the different phases of bacterial growth. In addition, application of Extract (25 g L-1) as a sanitizer was effective to reduce the populations of all bacteria inoculated in lettuce (0.859-1.884 log reduction) and spinach (0.843-2.605 log reduction). This study emphasizes the potential of grape processing byproducts as an emergent and attractive source of bioactive compounds with antioxidant properties and antimicrobial activity against important foodborne pathogens. The study demonstrated that stem extract could be used to control the presence of human pathogenic bacteria in fresh leafy vegetables.


EEG for children with complex febrile seizures.
Febrile seizures can be classified as simple or complex. Complex febrile seizures are associated with fever that lasts longer than 15 minutes, occur more than once within 24 hours, and are confined to one side of the child's body. It is common in some countries for doctors to recommend an electroencephalograph (EEG) for children with complex febrile seizures. A limited evidence base is available to support the use of EEG and its timing after complex febrile seizures among children. To assess the use of EEG and its timing after complex febrile seizures in children younger than five years of age. For the latest update of this review, we searched the Cochrane Epilepsy Group Specialized Register (23 January 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 23 January 2017), MEDLINE (Ovid, 23 January 2017), and ClinicalTrials.gov (23 January 2017). We applied no language restrictions. All randomised controlled trials (RCTs) that examined the utility of an EEG and its timing after complex febrile seizures in children. The review authors selected and retrieved the articles and independently assessed which articles should be included. Any disagreements were resolved by discussion and by consultation with the Cochrane Epilepsy Group. We applied standard methodological procedures expected by Cochrane. Of 41 potentially eligible studies, no RCTs met the inclusion criteria. We found no RCTs as evidence to support or refute the use of EEG and its timing after complex febrile seizures among children. An RCT can be planned in such a way that participants are randomly assigned to the EEG group and to the non-EEG group with sufficient sample size. Since the last version of this review, we have found no new studies.


From beta-glucanase to beta-glucansynthase: glycosyl transfer to alpha-glycosyl fluorides catalyzed by a mutant endoglucanase lacking its catalytic nucleophile.
Removal of the catalytic nucleophile Glu134 of the retaining 1,3-1,4-beta-glucanase from Bacillus licheniformis by mutation to alanine yields an enzyme with no glycosidase activity. The mutant is able to catalyze the regio- and stereospecific glycosylation of alpha-laminaribiosyl fluoride with different glucoside acceptors through a single-step inverting mechanism. The main advantage of the mutant as glycosylation catalyst with respect to the kinetically controlled transglycosylation using the wild-type enzyme is that the reaction products cannot be hydrolyzed by the mutant enzyme, and glycosylation yields rise to 90%.


Chemosaturation with percutaneous hepatic perfusion is effective in patients with ocular melanoma and cholangiocarcinoma.
Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a novel interventional procedure, which delivers high doses of melphalan directly to the liver in patients with liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. We have previously shown promising efficacy for patients with ocular melanoma (OM) and cholangiocarcinoma (CCA) within our single-center and multi-center experiences. The aim of this study was to analyze the safety and efficacy of CS-PHP after 141 treatments at Hannover Medical School, Germany. Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median Overall survival (mOS), median progression-free survival (mPFS), and median hepatic PFS (mhPFS) were analyzed using the Kaplan-Meier estimation. Overall, 60 patients were treated with CS-PHP in the salvage setting from October 2014 until January 2019 at Hannover Medical School with a total of 141 procedures. Half of the patients were patients with hepatic metastases of ocular melanoma (OM) (n = 30), 14 patients had CCA (23.3%), 6 patients had hepatocellular carcinoma (10%), and 10 patients were treated for other secondary liver malignancies (16.7%). In total, ORR and disease stabilization rate were 33.3% and 70.3% (n = 25), respectively. ORR was highest for patients with OM (42.3%), followed by patients with CCA (30.8%). Independent response-associated factors were normal levels of lactate dehydrogenase (odds ratio (OR) 13.7; p = 0.015) and diagnosis with OM (OR 9.3; p = 0.028). Overall, mOS was 9 months, mPFS was 4 months, and mhPFS was 5 months. Patients with OM had the longest mOS, mPFS, and mhPFS with 12, 6, and 6 months, respectively. Adverse events included most frequently significant, but transient, hematologic toxicities (80% of grade 3/4 thrombopenia), less frequently hepatic injury up to liver failure (3.3%) and cardiovascular events including two cases of ischemic insults (5%). Salvage treatment with CS-PHP is safe and effective particularly in patients OM and CCA. Careful attention should be paid to possible, serious hepatic, and cardiovascular complications.


Thiophene Syntheses by Ring Forming Multicomponent Reactions.
Thiophenes occur as important building blocks in natural products, pharmaceutical active compounds, and in materials for electronic and opto-electronic devices. Therefore, there is a considerable demand for efficient synthetic strategies for producing these compounds. This review focuses on ring-forming multicomponent reactions for synthesizing thiophenes and their derivatives.


Spatial heterogeneity enhance robustness of large multi-species ecosystems.
Understanding ecosystem stability and functioning is a long-standing goal in theoretical ecology, with one of the main tools being dynamical modelling of species abundances. With the help of spatially unresolved (well-mixed) population models and equilibrium dynamics, limits to stability and regions of various ecosystem robustness have been extensively mapped in terms of diversity (number of species), types of interactions, interaction strengths, varying interaction networks (for example plant-pollinator, food-web) and varying structures of these networks. Although many insights have been gained, the impact of spatial extension is not included in this body of knowledge. Recent studies of spatially explicit modelling on the other hand have shown that stability limits can be crossed and diversity increased for systems with spatial heterogeneity in species interactions and/or chaotic dynamics. Here we show that such crossing and diversity increase can appear under less strict conditions. We find that the mere possibility of varying species abundances at different spatial locations make possible the preservation or increase in diversity across previous boundaries thought to mark catastrophic transitions. In addition, we introduce and make explicit a multitude of different dynamics a spatially extended complex system can use to stabilise. This expanded stabilising repertoire of dynamics is largest at intermediate levels of dispersal. Thus we find that spatially extended systems with intermediate dispersal are more robust, in general have higher diversity and can stabilise beyond previous stability boundaries, in contrast to well-mixed systems.


Functional heterogeneity and T cell-dependent activation of macrophages from murine sarcoma virus (MSV)-induced tumors.
In studies on the functional activity of macrophages isolated from murine sarcoma virus (MSV)-induced tumors, we have found that these cells may suppress immune responses as well as act as effector cells against the tumor. Previously, we reported that macrophages from the tumor could inhibit the antitumor response by suppressing proliferation-dependent immune functions. Here, we demonstrate that macrophages can also suppress the production of migration inhibition factor (MIF) and macrophage activation factor (MAF), two lymphocyte activities that are independent of cell proliferation. Conversely, we and others have found that macrophages from the tumor can exert an antitumor, cytolytic effect. In this study, using 1 g velocity sedimentation separation techniques, we have been able to identify 2-3 subpopulations of cytolytic macrophages in regressing tumors but in progressing tumors, only the smallest subpopulation of macrophages was active. T cells appeared to be required for activation of macrophages within the tumor, since MSV tumors induced in athymic, nude mice did not contain cytolytic macrophages.


Acute Decompensated Heart Failure in the Setting of Acute Coronary Syndrome.
Acute coronary syndrome (ACS) is frequently complicated by evidence of heart failure (HF). Those at highest risk for acute decompensated HF in the setting of ACS (ACS-HF) are older, female, and have preexisting heart disease, type 2 diabetes mellitus, hypertension, and/or kidney disease. The presence of ACS-HF is strongly associated with higher mortality and more frequent readmissions, especially for HF. Low implementation of guideline-directed medical therapy has further complicated the clinical care of this high-risk population. Improved utilization of current therapies, coupled with further investigation of strategies to manage ACS-HF, is desperately needed to improve outcomes in this vulnerable population, and the results of currently ongoing or recently concluded ACS-HF studies in this population are of great interest. In this review, we explore the pathophysiology, epidemiology, risk factors, and outcomes for patients with ACS-HF, and describe both existing evidence for management of this challenging condition and areas requiring further research.


Medical schools seek to overcome "invisibility" of gay patients, gay issues in curriculum.
Dr. Gary Gibson of Cambridge, Ont., went many years without identifying a single gay patient in his practice. When he "came out" about his homosexuality in 1981, about 15 of his patients revealed they were gay. Gibson, a professor of family medicine at the University of Western Ontario who is active in the College of Family Physicians of Canada, says such information is useful, because "if they don't identify, they may not get the medical advice they need." He wants medical students to receive more education in gay and lesbian issues, and recently drafted a gay and lesbian curriculum for postgraduate family medicine, which has been endorsed by the CMA.


Edaravone neuroprotection effected by suppressing the gene expression of the Fas signal pathway following transient focal ischemia in rats.
Preclinical and clinical studies have demonstrated that a free radical scavenger edaravone has neuroprotective effects on ischemic stroke but the underlying mechanism is not fully understood. The aim of this research is to explore the effect of edaravone on the apoptotic process involving the Fas/FasL signaling pathway. Transient focal ischemia in rats was induced for 2 hours by middle cerebral artery occlusion (MCAO). After reperfusion rats were treated i.v. with either edaravone or physiological saline. The expression of Fas-associated death domain protein (FADD), death-associated protein (Daxx) and caspase-8 was examined by immunohistochemistry. The mRNA levels for FADD and Daxx by reverse-transcriptase PCR (RT-PCR) and apoptosis was assessed by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL). Neurological scores and infarction volumes were also evaluated. Edaravone significantly improved the neurological outcome (p<0.05) and reduced the total infarct volumes (p<0.05), compared with saline control. In addition, edaravone-treatment significantly reduced the number of TUNEL-positive cells (p<0.01), reduced expression levels of FADD, Daxx and caspase-8 immunoreactivity (p <0.05 approximately 0.01), and decreased mRNA levels of FADD and Daxx (p<0.05 approximately 0.01) within the peri-infarct area. We conclude that edaravone may protect ischemic neurons from apoptosis via suppressing the gene expression of the Fas/FasL signaling pathway.


Production enhancement and characterization of the polyhydroxyalkanoate produced by Natrinema ajinwuensis (as synonym) ≡ Natrinema altunense strain RM-G10.
Application of halophiles can decrease the cost of polyhydroxyalkanoate (PHA) production or bioplastic which are an alternative to the petroleum-derived plastic. Extremely halophilic archaeon, Natrinema ajinwuensis RM-G10 accumulated 61.02±0.68% PHA of its cell dry mass at 72h in repeated batch cultures yielding 0.210±0.001gL-1h-1 volumetric productivity after selection of the best cultivation conditions. Transmission electron microscopy showed the presence of PHA granules inside the archaeal cells. Characterization by gas chromatographic analysis, gas chromatographic- mass spectrophotometric analysis, thermogravimetric analysis, differential scanning calorimetric analysis, X-ray diffraction analysis, Fourier transform infra red spectroscopy and nuclear magnetic resonance spectroscopy revealed the polymer to be poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with 13.93mol% 3-hydroxyvalerate content and having 35.45% crystallinity, -12.3°C glass transition temperature, 143°C and 157.5°C melting temperatures and 284°C degradation temperature. This is the first report on production enhancement (on a small scale) and characterization of the polyhydroxyalkanoate produced by Natrinema ajinwuensis (as synonym) ≡ Natrinema altunense strain RM-G10 and the Natrinema genus in general.


Low-dose acetylsalicylic acid (ASA) plus dipyridamole versus dipyridamole alone in the prevention of stroke in patients with reversible ischemic attacks.
A total of 243 patients who had reversible ischemic attacks (RIA) were submitted to clinical trial to determine whether dipyridamole (400 mg/day) (D) or aspirin (100 mg/48 hours) + dipyridamole (300 mg/day) (ASA + D) would produce significant reduction in the subsequent occurrence of RIA and completed stroke. One hundred and fifteen were selected for Group ASA + D and 71 were treated with dipyridamole only. The treatment groups were similar in relation to age, sex, risk factors, duration and presumed vascular territory of RIA, incidence of alterations of arterial supra-aortic trunks, cerebral infarct (CT scan), and platelet function. Patients were followed for a mean time of 21 months. At the end of the study, 21.7% of the ASA + D group and 19.7% in the D group had suffered new episodes of RIA or completed stroke (p = 0.88). Frequency of stroke (reversible ischemic neurologic deficit or completed stroke) was 7.8% in the ASA + D patients and 9.8% in the D patients (p = 0.83). Subgroup analysis did not show significant differences either. It is concluded that ASA + D has no significantly greater beneficial effect than that observed with D alone in the secondary prevention of atherothrombotic cerebral ischemia. However, a statistical Type II error cannot be excluded by the reduced number of recurrences.


p190RhoGAP has cellular RacGAP activity regulated by a polybasic region.
p190RhoGAP is a GTPase-activating protein (GAP) known to regulate actin cytoskeleton dynamics by decreasing RhoGTP levels through activation of the intrinsic GTPase activity of Rho. Although the GAP domain of p190RhoGAP stimulates the intrinsic' GTPase activity of several Rho family members (Rho, Rac, Cdc42) under in vitro conditions, p190RhoGAP is generally regarded as a GAP for RhoA in the cell. The cellular RacGAP activity of the protein has not been proven directly. We have previously shown that the in vitro RacGAP and RhoGAP activity of p190RhoGAP was inversely regulated through a polybasic region of the protein. Here we provide evidence that p190RhoGAP shows remarkable GAP activity toward Rac also in the cell. The cellular RacGAP activity of p190RhoGAP requires an intact polybasic region adjacent to the GAP domain whereas the RhoGAP activity is inhibited by the same domain. Our data indicate that through its alternating RacGAP and RhoGAP activity, p190RhoGAP plays a more complex role in the Rac-Rho antagonism than it was realized earlier.


Recombinant tissue plasminogen activator for neonatal and pediatric vascular thrombolytic therapy.
Thrombotic vascular occlusion may complicate the clinical course of many neonatal and pediatric pathologic processes. Systemic thrombolytic therapy with heparin, urokinase, or streptokinase may not be appropriate in the critically ill neonate because these agents generate a diffuse coagulopathic state. Direct surgical intervention for repair may be precluded by the small size of the vessels involved. Recombinant tissue plasminogen activator (rTPA) induces only a minimal proteolytic state while inducing thrombolysis within the local environment of the clot. We report our experience with regional rTPA infusion in four critically ill patients with venous and arterial thrombotic disorders. there were two brachial artery occlusive lesions--a neonate with iatrogenic occlusion due to a misplaced intravenous catheter and a 2-year-old child with inadvertent arterial ligation during an attempted venous cutdown. Two venous lesions consisted of a full-term neonate with renal vein/inferior vena caval thrombosis and a 32-week infant with partial superior vena caval thrombosis due to a Broviac catheter. Systemic thrombolytic therapy was contraindicated in these patients because of underlying illnesses. Pretherapy vascular evaluation included Doppler examination and angiography. The rTPA infusion was continued until there was evidence of clot lysis by ultrasound, angiogram, or venogram. Infusion rate of rTPA was adjusted according to fibrinogen levels. All three neonates responded successfully to rTPA therapy. Two neonates required only bolus administration and one responded to combined bolus and continuous infusion therapy after 58 hours. rTPA failed to reverse brachial artery occlusion in the 2-year-old child with purpura fulminans.(ABSTRACT TRUNCATED AT 250 WORDS)


Neurofunctional model of large-scale correlates of selective attention governed by stimulus-novelty.
Multiple studies demonstrate the influence of the limbic system on the processing of sensory events and attentional guidance. But the mechanisms involved therein are yet not entirely clear. The close connection of handling incoming sensory information and memory retrieval, like in the case of habituation towards insignificant stimuli, suggests a crucial impact of the hippocampus on the direction of attention. In this paper we thus present a neurofunctional forward model of a hippocampal comparator function based on the theory of theta-regulated attention. Subsequently we integrated this comparator model into a multiscale framework for the simulation of evoked responses. The results of our simulations were compared to experimental data on electroencephalographic (EEG) correlates of habituation towards familiar stimuli using time-scale analysis. In consequence we are able to present additional evidence for limbic influences on the direction of attention driven by stimulus novelty and a systems neuroscience framework for the statements given in the theta-regulated attention hypothesis.


Lycorine-derived phenanthridine downregulators of host Hsc70 as potential hepatitis C virus inhibitors.
A new series of potential phenanthridine hepatitis C virus (HCV) inhibitors which work by suppressing Hsc70 expression in the host cell was designed and synthesized from lycorine. Thirty-one new potential phenanthridine HCV inhibitors were synthesized and five of these compounds exhibited good anti-HCV activity and these inhibitors probably inhibit HCV by downregulating the host Hsc70 expression. Structure-activity analysis of these compounds revealed that the double bond between C-11 and C-12 and the substituents at C-8 and C-9 are important for their activity against HCV. Suppression of Hsc70 expression in the host cell to limit HCV replication is a potential anti-HCV strategy. Phenanthridines are probably the HCV inhibitors with this mode of action.


Interference between a fast-paced spatial puzzle task and verbal memory demands.
Research continues to provide evidence that people are poor multi-taskers. Cognitive resource theory is a common explanation for the inability to efficiently perform multiple tasks at the same time. This theory proposes that one's limited supply of cognitive resources can be utilized faster than it is replenished, which results in a performance decline, particularly when these limited resources must be allocated among multiple tasks. Researchers have proposed both domain-specific, for example, spatial versus verbal processing resources, and domain general cognitive resources. In the present research, we investigated whether a spatial puzzle task performed simultaneously with a verbal recall task would impair performance in either task or both tasks, compared to performance on the tasks individually. As hypothesized, a reduction in word recall was found when dual-tasking, though performance on the puzzle task did not significantly differ between the single- and dual-task conditions. This is consistent, in part, with both a general resource theory and a Multiple Resource Theory, but further work is required to better understand the cognitive processing system. The employment of the recall task in the dual-task paradigm with a variety of secondary tasks will help to continue mapping out the specificity (or lack thereof) of cognitive resources utilized in various mental and physical tasks.


Know safety, no fear.
Every day we are bombarded by stimuli that must be assessed for their potential for harm or benefit. Once a stimulus is learned to predict harm, it can elicit fear responses. Such learning can last a lifetime but is not always beneficial for an organism. For an organism to thrive in its environment, it must know when to engage in defensive, avoidance behaviors and when to engage in non-defensive, approach behaviors. Fear should be suppressed in situations that are not dangerous: when a novel, innocuous stimulus resembles a feared stimulus, when a feared stimulus no longer predicts harm, or when there is an option to avoid harm. A cardinal feature of anxiety disorders is the inability to suppress fear adaptively. In PTSD, for instance, learned fear is expressed inappropriately in safe situations and is resistant to extinction. In this review, we discuss mechanisms of suppressing fear responses during stimulus discrimination, fear extinction, and active avoidance, focusing on the well-studied tripartite circuit consisting of the amygdala, medial prefrontal cortex and hippocampus.


The Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala During the First Extinction Episode Has Persistent Effects on Extinction Expression.
Adaptive behavior depends on the delicate and dynamic balance between acquisition and extinction memories. Disruption of this balance, particularly when the extinction of memory loses control over behavior, is the root of treatment failure of maladaptive behaviors such as substance abuse or anxiety disorders. Understanding this balance requires a better understanding of the underlying neurobiology and its contribution to behavioral regulation. We microinjected Daun02 in Fos-lacZ transgenic rats following a single extinction training episode to delete extinction-recruited neuronal ensembles in the basolateral amygdala (BLA) and central nucleus of the amygdala (CN) and examined their contribution to behavior in an appetitive Pavlovian task. In addition, we used immunohistochemistry and neuronal staining methods to identify the molecular markers of activated neurons in the BLA and CN during extinction learning or retrieval. CN neurons were preferentially engaged following extinction, and deletion of these extinction-activated ensembles in the CN but not the BLA impaired the retrieval of extinction despite additional extinction training and promoted greater levels of behavioral restoration in spontaneous recovery and reinstatement. Disrupting extinction processing in the CN in turn increased activity in the BLA. Our results also show a specific role for CN PKCδ+ neurons in behavioral inhibition but not during initial extinction learning. We showed that the initial extinction-recruited CN ensemble is critical to the acquisition-extinction balance and that greater behavioral restoration does not mean weaker extinction contribution. These findings provide a novel avenue for thinking about the neural mechanisms of extinction and for developing treatments for cue-triggered appetitive behaviors.


Age and social composition factors as explanations for cleavages in socio-political values.
While age group differences on social and political values have been frequently documented in survey data, it is often claimed that these differences are due to social composition factors rather than to age itself. In this analysis we test for the effects of age vs. social composition in explaining variation in four attitudinal dependent variables. Using a sample especially drawn to study generational differences, and employing a multivariate statistical model, it was found that age differences were only modestly reduced by social composition variables. It is concluded that nonartifactual age group differences do exist on the dependent variables.


Case and partnership reproduction numbers for a curable sexually transmitted infection.
Sexually transmitted infections (STIs) are, by definition, transmitted between sexual partners. For curable STIs an infected index case can potentially re-infect the same partner multiple times. Thus, R0, the average number of secondary infections one typical infected individual will produce during his or her infectious period is not necessarily the same as the average number of secondary cases (infected persons). Here we introduce the new concept of the case reproduction number (Rc). In addition, we define the partnership reproduction number (Rp) as the average number of secondary partnerships consisting of two infected individuals one typical infected individual will produce over his or her infectious lifetime. Rp takes into account clearance and re-infection within partnerships, which results in a prolongation of the duration of the infectious period. The two new reproduction numbers were derived for a deterministic pair model with serial monogamous partnerships using infection parameters for Chlamydia trachomatis, an example of a curable STI. We showed that re-infection within partnerships means that curable STIs can be sustained endemically even when the average number of secondary cases a person produces during his or her infectious period is below one.


Safety and feasibility of CDK4/6 inhibitors treatment combined with radiotherapy in patients with HR-positive/HER2-negative breast cancer. A systematic review and meta-analysis.
The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy in hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-) breast cancer has led to practice-changing improvements in overall survival. However, there are conflicting data concerning the safety of CDK4/6i combination with radiotherapy, and no consensus guidelines exist to guide practice. We conducted a meta-analysis to assess the safety and feasibility of CDK4/6i treatment with radiotherapy. A comprehensive search was performed in PubMed/MEDLINE, Web of Science, and Scopus, for studies in advanced/metastatic breast cancer receiving CDK4/6i and radiotherapy with the provided safety data on the occurrence of toxicity. The main outcomes were safety (grade 3-5 adverse events), CDK 4/6i dose reduction, and the discontinuation rate due to toxicity. Fifteen studies comprising 1133 patients with HR+/HER2- breast cancer patients were included. Among them, 617 pts received CDK4/6i and radiotherapy; the median follow-up was 17.0 months (IQR 9.2 - 18.0), and the median age was 58.8 years (IQR 55.5---62.5). The pooled prevalence of severe hematologic toxicity was 29.4% (95% CI 14.0% - 47.4%; I2 = 93%; τ2 = 0.084; p < 0.01 and severe non-hematologic toxicity was 2.8% (95% CI 1.1% - 4.8%; I2 = 0%; τ2 = 0.0; p = 0.67). The pooled prevalence of CDK4/6i dose reduction was 24.0% (95% CI 11.1% - 39.4%; I2 = 90%; τ2 = 0.052; p < 0.01) with no difference between CDK4/6i plus RT vs. CDK4/6i (odds ratio of 0.934; 95% CI 0.66 - 1.33; I2 = 0%; τ2 = 0.0; p = 0.56). The pooled prevalence of CDK4/6i discontinuation due to toxicity was 2.3% (95% CI 0.4% - 5.2%; I2 = 23%; τ2 = 0.002; p = 0.24). The findings of this study suggest that radiotherapy in addition to CDK4/6i treatment in breast cancer patients is generally safe and well tolerated and remains a viable treatment option.


Physical interaction of p73 with c-Myc and MM1, a c-Myc-binding protein, and modulation of the p73 function.
p73 shares high sequence homology with the tumor suppressor p53. Like p53, ectopic overexpression of p73 induces cell cycle arrest and/or apoptosis, and these biological activities are linked to its sequence-specific transactivation function. The COOH-terminal region of p73 is unique and has a function to modulate DNA-binding ability and transactivation activity. To identify and characterize cellular proteins that interact with the COOH-terminal region of p73 alpha and regulate its activity, we employed a yeast-based two-hybrid screen with a human fetal brain cDNA library. We found MM1, a nuclear c-Myc-binding protein, was associated with p73 alpha in both yeast two-hybrid and in vitro pull-down assays. In mammalian cells, MM1 co-immunoprecipitated with p73 alpha, whereas p73 beta and tumor suppressor p53 did not interact with MM1. Overexpression of MM1 in p53-deficient osteosarcoma SAOS-2 cells enhanced the p73 alpha-dependent transcription from the p53/p73-responsive Bax and PG13 promoters, whereas p73 beta- and p53-mediated transcriptional activation was unaffected in the presence of MM1. MM1 also stimulated the p73 alpha-mediated growth suppression in SAOS-2 cells. More importantly, we found that c-Myc was physically associated with p73 alpha and significantly impaired the transcriptional activity of p73 alpha on Bax and p21(waf1) promoters. Expression of MM1 strongly reduced the c-Myc-mediated inhibitory activity on p73 alpha. These results suggest that MM1 may act as a molecular partner for p73 to prevent the c-Myc-mediated inhibitory effect on its activity.


Why is chest disease so common in South Wales? Smoking, social class, and lung function: a survey of elderly men in two areas.
A respiratory survey was conducted in two British towns, one with a high mortality (Caerphilly) and one with a low mortality (Bath) from respiratory disease. A total of 513 men aged 65-74 years were seen. The Caerphilly men had poorer lung function than the Bath men; the overall difference in FEV1 and FVC for men aged 70 and 1.68m tall was 0.16 1 and 0.17 1 respectively. These differences appeared to be largely due to the greater tendency of the Caerphilly men to smoke and to an effect related to social class. Respiratory symptoms were also more common in Caerphilly, principally because of the effects of smoking and occupational group, although when these factors were allowed for there was still a significantly greater prevalence of breathless wheezing in Caerphilly.


Platelet-derived growth factor C deficiency in C57BL/6 mice leads to abnormal cerebral vascularization, loss of neuroependymal integrity, and ventricular abnormalities.
Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors (PDGFRs) are known to play important roles during development of the lungs, central nervous system (CNS), and skeleton and in several diseases. PDGF-C is a ligand for the tyrosine kinase receptor PDGFRα. Mutations in the gene encoding PDGF-C have been linked to clefts of the lip and/or palate in humans, and ablation of PDGF-C in 129/Sv background mice results in death during the perinatal period. In this study, we report that ablation of PDGF-C in C57BL/6 mice results in a milder phenotype than in 129/Sv mice, and we present a phenotypic characterization of PDGF-C deficiency in the adult murine CNS. Multiple congenital defects were observed in the CNS of PDGF-C-null C57BL/6 mice, including cerebral vascular abnormalities with abnormal vascular smooth muscle cell coverage. In vivo imaging of mice deficient in PDGF-C also revealed cerebral ventricular abnormalities, such as asymmetry of the lateral ventricles and hypoplasia of the septum, reminiscent of cavum septum pellucidum in humans. We further noted that PDGF-C-deficient mice displayed a distorted ependymal lining of the lateral ventricles, and we found evidence of misplaced neurons in the ventricular lining. We conclude that PDGF-C plays a critical role in the development of normal cerebral ventricles and neuroependymal integrity as well as in normal cerebral vascularization.


Methylene-bridged bay region chrysene and phenanthrene derivatives and their keto-analogs: mutagenicity in Salmonella typhimurium and tumor-initiating activity on mouse skin.
A series of methylene-bridged and keto-bridged bay region derivatives of chrysene and phenanthrene were prepared and evaluated for mutagenic activity in Salmonella typhimurium TA100 and for tumor-initiating activity on CD-1 mouse skin. The compounds included in this series were 4H-cyclopenta[def]phenanthrene, 4H-cyclopenta[def]phenanthrene-4-one, 1-methyl-4H-cyclopenta[def]phenanthrene, 1-methyl-4H-cyclopenta[def] phenanthren-4-one, 4H-cyclopenta[def] chrysene, and 4H-cyclopenta[def] chrysen-4-one. Among these compounds only 4H-cyclopenta[def]phenanthrene and 1-methyl-4H-cyclopenta[def]phenanthren-4-one were not significantly mutagenic when assayed with metabolic activation using Aroclor-induced rat liver homogenate. None of the compounds assayed were active without metabolic activation. 4H-Cyclopenta[def]chrysene was the most tumorigenic of the methylene-bridged bay region PAH tested on mouse skin. At a dose of 1.0 mg this compound resulted in 100% of the animals bearing papillomas with 5.63 papillomas/animal. 4H-Cyclopenta[def]chrysen-4-one and 1-methyl-4H-cyclopenta[def]phenanthrene displayed weak tumorigenic activity at a total initiating dose of 1.0 mg.


Chemoproteomic characterization of protein kinase inhibitors using immobilized ATP.
Protein kinase inhibitors have emerged as indispensable tools for the elucidation of the biological functions of specific signal transduction pathways and as promising candidates for molecular-targeted therapy. However, because many protein kinase inhibitors are ATP-competitive inhibitors targeting the catalytic site of specific protein kinases, the large number of protein kinases that are encoded within eukaryotic genomes and the existence of many other cellular proteins that bind ATP result in the prospect of off-target effects for many of these compounds. Many of the potential off-target effects remain unrecognized because protein kinase inhibitors are often developed and tested primarily on the basis of in vitro assays using purified components. To overcome this limitation, we describe a systematic approach to characterize ATP-competitive protein kinase inhibitors employing ATP-sepharose to capture the purine-binding proteome from cell extracts. Protein kinase inhibitors can be used in competition experiments to prevent binding of specific cellular proteins to ATP-sepharose or to elute bound proteins from ATP-sepharose. Collectively, these strategies can enable validation of interactions between a specific protein kinase and an inhibitor in complex mixtures and can yield the identification of inhibitor targets.


Identification of Erwinia sp., causing stalk rot of maize in Egypt.
The physiological characteristics, pathogenic propensities, and the sensitivity towards certain antibiotics of the causal bacterium of stalk rot of maize, isolated in Egypt, were studied. Different isolates of Erwinia carotovora and E. atroseptica were included for comparative studies. The antibiotic sensitivity tests (including erythromycin) are of no value in differentiating between E. carotovora and E. atroseptica. The cultures of the causal bacterium of stalk rot of maize showed physiological characteristics similar to those known for E. chrysanthemi. The pathogenic propensities of E. chrysanthemi isolates suggest the presence of a number of pathotypes of E. chrysanthemi. The proposal of HARTMAN and KELMAN to identify maize stalk rot pathogen as E. chrysanthemi (corn pathotype) seems, therefore, to be the most appropriate name for this bacterium.


Cellular Interactome Dynamics during Paclitaxel Treatment.
Cell-cycle inhibitors, including paclitaxel, are among the most widely used and effective cancer therapies. However, several challenges limit the success of paclitaxel, including drug resistance and toxic side effects. Paclitaxel is thought to act primarily by stabilizing microtubules, locking cells in a mitotic state. However, the resulting cytotoxicity and tumor shrinkage rates observed cannot be fully explained by this mechanism alone. Here we apply quantitative chemical cross-linking with mass spectrometry analysis to paclitaxel-treated cells. Our results provide large-scale measurements of relative protein levels and, perhaps more importantly, changes to protein conformations and interactions that occur upon paclitaxel treatment. Drug concentration-dependent changes are revealed in known drug targets including tubulins, as well as many other proteins and protein complexes involved in apoptotic signaling and cellular homeostasis. As such, this study provides insight into systems-level changes to protein structures and interactions that occur with paclitaxel treatment.


Degradation by rat tissues in vitro of organophosphorus esters which inhibit cholinesterase.
Hydrolytic "A"-esterase activities of various tissues of rat (plasma, liver, kidney, brain and intestinal mucosa) against selected OP esters of diverse structure as potential substrates (paraoxon, di-n-propyl paraoxon, di-n-butyl paraoxon, chlorpyrifos oxon, di-(4-phenyl butyl) phosphorofluoridate and the chiral isomers of ethyl 4-nitrophenyl phenylphosphonate) were studied. We have developed a sensitive and widely applicable assay depending on measuring decline in residual inhibitory power of any chosen OP against horse serum cholinesterase: for seven compounds examined so far I50s against BuChE ranged from 0.07 to 70 nM, and it is easy to monitor loss of OP starting from an initial 25 microM concentration. Progressive destruction rates were always highest in liver and plasma with activity sometimes detectable in kidney, brain but not in intestinal mucosa, but the ratios of activity between tissues differed for different substrates. At 25 microM/37 degrees/pH 7.2 hydrolysis rates ranged from 8500 nmol/min/g liver for di-(4-phenylbutyl) phosphorofluoridate down to 0.8 nmol/min for the butyl analogue of paraoxon; the rate for L(-) isomer of EPN oxon (23 nmol/min/g liver) was greater than 2x that for the D(+) isomer and for paraoxon. From our data we conclude that several OP hydrolases exist whose identity may be further characterised by use of selective substrates.


Pharmacological interference with the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse.
The effect of pretreatment with various MAO and catecholamine uptake inhibitors on the MPTP-induced reduction of endogenous catecholamine levels and [3H]catecholamine uptake in mouse striatum and cerebral cortex associated with the neurotoxic action of MPTP on dopamine and noradrenaline neurons was investigated. Pargyline and deprenyl almost completely reversed the MPTP-induced reduction of these parameters in both regions while chlorgyline was without effect. Pretreatment with the dopamine uptake inhibitor amfolenic acid preferentially counteracted the depleting effect of MPTP on striatal dopamine levels. The noradrenaline uptake inhibitors desipramine, nortriptyline and LY 139603 all antagonized the MPTP-induced reduction of noradrenaline levels in cerebral cortex, while none of these inhibitors affected the action of MPTP on striatal dopamine. The results suggest that MAO-B and the catecholamine uptake system may be critically involved at certain steps in the neurotoxic action of MPTP on catecholamine neurons. The interaction with the uptake mechanism most likely explains the selective neurotoxic action of MPTP on catecholamine neurons.