A Bismuth Metal-Organic Framework as a Contrast Agent for X-ray Computed Tomography.
A new bismuth metal-organic framework (MOF), bismuth-NU-901 (Bi-NU-901), featuring the scu topology and a pore with a diameter of ∼11 Å, was solvothermally synthesized, and its use as an X-ray computed tomography (CT) contrast agent was tested. X-ray CT is a common diagnostic method used in the medical field. Inside the body, contrast media enhance the distinction between tissues and organs of similar density. Bi-NU-901 consists of eight connected Bi6 nodes and tetratopic 1,3,5,8-(p-benzoate)pyrene linkers (TBAPy). Numerous material characterization studies including powder X-ray diffraction (PXRD), scanning transmission electron microscopy (STEM), and DFT pore size distribution support the scu structure. Additionally, given the framework's high density of nontoxic heavy atoms, Bi-NU-901 was evaluated as an X-ray computed tomography (CT) agent. Importantly, in vitro studies revealed this new bismuth MOF demonstrates ∼7 times better contrast intensity compared to a zirconium MOF featuring the same topology and ∼14 times better contrast than a commercially available CT contrast agent. These results suggest bismuth MOFs may be promising CT contrast agents.


Novel 3D pharmacophore of alpha-MSH/gamma-MSH hybrids leads to selective human MC1R and MC3R analogues.
To further evaluate elements that could contribute to the 3D topographical structure of gamma-MSH, we have systematically designed a group of linear gamma-MSH analogues and evaluated their biological activities: without a N-terminal acetyl, with and without a C-terminal amide, with Nle(3), with l- or d-Phe(6) or d-Nal(2')(6), and with d-Trp(8) or d-Nal(2')(8). It was found that changing the C-terminal acid in gamma-MSH to an amide and replacing Met with Nle leads to increased binding affinities at all four subtypes of melanocortin receptors (10-100 fold). Substitution of Trp(8) with d-Nal(2')(8) and Phe(6) with d-Phe(6) in gamma-MSH-NH(2) forms a selective antagonist for the hMC3R, whereas, substitution of Phe(6) with d-Nal(2')(6) and replacing Trp(8) with d-Trp(8) at gamma-MSH-NH(2) yields a selective partial agonist for the hMC1R. Finally, substitution of His(5) with Pro(5) and Trp(8) with d-Nal(2')(8) in gamma-MSH-NH(2) leads to a highly potent and selective agonist for the hMC1R. Molecular modeling showed that, at the C-terminal of Nle(3)-gamma-MSH-NH(2), there is a reverse-turn-like structure, suggesting that there might be a secondary binding site involved in ligand-receptor interaction for gamma-MSH analogues that may explain the enhanced binding affinities of the Nle(3)-gamma-MSH-NH(2) analogues. Our results indicate that increasing the hydrophobicity and replacing Phe(6) and Trp(8) with bulkier aromatic amino acid residues is very important for selectivity of alpha-MSH/gamma-MSH hybrids for hMCRs.


Taraxacum officinale and related species-An ethnopharmacological review and its potential as a commercial medicinal plant.
Dandelion (Taraxacum spec) is a wild plant that has been used for centuries as a traditional medicine in the relief and treatment of several diseases. This use is due to the presence of sesquiterpenes, saponins, phenolic compounds, flavonoids, and sugars, among others, found in the organs of the plant. The aim of this work is to provide a current review of developments and trends in research on the Taraxacum genus, with a focus on traditional uses and pharmacological properties. This should shed light on the potential of this plant as an attractive commercial herbal medicine. Documents were collected, analyzed, and classified for information regarding medical, agronomic, genetic, and biological aspects of the Taraxacum species. This process was based on a thorough search of documents indexed by scientific search engines. Two important periods of research on Taraxacum have been identified: the first, between 1930 and 1950; and the second, from 1990 to today. During the former, agricultural and genetics research on this plant were, due to the shortage of natural rubber, the focus. In contrast, the main drive in Taraxacum research is now the recovery of bioactives and/or applications in medicine. Pharmacology is the main area in which these plants have been tested, thanks in part to its widely known traditional uses; however, there is less than enthusiastic interest in further human clinical trials. In other areas, Taraxacum sports an enormous list of compounds of industrial interest; and while it is true that only a small amount of these compounds is immediately available in Taraxacum organs and makes it relatively commercially unattractive, only scarce efforts have been made to improve yields. Compounding this issue, most studies of its growth and cultivation have been focused mainly on controlling it as a weed detrimental to certain industrial crops. To wit, in spite of all the research carried out, less than 1% of all the species identified so far (>2500) have been studied (including Taraxacum officinale, Taraxacum coreanum, Taraxacum mongolicum and Taraxacum platycarpum). This is a indication of the little knowledge that we have about this genus so far. Biotechnology (involving genetics, agriculture, and biology) is the most powerful means by which to take advantage of all the medicinal potential of Taraxacum. Great strides have been made in identifying metabolic pathways for synthesizing terpenes, one of the most important compound families in clinical applications. In order to improve yield and performance of the plant in the field, greenhouse cultivation is another aspect taken into account, deriving an increase in recovery of bioactives from Taraxacum organs. Even while considering that only a few species have been studied, their different biochemical and cultivation profiles indicate huge potential for qualitative improvements in composition through genetic engineering, thus directly impacting pharmacological properties. Taraxacum is has been traditionally considered a natural remedy, well-inserted into popular knowledge, but with low commercial applicability. Only once the recovery of pure and highly reactive compounds can be pursued at (a qualitatively and quantitatively attractive) economical scale, human clinical trials would be of interest in order to prove their efficacy and safety, positioning Taraxacum as an important commercial source of natural drugs.


Isolation of a virus closely related to gibbon ape leukaemia virus from cells infected with virus (HL-23V) released by human leukaemic cells.
Canine thymus cells infected with virus (HL-23V) produced by human acute myelogenous leukaemia cells in culture were shown in previous reports to produce transforming and non-transforming type C virus similar or identical to the simian sarcoma virus complex SSV(SSAV) and to induce tumours in marmoset monkeys (Bergholz et al. 1977a). In these earlier studies the appearance of breakthrough foci at low dilutions of antiserum in neutralization tests with high-titred anti-SSV(SSAV) serum suggested the presence of another virus, distinct from SSV-(SSAV). We now report the isolation of this component and, by comparative neutralization analysis, demonstrate that it is most closely related to gibbon ape leukaemia virus (GALV). It is distinguished from SSV(SSAV) by kinetics of neutralization and molecular hybridization experiments. This component was readily cloned both from virus produced by HL-23V chronically-infected canine thymus cells established by Teich et al. (1975) when HL-23V was first isolated and from virus produced by HL-23V-induced marmoset tumour cells in culture. The presence of this component in the original leukaemic cell cultures is discussed.


A speckle target adaptive imaging technique in the presence of distributed aberrations.
Acoustic velocity inhomogeneities in tissue result in aberration of ultrasound images. These aberrations can be modeled as a near field thin phase screen or as a distributed aberrator. The effect of a near field thin phase screen is to time shift the received echo at each element, while distributed aberrators result in both pulse distortions and time shifts from element to element. Most current techniques for the correction of distributed aberrators are limited to application on point targets. A new technique is proposed which uses multiple transmits from spatially shifted transmit apertures (the translating transmit aperture algorithm), in conjunction with phase conjugate filters, to correct for distributed aberrations in the presence of speckle targets. The performance of the translating transmit aperture algorithm in improving the correlation between signals received by elements of different spatial separations is measured, and factors affecting the performance of this technique are investigated in simulation and experiment.


Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia.
The identification of neurobiological intermediate phenotypes may hasten the search for susceptibility genes in complex psychiatric disorders such as schizophrenia. Earlier family studies have suggested that deficits in executive cognition and working memory may be related to genetic susceptibility for schizophrenia, but the biological basis for this behavioral phenotype has not been identified. The authors used functional magnetic resonance imaging (fMRI) during performance of the N-back working memory task to assess working memory-related cortical physiology in nonschizophrenic, cognitively intact siblings of patients with schizophrenia. They compared 23 unaffected siblings of schizophrenic patients to 18 matched comparison subjects. As a planned replication, they studied another 25 unaffected siblings and 15 comparison subjects. In both cohorts, there were no group differences in working memory performance. Nevertheless, both groups of siblings showed an exaggerated physiological response in the right dorsolateral prefrontal cortex that was qualitatively similar to results of earlier fMRI studies of patients with schizophrenia. These fMRI data provide direct evidence of a primary physiological abnormality in dorsolateral prefrontal cortex function in individuals at greater genetic risk for schizophrenia, even in the absence of a manifest cognitive abnormality. This exaggerated fMRI response implicates inefficient processing of memory information at the level of intrinsic prefrontal circuitry, similar to earlier findings in patients with schizophrenia. These data predict that inheritance of alleles that contribute to inefficient prefrontal information processing will increase risk for schizophrenia.


[Eosinophilic gastroenteritis: a rare case of dyspepsia].
Eosinophilic gastroenteritis is a rare and heterogeneous disease that is probably misdiagnosed in clinical practice because it meets a high degree of suspicion, and an endoscopy with biopsy is needed for diagnosis. The authors describe, with a brief thematic review, a case of eosinophilic gastroenteritis presenting as dyspepsia syndrome and mild peripheral eosinophilia.


Phosphatase activation by epidermal growth factor family ligands regulates extracellular regulated kinase signaling in undifferentiated hen granulosa cells.
Previous work has demonstrated that epidermal growth factor family ligands, signaling through the MAPK/ERK pathway, prevent hen granulosa cell differentiation, in vitro, even in the presence of factors that promote differentiation (e.g. TGFbeta and FSH). The working hypothesis is that a release from tonic inhibitory ERK signaling is prerequisite for the initiation of hen granulosa cell differentiation. Initial results demonstrate that the ERK signaling pathway is desensitized after treatment with TGFalpha or betacellulin. Thus, studies were conducted to evaluate a role for MAPK phosphatases in the termination of ERK signaling in undifferentiated granulosa cells. Subsequent to ligand-induced translocation of ERK to the nucleus, de novo transcription and translation of one or more protein tyrosine or dual-specificity phosphatases results in dephosphorylation and localization of inactivated ERK within the nucleus. RT-PCR amplification reveals expression of the MAPK-selective phosphatases (MKP), MKP-1, -3, and dual-specificity phosphatase 5, in granulosa cells. TGFalpha induces expression (within 3 h) of mRNA encoding the ERK-selective nuclear phosphatase, dual-specificity phosphatase 5, and subsequently (by 20 h) induces mRNA encoding the cytoplasmic phosphatase, MKP-3. Increased expression of phosphatases is associated with the intracellular localization and dephosphorylation of ERK and is inhibited by the selective ERK inhibitor, U0126. In turn, regulation of phosphatase activity occurs via the ubiquitin-proteasome degradation pathway because treatment of cells with the proteasome inhibitor, Z-LLF-CHO, markedly promotes ERK dephosphorylation. These data provide direct evidence for ERK-mediated negative feedback due to regulation of phosphatase activity in undifferentiated granulosa cells.


How does duration of curing affect the radiopacity of dental materials?
Clinicians commonly encounter cases in which it is difficult to determine whether adjacent radiopacities are normal or pathologic. The ideal radiopacity of composite resin is equal to or higher than that of the same thickness of aluminum. We aimed to investigate the possible effects of different curing times on the post-24-hour radiopacity of composite resins on digital radiographs. One mm thick samples of Filtek P60 and Clearfil resin composites were prepared and cured with three regimens of continuous 400 mW/cm(2) irradiance for 10, 20 and 30 seconds. Along with a 12-step aluminum step wedge, digital radiographs were captured and the radiopacities were transformed to the equivalent aluminum thicknesses. Data were compared by a general linear model and repeated-measures of ANOVA. Overall, the calculated equivalent aluminum thicknesses of composite resins were increased significantly by doubling and tripling the curing times (F(2,8)=8.94, p=0.002). Notably, Bonferroni post-hoc tests confirmed that the radiopacity of the cured Filtek P60 was significantly higher at 30 seconds compared with 10 seconds (p=0.04). Although the higher radiopacity was observed by increasing the time, other comparisons showed no statistical significance (p>0.05). These results supported the hypothesis that the radiopacity of resin composites might be related to the duration of light curing. In addition to the current standards for radiopacity of digital images, defining a standard protocol for curing of dental materials should be considered, and it is suggested that they should be added to the current requirements for dental material.


Endothelin induces diuresis and natriuresis in the rat by acting on proximal tubular cells through a mechanism mediated by lipoxygenase products.
Besides being a potent renal vasoconstrictor, endothelin causes diuresis and natriuresis. At which site along the nephron and how endothelin alters water and sodium handling in the tubule remain to be clarified. It was found that endothelin (75 pmol) given as an i.v. infusion in vivo to rats caused diuresis and urinary sodium excretion to double but did not affect glomerular filtration rate and renal plasma flow. On raising the dose of endothelin to 150 pmol, a further increase in diuresis and natriuresis was found, whereas glomerular filtration rate fell 33% and renal plasma flow fell 36%; 300 pmol of endothelin reduced glomerular filtration rate by 73% and renal plasma flow by 77% but did not significantly affect diuresis and absolute sodium excretion. It did, however, increase fractional sodium excretion eightfold. Lithium clearance studies of changes in tubular handling of water and sodium indicated that infusion of 150 pmol of endothelin to rats caused a reduction in absolute (pre, 84.7 +/- 5.9; post, 47.9 +/- 6.1 microEq/min/100 g) and fractional (pre, 85.7 +/- 3.0; post, 64.7 +/- 6.4%) proximal reabsorption of sodium. Endothelin infusion (150 pmol) was not associated with any significant change in plasma atrial natriuretic peptide levels, which on average remained comparable to those in rats given the vehicle alone (49.7 +/- 8.4 versus 46.3 +/- 5.6 pg/mL). In the isolated perfused rat kidney preparation, exposure to 150 pmol of endothelin significantly increased fractional sodium excretion over preinjection values (pre, 2.2 +/- 0.2; post, 7.3 +/- 1.0%) despite a marked decrease in glomerular filtration rate and renal perfusate flow. Additional in vivo experiments showed that oral administration of the specific 5-lipoxygenase inhibitor L-651,392 to rats prevented the increase in urine flow rate (pre, 5.7 +/- 0.1; post, 6.6 +/- 0.8 microL/min), and in absolute (pre, 0.33 +/- 0.04; post, 0.37 +/- 0.05 microEq/min) and fractional (pre, 0.10 +/- 0.02; post, 0.11 +/- 0.03%) sodium excretion caused by bolus i.v. infusion of endothelin (150 pmol). Similarly, a specific leukotriene C4/D4 receptor antagonist, L-649,923, also prevented the diuretic and natriuretic effect of 150 pmol of endothelin i.v. infusion. These findings show that (1) endothelin has a diuretic and natriuretic effect that is independent of its action on renal hemodynamics; (2) this effect depends on a direct action on the proximal tubules; (3) atrial natriuretic peptide does not appear to be involved in this effect; and (4) the diuretic and natriuretic responses to endothelin are mediated by 5-lipoxygenase products.


[Persistent common trunk. Anatamopathological study of 25 specimen].
In order to inform the pathologic features and their associated anomalies twenty five hearts with common trunk were studied with the segmental sequential system. An anatomico-embryological correlation was made to understand the pathological complex of this malformation. The results were: type I truncus (96%), infundibular ventricular septal defect (96%), displastic truncal valve (28%), ventriculo infundibular fold (92%), left coronary artery arising from the posterior wall of the truncus (75%), right coronary artery arising from their anterior wall (96%), coronary arteries arising from opposite Valsalva sinuses in the tetracuspid valves; the biventricular conection of the truncus was balanced in 60%, prevailing on the right (16%) or on the left (16%) ventricles. Among the associated anomalies there were right aortic arch, interruption of the aortic arch, anomalous origin of the left subclavian artery, vascular ring, aneurysm of the sinus of Valsalva, and absence of the left branch of the pulmonary artery. Developmentally common trunk is explained as a failure of truncoconal septation in the embryonic heart; a migration arrest of neural crest cells is implicated in the Di George syndrome. Knowledge of the anatomic features of common trunk and their associated anomalies, provides the morphological basis to interpret correctly the clinical diagnostic imagenology.


Microbiota Detection Patterns Correlate With Presence and Severity of Barrett's Esophagus.
The microbiome has been increasingly associated with different disease processes, but its role in esophagus is largely unknown. Our goal was to determine the associations of the esophageal microbiota with Barrett's esophagus. A total of 74 patients were included in this prospective study, including 34 patients with Barrett's esophagus and 40 patients without Barrett's esophagus. Esophageal swabs were obtained from the uvula, and mucosal biopsies were obtained from the proximal esophagus and distal esophagus in each patient. The microbiome of each sample was assessed using a customized Esophageal Microbiome qPCR array (EMB). For each clinical sample, we completed a detection/non-detection analysis for each organism in the EMB. The limit of detection (LOD) for each target was established by analysis of plasmid dilutions. Average age was 60.2 years. There were significantly different microbial detection patterns in patients with Barrett's esophagus compared to the control population. There were a greater number of organisms which had different likelihoods of detection in the distal esophagus, compared to the proximal esophagus or uvula. In addition, as the length of the Barrett's column increased, multiple organisms were less likely to be detected. This decreased likelihood occurred only in the distal esophagus. Beside Barrett's esophagus, no other demographic factors were associated with differences in detection patterns. Microbial community structures differ between patients with and without Barrett's esophagus. Certain organisms are less likely to be detected as the severity of Barrett's esophagus worsens. These results suggest that particular organisms may have a protective effect against the development of Barrett's esophagus.


Impact of genetically engineered maize on agronomic, environmental and toxicological traits: a meta-analysis of 21 years of field data.
Despite the extensive cultivation of genetically engineered (GE) maize and considerable number of scientific reports on its agro-environmental impact, the risks and benefits of GE maize are still being debated and concerns about safety remain. This meta-analysis aimed at increasing knowledge on agronomic, environmental and toxicological traits of GE maize by analyzing the peer-reviewed literature (from 1996 to 2016) on yield, grain quality, non-target organisms (NTOs), target organisms (TOs) and soil biomass decomposition. Results provided strong evidence that GE maize performed better than its near isogenic line: grain yield was 5.6 to 24.5% higher with lower concentrations of mycotoxins (-28.8%), fumonisin (-30.6%) and thricotecens (-36.5%). The NTOs analyzed were not affected by GE maize, except for Braconidae, represented by a parasitoid of European corn borer, the target of Lepidoptera active Bt maize. Biogeochemical cycle parameters such as lignin content in stalks and leaves did not vary, whereas biomass decomposition was higher in GE maize. The results support the cultivation of GE maize, mainly due to enhanced grain quality and reduction of human exposure to mycotoxins. Furthermore, the reduction of the parasitoid of the target and the lack of consistent effects on other NTOs are confirmed.


A single dose of the potent gonadotropin-releasing hormone antagonist acyline suppresses gonadotropins and testosterone for 2 weeks in healthy young men.
Acyline is a novel GnRH antagonist that reliably inhibits gonadotropins and testosterone (T) levels in men for 48 h after a single dose up to 75 microg/kg. In this study we examined gonadotropin and T levels in 28 healthy young men administered acyline as single doses of 150 or 300 microg/kg or serial injections of 75 microg/kg. A single 300 microg/kg dose of acyline suppressed gonadotropins and T to castrate levels for 15 d (baseline, 21.1 +/- 3.1; nadir, 1.95 +/- 0.4 nmol/liter; mean +/- sem; P < 0.05). Serum acyline levels peaked 90 min after the injection of 300 microg/kg acyline to a maximum concentration of 112.4 +/- 18 ng/ml (n = 7; t(1/2) = 4.9 d). Injections of 75 microg/kg acyline every 2 d for five doses suppressed gonadotropins for more than 20 d (nadir T, 1.06 +/- 0.17 nmol/liter; P < 0.05 compared with baseline). Adverse events were mild and included erythema and pruritus at the injection site. Acyline, therefore, is one of the most potent peptide GnRH antagonists studied to date with minimal adverse events. A twice monthly injection of acyline could be used as a potent suppressor of the GnRH axis to advance the development of a hormonal male contraceptive or for treatment of hormonally dependent disease.


Overland and near-surface transport of Cryptosporidium parvum from vegetated and nonvegetated surfaces.
Understanding microbial pathogen transport patterns in overland flow is important for developing best management practices for limiting microbial transport to water resources. Knowledge about the effectiveness of vegetative filter strips (VFS) to reduce pathogen transport from livestock confinement areas is limited. In this study, overland and near-surface transport of Cryptosporidium parvum has been investigated. Effects of land slopes, vegetation, and rainfall intensities on oocyst transport were examined using a tilting soil chamber with two compartments, one with bare ground and the other with brome (Bromus inermis Leyss.) vegetation. Three slope conditions (1.5, 3.0, and 4.5%) were used in conjunction with two rainfall intensities (25.4 and 63.5 mm/h) for 44 min using a rainfall simulator. The vegetative surface was very effective in reducing C. parvum in surface runoff. For the 25.4 mm/h rainfall, the total percent recovery of oocysts in overland flow from the VFS varied from 0.6 to 1.7%, while those from the bare ground condition varied from 4.4 to 14.5%. For the 63.5 mm/h rainfall, the recovery percentages of oocysts varied from 0.8 to 27.2% from the VFS, and 5.3 to 59% from bare-ground conditions. For all slopes and rainfall intensities, the total (combining both surface and near-surface) recovery of C. parvum oocysts was considerably less from the vegetated surface than those from the bare-ground conditions. These results indicate that the VFS can be a best management practice for controlling C. parvum in runoff from animal production facilities.


Predictors of return to work among stroke survivors in south-west Nigeria.
Stroke is acknowledged globally and among Nigerian rehabilitation researchers as a public health problem that leaves half of its survivors with significant neurological deficits and inability to re-establish pre-existing roles. Consequent to the dearth of country specific data on return to work and its determinants for stroke survivors in Nigeria, this study investigated the predictors of return to work among stroke survivors in south-west Nigeria. Two hundred and ten stroke survivors from five tertiary health facilities in Osun state, Nigeria responded to a validated three-section questionnaire assessing return to work rates and its determinants after stroke in this study. Collected data were analysed using descriptive statistics and inferential statistic of chi-square, t-test and multiple logistic regression. The mean age of the respondents was 52.90 ± 7.92 years. Over 60% of the respondents returned to work with about half of them in full time employment (32.9%). Majority of the respondents noted that travel to and from work (43.8%) and access at work (43.3%) had an impact on their ability to work. The symptoms of stroke (odds ratio (OR) = 0.87), the environment (OR = 0.83), body function impairments (OR = 0.86) as well as activity and participation problems (OR = 0.80) were the significant predictors of return to work. Hemiplegia or paresis of the non-dominant side of the body was associated with a higher chance of return to work (OR = 7.64). Body function impairments, activity and participation problems were independent predictors of return to work after stroke. Similarly, side of hemiplegia plays a prominent role in resumption of the worker role of stroke survivors in south-west Nigeria.


Atopic dermatitis and cytokines: recent patents in immunoregulatory and therapeutic implications of cytokines in atopic dermatitis--part I: cytokines in atopic dermatitis.
Atopic dermatitis is a chronic allergic inflammatory disease of the skin. Its pathophysiology involves an orchestrated sequence of allergic provocation by IgE-mediated and non-IgE-mediated Th2 responses to allergens. Allergen sensitization precedes the immunopathogenesis. Th2 cytokines such as IL-4 and IL-5 play a key role in both the sensitization and effector phases of allergic skin inflammation. Recently, the roles of new cytokines including IL-16, IL-17, IL-21, IL-22, IL-23, IL-27, IL-31, IL-33, IL-35 and thymus stromal lymphopoietin (TSLP), and Th2 polarization in the immunopathogenesis of skin inflammation and physically injured skin have been described, in addition to roles for IL-4, IL- 5, IL-9, IL-13, IFN-γ and TGF-β. Sensitization occurs via the skin for aeroallergen including house dust mites and superantigens and through the gastrointestinal tract for food allergens. Alternatively, food allergens can be sensitized through skin. Atopic dermatitis is described under the structure of sensitization phase and effector phase in this review. Especially, the clinically effective applications of cytokines in AD and relevant patents are updated in this review.


Cultured endothelial cells synthesize both platelet-activating factor and prostacyclin in response to histamine, bradykinin, and adenosine triphosphate.
Cultured human endothelial cells synthesize prostacyclin (PGI2), a potent inhibitor of platelet function, when stimulated with histamine, bradykinin, or ATP. Paradoxically, we report that these agonists also induced the rapid and sustained synthesis of platelet-activating factor (PAF) by endothelial cells. In fact, the synthesis of this potent activator of platelets and neutrophils was induced by stimulation of the same receptor subtype that induced PGI2 synthesis: stimulation of a histamine H1 or a bradykinin B2 receptor induced both PAF and PGI2 synthesis. However, two physiologically important differences exist between the production of PAF and PGI2 by endothelial cells. The synthesis of PGI2 proceeded for only 7.5 min before the abrupt termination of synthesis, whereas the synthesis of PAF was clearly detectable even 45 min after stimulation. Although maximal accumulation of PAF occurred after 10-15 min of stimulation, the prolonged synthesis resulted in the presence of PAF for up to 1 h after stimulation. Secondly, whereas PGI2 was released from the cell monolayer, PAF remained cell-associated without significant release to the external medium. Endothelial cell-generated PAF, therefore, does not function as a hormone. The prolonged association of this potent activator of platelets and neutrophils with endothelial cells may mediate some of the inflammatory properties of histamine and bradykinin. It may also be a factor in the formation of a thrombogenic vascular surface, an event suggested to play a primary role in the pathogenesis of thrombosis and atherosclerosis.


Inhibition of Mammalian Target of Rapamycin Signaling with Rapamycin Prevents Trauma-Induced Heterotopic Ossification.
A pressing clinical need exists for 63% to 65% of combat-wounded service members and 11% to 20% of civilians who develop heterotopic ossification (HO) after blast-related extremity injury and traumatic injuries, respectively. The mammalian target of rapamycin pathway is a central cellular sensor of injury. We evaluated the prophylactic effects of rapamycin, a selective inhibitor of mammalian target of rapamycin signaling, on HO formation in a rat model of blast-related, polytraumatic extremity injury. Rapamycin was administered intraperitoneally daily for 14 days at 0.5 mg/kg or 2.5 mg/kg. Ectopic bone formation was monitored by micro-computed tomography and confirmed by histologic examination. Connective tissue progenitor cells, platelet-derived growth factor receptor-α-positive cells, and α-smooth muscle actin-positive blood vessels were assayed at postoperative day 7 by colony formation and immunofluorescence. Early gene expression changes were determined by low-density microarray. There was significant attenuation of 1) total new bone and soft tissue ectopic bone with 0.5 mg/kg (38.5% and 14.7%) and 2.5 mg/kg rapamycin (90.3% and 82.9%), respectively, 2) connective tissue progenitor cells, 3) platelet-derived growth factor receptor-α-positive cells, 4) α-smooth muscle actin-positive blood vessels, and 5) of key extracellular matrix remodeling (CD44, Col1a1, integrins), osteogenesis (Sp7, Runx2, Bmp2), inflammation (Cxcl5, 10, IL6, Ccl2), and angiogenesis (Angpt2) genes. No wound healing complications were noted. Our data demonstrate the efficacy of rapamycin in inhibiting blast trauma-induced HO by a multipronged mechanism.


Inhibition of PARS attenuates endotoxin-induced dysfunction of pulmonary vasorelaxation.
Endotoxin (Etx) causes excessive activation of the nuclear repair enzyme poly(ADP-ribose) synthase (PARS), which depletes cellular energy stores and leads to vascular dysfunction. We hypothesized that PARS inhibition would attenuate injury to mechanisms of pulmonary vasorelaxation in acute lung injury. The purpose of this study was to determine the effect of in vivo PARS inhibition on Etx-induced dysfunction of pulmonary vasorelaxation. Rats received intraperitoneal saline or Etx (Salmonella typhimurium; 20 mg/kg) and one of the PARS inhibitors, 3-aminobenzamide (3-AB; 10 mg/kg) or nicotinamide (Nic; 200 mg/kg), 90 min later. After 6 h, concentration-response curves were determined in isolated pulmonary arterial rings. Etx impaired endothelium-dependent (response to ACh and calcium ionophore) and -independent (sodium nitroprusside) cGMP-mediated vasorelaxation. 3-AB and Nic attenuated Etx-induced impairment of endothelium-dependent and -independent pulmonary vasorelaxation. 3-AB and Nic had no effect on Etx-induced increases in lung myeloperoxidase activity and edema. Lung ATP decreased after Etx but was maintained by 3-AB and Nic. Pulmonary arterial PARS activity increased fivefold after Etx, which 3-AB and Nic prevented. The beneficial effects were not observed with benzoic acid, a structural analog of 3-AB that does not inhibit PARS. Our results suggest that PARS inhibition with 3-AB or Nic improves pulmonary vasorelaxation and preserves lung ATP levels in acute lung injury.


Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation.
Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.


Ocular findings in Fabry disease in Colombian patients
Fabry disease is a rare X-linked disorder caused by an alpha-galactosidase enzyme deficiency, which leads to a progressive lysosomal glycosphingolipids accumulation, mainly globotriaosylceramide, in multiple organism tissues including the eye. This case series describes the first ophthalmological Colombian report of Fabry disease highlighting the importance of ocular signs as markers of the disease, useful in diagnosis and treatment to avoid long-term complications that lead to a morbi-mortality increment. We describe five cases of Fabry disease from Bogotá, Colombia, including a complete clinical history, ophthalmologic, optometric examination, and photographs. We found that all patients had refractive defects and that in all cases corneal verticillata pattern was found. Four patients presented with posterior capsule lens brown-beige deposits and four patients had conjunctival and retinal tortuous vessels. A complete ophthalmologic examination is important for prompt diagnosis, which is key to starting a multidisciplinary treatment and reducing morbi-mortality.


Mining antimicrobial peptides from small open reading frames in Ciona intestinalis.
Though being able to encode various kinds of bioactive peptides, small open reading frames (sORFs) are poorly annotated in many genomic data. The present study was conducted to evaluate the potential of sORFs in encoding antimicrobial peptides (AMPs) in the basal chordate model Ciona intestinalis. About 4.8 m genomic sequence was first retrieved for sORFs mining by the program sORF finder, then the sORFs were translated into amino acid sequences for AMP prediction via CAMP server, and thereafter, ten putative AMPs were selected for expression and antimicrobial activity validation. In total, over 180 peptides deduced from the sORFs were predicted to be AMPs. Among the ten tested peptides, six were found to have significant expressed sequence tag matches, providing strong evidence for gene expression; five were proved to be active against the bacterial strains. These results indicate that many sORFs in C. intestinalis genome contain AMP information. This work can serve as an important initial step to investigate the role of sORFs in the innate defense of C. intestinalis.


[Burkitt lymphoma. Study of 110 patients].
A review of 110 children with Burkitt's lymphoma admitted to the University of Nigeria Teaching Hospital, Enugu during a 7-year period revealed a preponderance of males over females (1.9:1) and a peak incidence at five years. The main sites affected initially by the tumour in order of frequency were the face and abdomen. The spinal column, spleen, and lungs were less affected. It is postulated that an interaction between malarial and Epstein-Barr virus infections and malnutrition are important in the aetiology of the tumour. The most effective drug is cyclophosphamide. A combination of this drug with vincristine and methotrexate is equally effective in inducing remissions, but is better than the single agent in preventing systemic relapse. Follow-up of the patients revealed good survival.


Delay in onset of awareness of acute hypoglycemia and of restoration of cognitive performance during recovery.
To examine the time course for the onset of, and recovery from, acute hypoglycemia in healthy subjects. Eight healthy male volunteers were studied on 2 occasions in random order using a hyperinsulinemic (1.5 mU x kg(-1) x min(-1)) glucose clamp technique. During control studies, euglycemia (5.01 +/- 0.02 mmol/l) was maintained for 225 +/- 3 min. On the other occasion, after a euglycemic baseline period, arterialized plasma glucose was allowed to fall rapidly to 2.65 +/- 0.02 mmol/l, then maintained at this nadir for 90 min before euglycemia was rapidly restored. Cognitive function assessed by a battery of sensitive tests (4-choice reaction time, Stroop word, and color-word test) became impaired immediately at onset of hypoglycemia (P < 0.05 for all in the hypoglycemic study vs. those in the euglycemic study). Counterregulatory hormone responses (epinephrine, norepinephrine, glucagon, cortisol, and growth hormone) and symptomatic awareness of hypoglycemia (assessed by a questionnaire) were relatively delayed, being detected 20 min after the onset of hypoglycemia. There was no diminution (adaptation) of any responses, cognitive, humoral, or symptomatic, during sustained hypoglycemia. During recovery, the 4-choice reaction time continued to be abnormal even after resolution of symptomatic awareness (P = 0.025). During hypoglycemia, cognitive performance may become impaired before symptomatic awareness. During recovery from hypoglycemia, recovery of cognitive function lags behind the restoration of glucose levels and resolution of symptoms. Our findings have implications for the design of studies examining experimental hypoglycemia and need to be investigated in people with diabetes.


Single point mutations distributed in 10 soluble and membrane regions of the Nicotiana plumbaginifolia plasma membrane PMA2 H+-ATPase activate the enzyme and modify the structure of the C-terminal region.
The Nicotiana plumbaginifolia pma2 (plasma membrane H+-ATPase) gene is capable of functionally replacing the H+-ATPase genes of the yeast Saccharomyces cerevisiae, provided that the external pH is kept above 5.0. Single point mutations within the pma2 gene were previously identified that improved H+-ATPase activity and allowed yeast growth at pH 4.0. The aim of the present study was to identify most of the PMA2 positions, the mutation of which would lead to improved growth and to determine whether all these mutations result in similar enzymatic and structural modifications. We selected additional mutants in total 42 distinct point mutations localized in 30 codons. They were distributed in 10 soluble and membrane regions of the enzyme. Most mutant PMA2 H+-ATPases were characterized by a higher specific activity, lower inhibition by ADP, and lower stimulation by lysophosphatidylcholine than wild-type PMA2. The mutants thus seem to be constitutively activated. Partial tryptic digestion and immunodetection showed that the PMA2 mutants had a conformational change making the C-terminal region more accessible. These data therefore support the hypothesis that point mutations in various H+-ATPase parts displace the inhibitory C-terminal region, resulting in enzyme activation. The high density of mutations within the first half of the C-terminal region suggests that this part is involved in the interaction between the inhibitory C-terminal region and the rest of the enzyme.


Spatial distribution of selenium-mercury in Arctic seabirds.
Mercury (Hg) is a metallic trace element toxic for humans and wildlife that can originate from natural and anthropic sources. Hg spatial gradients have been found in seabirds from the Arctic and other oceans, suggesting contrasting toxicity risks across regions. Selenium (Se) plays a protective role against Hg toxicity, but its spatial distribution has been much less investigated than that of Hg. From 2015 to 2017, we measured spatial co-exposure of Hg and Se in blood samples of two seabird species, the Brünnich's guillemot (Uria lomvia) and the black-legged kittiwake (Rissa tridactyla) from 17 colonies in the Arctic and subarctic regions, and we calculated their molar ratios (Se:Hg), as a measure of Hg sequestration by Se and, therefore, of Hg exposure risk. We also evaluated concentration differences between species and ocean basins (Pacific-Arctic and Atlantic-Arctic), and examined the influence of trophic ecology on Hg and Se concentrations using nitrogen and carbon stable isotopes. In the Atlantic-Arctic ocean, we found a negative west-to-east gradient of Hg and Se for guillemots, and a positive west-to-east gradient of Se for kittiwakes, suggesting that these species are better protected from Hg toxicity in the European Arctic. Differences in Se gradients between species suggest that they do not follow environmental Se spatial variations. This, together with the absence of a general pattern for isotopes influence on trace element concentrations, could be due to foraging ecology differences between species. In both oceans, both species showed similar Hg concentrations, but guillemots showed lower Se concentrations and Se:Hg than kittiwakes, suggesting a higher Hg toxicity risk in guillemots. Within species, neither Hg, nor Se or Se:Hg differed between both oceans. Our study highlights the importance of considering Se together with Hg, along with different species and regions, when evaluating Hg toxic effects in marine predators in international monitoring programs.


[Enzymes of azurophilic neutrophil granules and matrix metalloproteinase-2 as markers of the developmental stages of experimental respiratory distress syndrome].
Acute Respiratory Distress Syndrome was reproduced in the non-linear male rats by the original method. The animals were injected lysate 45-55 thousand rat neutrophils in 0.2 mi 0.9% sodium chloride solution by puncture of the trachea (method patented RF). At each stage of syndrome development concentration of neutrophil elastase, myeloperoxidase and matrix metalloproteinase-2 in serum and bronchoalveolar lavage fluid was determined by ELISA. The increase of the concentration of neutrophil elastase and myeloperoxidase in plasma and lavage fluid has been shown to be a marker of exudative stage. Proliferative phase is marked by high levels of matrix metalloproteinase-2 at a constant content of elastase and myeloperoxidase in both liquids. Reduction of matrix metalloproteinase-2 concentration in both biological fluids is accompanied by the development of fibrotic phase distress syndrome.


Ficolin-1 gene (FCN1) -144 C/A polymorphism is associated with adverse outcome of severe pneumonia in the under-five Egyptian children: A multicenter study.
Pneumonia is the foremost cause of child death worldwide. M-ficolin is encoded by the FCN1 gene and represents a novel link between innate and adaptive immunity. To investigate the FCN1 -144 C/A (rs10117466) polymorphism as a potential marker for pneumonia severity and adverse outcome namely complications or mortality in the under-five Egyptian children. This was a prospective multicenter study that included 620 children hospitalized with World Health Organization-defined severe pneumonia and 620 matched healthy control children. Polymorphism rs10117466 of the FCN1 gene promoter was analyzed by PCR-SSP, while serum M-ficolin levels were assessed by ELISA. The FCN1 A/A genotype and A allele at the -144 position were more frequently observed in patients compared to the control children (43.4% vs 27.6%; odds ratio [OR]: 1.62; [95% confidence interval {CI}: 1.18-2.2]; for the A/A genotype) and (60.8% vs 52.5%; OR: 1.4; [95% CI: 1.19-1.65]; for the A allele); P < .01. The FCN1 -144 A/A homozygous patients had significantly higher serum M-ficolin concentrations (mean: 1844 ± 396 ng/mL) compared with those carrying the C/C or C/A genotype (mean: 857 ± 278 and 1073 ± 323 ng/mL, respectively; P = .002). FCN1 -144 A/A genotype was an independent risk factor for adverse outcomes in children with severe pneumonia (adjusted OR = 4.85, [95% CI: 2.96-10.25]; P = .01). The FCN1 A/A genotype at the -144 position was associated with high M-ficolin serum levels and possibly contributes to enhanced inflammatory response resulting in the adverse outcome of pneumonia in the under-five Egyptian children.


[Synostosis dynamics in human long tubular bones].
More than 8,000 roentgenograms and electroroentgenograms of brachial, ulnar, radiocarpal, coxofemoral, knee, talocrural joints have been studied in persons of both sex at the age from birth up to 25 years. The synostosis degree is appreciated by the six-mark system. The roentgenological data are corroborate histologically. The method of appreciation applied makes it possible to reveal cases of initially forming synostosis long before puberty. Three stages of synostosis process are defined. The first stage--slow increase of the synostosis mark. The second--quick synostosis formation. The third--final stage. According to the stages defined, a comparative analysis of the synostosis process in all metaepiphyseal zones of all long tubular bones, peculiarities of the process depending on the sex are demonstrated. The data on the time, when the points of ossification appear, on the beginning and completion of synostosis process in all metaepiphyseal zones of the long tubular bones are presented.


Physicochemical aspects of the liposome-wool interaction in wool dyeing.
Despite the promising application of liposomes in wool dyeing, little is known about the mechanism of liposome interactions with the wool fiber and dyestuffs. The kinetics of wool dyeing by two dyes, Acid Green 27 (hydrophobic) and Acid Green 25 (hydrophilic), were compared in three experimental protocols: (1) without liposomes, (2) in the presence of phosphatidylcholine (PC) liposomes, and (3) with wool previously treated with PC liposomes. Physicochemical interactions of liposomes with wool fibers were studied under experimental dyeing conditions with particular interest in the liposome affinity to the fiber surface and changes in the lipid composition of the wool fibers. The results obtained indicate that the presence of liposomes favors the retention of these two dyes in the dyeing bath, this effect being more pronounced in case of the hydrophobic dye. Furthermore, the liposome treatment is accompanied by substantial absorption of PC by wool fibers with simultaneous partial solubilization of their polar lipids (more evident at higher temperatures). This may result in structural modification of the cell membrane complex of wool fibers, which could account for a high level of the dye exhaustion observed at the end of the liposome dyeing process.


Comparative studies of host-cell reactivation, cellular capacity and enhanced reactivation of herpes simplex virus in normal, xeroderma pigmentosum and Cockayne syndrome fibroblasts.
Host-cell reactivation (HCR) of UV-irradiated herpes simplex virus type 2 (HSV-2), capacity of UV-irradiated cells to support HSV-2 plaque formation and UV-enhanced reactivation (UVER) of UV-irradiated HSV-2 were examined in fibroblasts from 4 patients with Cockayne syndrome (CS), 5 with xeroderma pigmentosum and 5 normals. All UV-survival curves for HSV-2 plaque formation showed 2 components. HCR was similar to normal for the XP variant strain and the 2 CS strains tested, but substantially reduced in the 4 excision-deficient XP strains. The capacity of UV-irradiated fibroblasts to support HSV-2 plaque formation was determined by UV-irradiating fibroblast monolayers with various doses of UV and 48 h later, infecting the monolayers with unirradiated HSV-2. The D37 values for the delayed-capacity curves so obtained were in the range 8.6-12.4 J/m2 for the normal strains, 2.8-3.2 J/m2 for the CS strains, 6.7 J/m2 for an XP variant strain and between 0.3 and 1.5 for the XP excision-deficient strains tested. These results indicate that delayed capacity for HSV-2 plaque formation is a more sensitive assay than HCR in the detection of cellular DNA-repair deficiency for XP and CS. For the examination of UVER, fibroblasts were irradiated with various UV doses and subsequently infected with either unirradiated or UV-irradiated HSV and scored for plaque formation 2 days later. UVER expression was maximum when the delay between UV-irradiation of the cells and HSV infection was 48 h. The magnitude of UVER expression was also found to be dependent on the UV dose to the cells and increased with increasing UV dose to the virus. Using a UV dose to the virus resulting in a plaque survival of about 10(-2) on unirradiated cells, the the maximum UVER factor had a mean value of 1.3 for the normal strains following a dose of 15 J/m2 to the cells. Somewhat higher UVER values were found for all the patient strains tested and resulted from lower UV doses to the cells than for normal strains. Maximum UVER factors for the CS strains ranged from 2.2 to 3.3 at a dose of 5 J/m2 to the cells, for the XP excision-deficient strains; 2.1 to 2.6 at doses of 0.5 to 2.5 J/m2 to the cells and for the XP variant strain tested; 2.5 at UV dose of 10 J/m2 to the cells.


Antithrombotic strategies and outcomes in acute coronary syndrome with atrial fibrillation.
Atrial fibrillation (AF) frequently occurs with acute coronary syndromes (ACS) and adds complexity to the selection of an appropriate antithrombotic strategy. We determined whether associations of antithrombotic treatment with bleeding, stroke, and death differ between patients with ACS with and without AF. Residents of Olmsted County, Minnesota, hospitalized with incident ACS during 2005 to 2010 were classified according to the presence or absence of AF either before or during the index ACS hospitalization. Antithrombotic strategy at discharge was categorized as double/triple agents versus no/single agent. Patients were followed through 2012, and propensity scores were used to estimate associations of treatment with bleeding, ischemic stroke, and mortality. Of 1,159 patients with incident ACS, 252 (21.7%) had concomitant AF (ACS + AF). Over a median follow-up of 4.3 years, 312 bleeds, 67 ischemic strokes, and 268 deaths occurred. The overall risks of bleeding, stroke, and death were similar between treatment strategies. Although limited by the small number of events, a suggestion of a lower risk of ischemic stroke for patients with ACS + AF on double/triple therapy was observed; the hazard ratios for stroke with double/triple versus no/single therapy were 0.30 (0.07 to 1.26) and 1.10 (0.52 to 2.33) in those with and without AF, respectively (p value for interaction = 0.10). In conclusion, the choice of antithrombotic strategy is not associated with the risk of ischemic stroke, bleeding, or death in patients with ACS overall. Patients with ACS + AF on double/triple therapy may experience reduced risks of stroke, although future studies are needed to confirm this finding.


Association of the Hospital Readmissions Reduction Program With Mortality Among Medicare Beneficiaries Hospitalized for Heart Failure, Acute Myocardial Infarction, and Pneumonia.
The Hospital Readmissions Reduction Program (HRRP) has been associated with a reduction in readmission rates for heart failure (HF), acute myocardial infarction (AMI), and pneumonia. It is unclear whether the HRRP has been associated with change in patient mortality. To determine whether the HRRP was associated with a change in patient mortality. Retrospective cohort study of hospitalizations for HF, AMI, and pneumonia among Medicare fee-for-service beneficiaries aged at least 65 years across 4 periods from April 1, 2005, to March 31, 2015. Period 1 and period 2 occurred before the HRRP to establish baseline trends (April 2005-September 2007 and October 2007-March 2010). Period 3 and period 4 were after HRRP announcement (April 2010 to September 2012) and HRRP implementation (October 2012 to March 2015). Announcement and implementation of the HRRP. Inverse probability-weighted mortality within 30 days of discharge following hospitalization for HF, AMI, and pneumonia, and stratified by whether there was an associated readmission. An additional end point was mortality within 45 days of initial hospital admission for target conditions. The study cohort included 8.3 million hospitalizations for HF, AMI, and pneumonia, among which 7.9 million (mean age, 79.6 [8.7] years; 53.4% women) were alive at discharge. There were 3.2 million hospitalizations for HF, 1.8 million for AMI, and 3.0 million for pneumonia. There were 270 517 deaths within 30 days of discharge for HF, 128 088 for AMI, and 246 154 for pneumonia. Among patients with HF, 30-day postdischarge mortality increased before the announcement of the HRRP (0.27% increase from period 1 to period 2). Compared with this baseline trend, HRRP announcement (0.49% increase from period 2 to period 3; difference in change, 0.22%, P = .01) and implementation (0.52% increase from period 3 to period 4; difference in change, 0.25%, P = .001) were significantly associated with an increase in postdischarge mortality. Among patients with AMI, HRRP announcement was associated with a decline in postdischarge mortality (0.18% pre-HRRP increase vs 0.08% post-HRRP announcement decrease; difference in change, -0.26%; P = .01) and did not significantly change after HRRP implementation. Among patients with pneumonia, postdischarge mortality was stable before HRRP (0.04% increase from period 1 to period 2), but significantly increased after HRRP announcement (0.26% post-HRRP announcement increase; difference in change, 0.22%, P = .01) and implementation (0.44% post-HPPR implementation increase; difference in change, 0.40%, P < .001). The overall increase in mortality among patients with HF and pneumonia was mainly related to outcomes among patients who were not readmitted but died within 30 days of discharge. For all 3 conditions, HRRP implementation was not significantly associated with an increase in mortality within 45 days of admission, relative to pre-HRRP trends. Among Medicare beneficiaries, the HRRP was significantly associated with an increase in 30-day postdischarge mortality after hospitalization for HF and pneumonia, but not for AMI. Given the study design and the lack of significant association of the HRRP with mortality within 45 days of admission, further research is needed to understand whether the increase in 30-day postdischarge mortality is a result of the policy.


Preventive action of zinc against lead toxicity.
The study was aimed to assess the protective efficacy of zinc against hemo and hematotoxicity induced by lead. Two groups of 8 rats each, were administered lead acetate 20 mg/kg bw (ip) for 3 days. One group in addition was injected 5 mg/kg bw (ip) zinc acetate for next three days. A third group of 8 rats was given three injections of normal saline and served as control. All the animals were sacrificed on eighth day and assessed for hematological changes, heme synthesizing pathway enzymes, hepatic drug metabolizing status and sulfhydryl levels in blood and liver. Lead administration resulted in decreased hemoglobin, increased reticulocytosis, depression of delta aminolevulinic acid dehydratase (ALAD) and uroporphyrinogen I synthetase (UPS) activity in blood and liver. In vitro metabolism of drugs aminopyrine, aniline and p-nitroanisole by liver homogenate and in vivo metabolism of pentabarbitone was also reduced in lead exposed rate. Zinc treated rats showed improved hematological profile and activated ALAD and UPS activity, recovery of N-demethylation of aminopyrine and O-demethylation of p-nitroanisole and partial restoration of free thiol levels in blood and liver thereby indicating that zinc could confer protection against lead toxicity.


Early evolution of multifocal optics for well-focused colour vision in vertebrates.
Jawless fishes (Agnatha; lampreys and hagfishes) most closely resemble the earliest stage in vertebrate evolution and lamprey-like animals already existed in the Lower Cambrian [about 540 million years ago (MYA)]. Agnathans are thought to have separated from the main vertebrate lineage at least 500 MYA. Hagfishes have primitive eyes, but the eyes of adult lampreys are well-developed. The southern hemisphere lamprey, Geotria australis, possesses five types of opsin genes, three of which are clearly orthologous to the opsin genes of jawed vertebrates. This suggests that the last common ancestor of all vertebrate lineages possessed a complex colour vision system. In the eyes of many bony fishes and tetrapods, well-focused colour images are created by multifocal crystalline lenses that compensate for longitudinal chromatic aberration. To trace the evolutionary origins of multifocal lenses, we studied the optical properties of the lenses in four species of lamprey (Geotria australis, Mordacia praecox, Lampetra fluviatilis and Petromyzon marinus), with representatives from all three of the extant lamprey families. Multifocal lenses are present in all lampreys studied. This suggests that the ability to create well-focused colour images with multifocal optical systems also evolved very early.


Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation.
Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.


Differences in puff topography, toxicant exposure, and subjective response between waterpipe tobacco smoking men and women.
Waterpipe tobacco smoking (WTS) exposes users to toxicants in much greater amounts than a cigarette. Little is known about how gender affects WTS toxicant exposure and subjective response. Data from three WTS clinical laboratory studies were combined for analysis. Participants (N = 99; 38 women) completed a 45-min WTS session where they smoked a waterpipe ad libitum. Puff topography was measured throughout, and plasma nicotine concentration, expired air carbon monoxide (CO), and subjective responses were measured pre- and post-WTS. There was a gender effect for total puff volume with men inhaling a greater smoke volume, on average (M = 59.9 L, SD = 40.7), compared with women (M = 38.8 L, SD = 27.8; p < .01). Men had greater post-WTS mean plasma nicotine concentrations (M = 10.0 ng/ml, SD = 7.1) compared with women (M = 6.9 ng/ml, SD = 5.2; p < .05). Post-WTS expired air CO was not associated with gender (men M = 27.6 ppm, SD = 18.9; women M = 22.7 ppm, SD = 17.0, ns). Relative to men, women had higher post-WTS scores for subjective measures of "nauseous," "dizzy," "nervous," "headache," and "heart pounding." Men and women are exposed to toxicants during WTS, and men may achieve higher nicotine exposure than women, likely resulting from differences in smoke inhaled. However, similar post-WTS expired air CO between men and women and higher ratings of negative subjective responses among women may indicate that factors beyond puff topography may impact toxicant exposure and subjective response to WTS. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Integrated analysis of whole genome and transcriptome sequencing uncovers genetic differences between Zi goose and Xianghai flying goose.
Zi goose is a famous indigenous breed originating from northeast China with high annual egg production. Xianghai flying goose is a composite breed and is bred by crosses of the wild swan goose and the Zi goose. Our previous study revealed significant differences in muscle fiber characteristics between the two populations. Here, we aimed to reveal the underlying genetic basis of the above phenotype differences through whole-genome and transcriptome analysis. A total of 20 blood samples (10 Zi geese and 10 Xianghai flying geese) were used for whole genome sequencing, and eight breast muscle tissue samples (four Zi geese and four Xianghai flying geese) were used for RNA sequencing. Using the FST and XP-EHH analysis, some highly differentiated genome regions annotated with egg production (RORB, WNT4, BMPR1B) and breast muscle development (WNT7B) between the two populations were detected. RNA-sequencing analysis revealed differentially expressed genes related to muscle development (IGF1, PAX7). Moreover, several genes were detected by both genome and transcriptome analysis, and some of them were reported to be associated with muscle growth (SLIT2, PREX1) and intramuscular fat (COL6A1). These findings will help researchers better understand the genetic basis related to egg production and muscle development in geese.


The local strain distribution in bilayer materials: a multiscale study.
Recent studies show that small geometric changes can result in dramatic changes in physical properties and need to be carefully evaluated. In this regard, we calculate the distribution of local strains in bilayer graphene and two configurations of hexagonal BN (h-BN), which is different from previous studies that focus on homogeneous strains in such materials. We consider a mismatch of one lattice parameter and calculate how strain distributes without external stresses. This problem is equivalent to finding the core structure of a type of dislocation profuse in structural materials. The strain distribution is transformed into the core distribution of a dislocation, which is calculated using a new formulation proposed by us. The new formulation finds new lower-energy states for the 2D materials. Our results show that the strain of one-lattice mismatch in bilayer graphene forms two Lorentz peaks with half widths of 117b-120b (edge component) and 67b-80b (screw component), where b is the lattice constant. The case for bilayer h-BN is slightly more complicated but the results are also presented. Our analytic solutions, which are based on the new formulation with more freedom in structural relaxation, provide the basis for the next-step study of their electronic properties.


Does deterministic coexistence theory matter in a finite world?
Contemporary studies of species coexistence are underpinned by deterministic models that assume that competing species have continuous (i.e., noninteger) densities, live in infinitely large landscapes, and coexist over infinite time horizons. By contrast, in nature, species are composed of discrete individuals subject to demographic stochasticity and occur in habitats of finite size where extinctions occur in finite time. One consequence of these discrepancies is that metrics of species' coexistence derived from deterministic theory may be unreliable predictors of the duration of species coexistence in nature. These coexistence metrics include invasion growth rates and niche and fitness differences, which are now commonly applied in theoretical and empirical studies of species coexistence. In this study, we tested the efficacy of deterministic coexistence metrics on the duration of species coexistence in a finite world. We introduce new theoretical and computational methods to estimate coexistence times in stochastic counterparts of classic deterministic models of competition. Importantly, we parameterized this model using experimental field data for 90 pairwise combinations of 18 species of annual plants, allowing us to derive biologically informed estimates of coexistence times for a natural system. Strikingly, we found that for species expected to deterministically coexist, community sizes containing only 10 individuals had predicted coexistence times of more than 1000 years. We also found that invasion growth rates explained 60% of the variation in intrinsic coexistence times, reinforcing their general usefulness in studies of coexistence. However, only by integrating information on both invasion growth rates and species' equilibrium population sizes could most (>99%) of the variation in species coexistence times be explained. This integration was achieved with demographically uncoupled single-species models solely determined by the invasion growth rates and equilibrium population sizes. Moreover, because of a complex relationship between niche overlap/fitness differences and equilibrium population sizes, increasing niche overlap and increasing fitness differences did not always result in decreasing coexistence times, as deterministic theory would predict. Nevertheless, our results tend to support the informed use of deterministic theory for understanding the duration of species' coexistence while highlighting the need to incorporate information on species' equilibrium population sizes in addition to invasion growth rates.


Involvement of Brn3a-positive spinal dorsal horn neurons in the transmission of visceral pain in inflammatory bowel disease model mice.
The spinal dorsal horn plays a crucial role in the transmission and processing of somatosensory information. Although spinal neural circuits that process several distinct types of somatic sensations have been studied extensively, those responsible for visceral pain transmission remain poorly understood. In the present study, we analyzed dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) mouse models to characterize the spinal dorsal horn neurons involved in visceral pain transmission. Immunostaining for c-fos, a marker of neuronal activity, demonstrated that numerous c-fos-positive cells were found bilaterally in the lumbosacral spinal dorsal horn, and their distribution was particularly abundant in the shallow dorsal horn. Characterization of these neurons by several molecular markers revealed that the percentage of the Pit1-Oct1-Unc86 domain (POU domain)-containing transcription factor Brn3a-positive neurons among the c-fos-positive neurons in the shallow dorsal horn was 30%-40% in DSS-treated mice, which was significantly higher than that in the somatic pain model mice. We further demonstrated by neuronal tracing that, within the shallow dorsal horn, Brn3a-positive neurons were more highly represented in spino-solitary projection neurons than in spino-parabrachial projection neurons. These results raise the possibility that Brn3a-positive spinal dorsal horn neurons make a large contribution to visceral pain transmission, part of which is mediated through the spino-solitary pathway.


Norovirus disease associated with excess mortality and use of statins: a retrospective cohort study of an outbreak following a pilgrimage to Lourdes.
Although norovirus infection is generally known to be a mild disease, there is some evidence for severe outcome. An outbreak in a Dutch psychiatric institution, originating from pilgrims returning from Lourdes (France), provided an opportunity for performing a retrospective cohort study in order to identify risk factors for norovirus disease and excess mortality. Relative risks (RR) including 95% confidence intervals (CI) showed that attending the pilgrimage (RR 2·0, 95% CI 1·4-3·0) and age >70 (RR 1·7, 95% CI 1·2-2·2) were risk factors for symptomatic infection. In a subset of patients, for whom more detailed information was available, the use of statins was associated with norovirus disease when adjusted for underlying condition (adjusted odds ratio 3·9, 95% CI 1·2-13·0). Mortality was higher in cases infected during the pilgrimage compared to other residents (RR 20·9, 95% CI 4·7-93·8). Norovirus disease can lead to severe outcome. The newly identified risk of statins for contracting norovirus disease may have considerable consequences for the Western world and needs prospective confirmation.


[Sexual diversity, health and citizenship].
Non-heterosexual sexual orientations are no longer considered pathological by the American Psychiatric Association since 1973 and the World Health Organization since 1990. However, to many authors, these changes in Latin America have not been translated into an inclusive healthcare provision or the recognition of non-heterosexual citizens with full rights. The purpose of this document is to provide a theoretical view regarding sexuality, proposing proper conditions that allow to successfully facing arising challenges. Thus, the regulating role of medicine over sexuality has been exposed, which has led to both academic and political reactions. The progressive change given in medical science has been pointed out: from considering non-heterosexual sexuality to be pathological to offering, in theory at least, inclusion. The negative impacts of what an adverse social environment causes to an individual are described. Finally, specific actions are proposed to provide better health services to non-heterosexual citizens.


Haemostatic devices in parotid surgery: a systematic review.
The Harmonic Scalpel and Ligasure (Covidien) devices are commonly used in head and neck surgery. Parotidectomy is a complex and intricate surgery that requires careful dissection of the facial nerve. This study aimed to compare surgical outcomes in parotidectomy using these haemostatic devices with traditional scalpel and cautery. A systematic review of the literature was performed with subsequent meta-analysis of seven studies that compared the use of haemostatic devices to traditional scalpel and cautery in parotidectomy. Outcome measures included: temporary facial paresis, operating time, intra-operative blood loss, post-operative drain output and length of hospital stay. A total of 7 studies representing 675 patients were identified: 372 patients were treated with haemostatic devices, and 303 patients were treated with scalpel and cautery. Statistically significant outcomes favouring the use of haemostatic devices included operating time, intra-operative blood loss and post-operative drain output. Outcome measures that did not favour either treatment included facial nerve paresis and length of hospital stay. Overall, haemostatic devices were found to reduce operating time, intra-operative blood loss and post-operative drain output.


Inhibition of laminin alpha 1-chain expression leads to alteration of basement membrane assembly and cell differentiation.
The expression of the constituent alpha 1 chain of laminin-1, a major component of basement membranes, is markedly regulated during development and differentiation. We have designed an antisense RNA strategy to analyze the direct involvement of the alpha 1 chain in laminin assembly, basement membrane formation, and cell differentiation. We report that the absence of alpha 1-chain expression, resulting from the stable transfection of the human colonic cancer Caco2 cells with an eukaryotic expression vector comprising a cDNA fragment of the alpha 1 chain inserted in an antisense orientation, led to (a) an incorrect secretion of the two other constituent chains of laminin-1, the beta 1/gamma 1 chains, (b) the lack of basement membrane assembly when Caco2-deficient cells were cultured on top of fibroblasts, assessed by the absence of collagen IV and nidogen deposition, and (c) changes in the structural polarity of cells accompanied by the inhibition of an apical digestive enzyme, sucrase-isomaltase. The results demonstrate that the alpha 1 chain is required for secretion of laminin-1 and for the assembly of basement membrane network. Furthermore, expression of the laminin alpha 1-chain gene may be a regulatory element in determining cell differentiation.


Antibacterial activity of reactive quaternary ammonium compounds in solution and in nonleachable coatings.
Antibacterial polymers suitable for coating applications without leaching of the biocidal component have been obtained by UV copolymerization of acrylic resins with acrylic monomers containing quaternary ammonium moieties. Suitable reactive biocides, based on quaternary ammonium monomers (QAMs), endowed with undecylacryloyl group and alkyl chains with 2 (QAM-C2), 8 (QAM-C8), and 16 (QAM-C16) carbon atoms have been synthesized. Aqueous solutions of QAMs showed biocidal activity against Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes strains both in suspension and adhered to stainless steel surfaces. QAM-C16 and QAM-C8 evidenced higher activity toward bacteria in suspension and on stainless steel, respectively. The QAMs have shown sufficient reactivity to be copolymerized, by UV irradiation, with a commercial urethane acrylic resin for coating. Bioactivity tests, performed on free films of crosslinked coatings containing 1% of copolymerized QAM, have shown an increasing inactivation effect in the order of magnitude L. monocytogenes, E. coli, S. aureus with a maximum activity of the QAM-C8.


Long-term changes in entorhinal-dentate evoked potentials induced by electroconvulsive shock seizures in rats.
Entorhinal-dentate evoked potentials were measured in rats before and after: (1) eight electroconvulsive shock (ECS) seizures, or (2) matched handling. In animals that received ECS, evoked potentials were significantly enhanced, as evidenced by a long-lasting increase in the amplitude of the population spike. This increase in population-spike amplitude lasted for at least 3 months after the last ECS trial. No evoked-potential changes were observed in the subjects that received matched handling. These data suggest that ECS seizures produce long-lasting, perhaps permanent, changes in the brain.


The flat-footed child -- to treat or not to treat: what is the clinician to do?
This article addresses the treatment of pediatric flatfoot with foot orthoses and explores the existing knowledge from an evidence-based perspective. Studies investigating the use of foot orthoses for pediatric flatfoot were reviewed and ranked on the evidence hierarchy model according to research designs. Clinical guidelines and efficacy rating methods were also reviewed. Three randomized controlled trials exist, and a systematic review and possible meta-analysis of these studies is in progress. The results of these studies, although not definitive for the use of orthoses for pediatric flatfoot, provide useful direction. Clinical guidelines for the management of flatfoot are a useful supplement for clinical decision making and have been enhanced. This article presents a pragmatic and evidence-based clinical care pathway for clinicians to use for pediatric flatfoot. It uses a simple "traffic light" framework to identify three subtypes of pediatric flatfoot. The clinician is advised to 1) treat symptomatic pediatric flatfoot, 2) monitor (or with discretion simply treat) asymptomatic nondevelopmental pediatric flatfoot, and 3) identify and advise asymptomatic developmental pediatric flatfoot. (Children with juvenile arthritis should receive customized foot orthoses.) This approach will dispel much of the contention surrounding the use of foot orthoses in children.


Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex.
Although there is general consensus that deep brain stimulation (DBS) yields substantial clinical benefit in patients with Parkinson's disease (PD), the therapeutic mechanism of DBS remains a matter of debate. Recent studies demonstrate that DBS targeting the globus pallidus internus (GPi-DBS) suppresses pathological oscillations in firing rate and between-cell spike synchrony in the vicinity of the electrode but has negligible effects on population-level firing rate or the prevalence of burst firing. The present investigation examines the downstream consequences of GPi-DBS at the level of the primary motor cortex (M1). Multielectrode, single cell recordings were conducted in the M1 of two parkinsonian nonhuman primates (Macaca fasicularis). GPi-DBS that induced significant reductions in muscular rigidity also reduced the prevalence of both beta (12-30 Hz) oscillations in single unit firing rates and of coherent spiking between pairs of M1 neurons. In individual neurons, GPi-DBS-induced increases in mean firing rate were three times more common than decreases; however, averaged across the population of M1 neurons, GPi-DBS induced no net change in mean firing rate. The population-level prevalence of burst firing was also not affected by GPi-DBS. The results are consistent with the hypothesis that suppression of both pathological, beta oscillations and synchronous activity throughout the cortico-basal ganglia network is a major therapeutic mechanism of GPi-DBS.


Trimodality therapy in stage III non-small cell lung cancer: prediction of recurrence by assessment of p185neu.
In a trimodality treatment approach for stage III non-small cell lung cancer the prognostic impact of pretherapeutic p185neu assessment was evaluated. Fifty-four patients were admitted to chemotherapy followed by twice-daily radiation with concomittant low-dose chemotherapy and subsequent surgery. Immunohistochemical assessment of p185neu expression was performed in paraffin-embedded mediastinal lymph node metastases, by mediastinoscopy biopsy prior to therapy. Paraffin-embedded biopsies of mediastinal lymph node metastases were available in 33 cases. Seven out of eight patients with positive p185neu staining developed distant metastases, in contrast to seven out of 25 negative cases. Expression of p185neu in mediastinal lymph node metastases was a significant predictor for progression-free survival (p=0.047) and resulted mainly from significant differences in metastases-free survival (p185neu-positive versus p185neu-negative: median, 11 versus 19 months; 2- and 3-yr rates, 13% and 0% versus 40% and 32%; p=0.04). On the basis of these preliminary results it was concluded that further evaluation of p185neu expression in trials on neoadjuvant and adjuvant therapy is warranted. When the prognostic impact of p185neu in such trials with larger patient numbers is confirmed, this may contribute to the identification of stratification variables for future treatment approaches of non-small cell lung cancer.


[Respiratory pasteurellosis. Description of a first series in Spain].
To know the clinical and microbiological characteristics of a first series of 8 patients in whom Pasteurella multocida was detected in samples from low respiratory airways. Patients with respiratory disease who had positive cultures for P. multocida in several biologic samples between 1986 and 1998 were studied. Patient's data were obtained from clinical files; microbiological study included microscopic examination, qualitative culture in all samples and quantitative culture in low respiratory airway samples. P. multocida was detected in 7 males and one female, with a mean age of 63 years (range: 6-71). All but one had a previous bronchial disease: 5 had chronic obstructive bronchial disease, 2 had bronchiectasis and one had relapsing acute bronchitis. Three patients referred a previous contact with pets. The main diagnosis, at the time P. multocida was detected, was exacerbated bronchitis in 4 patients, pneumonia in 2 (one with sepsis and positive blood culture to P. multocida) and another one with empyema. In the only paediatric patient P. multocida was a casual finding. Two patients died, both having a severe immunosuppression. The percentage of P. multocida detection compared to all low respiratory airway isolates along the study period was 0.02%. All samples were purulent and more than 10(7) P. multocida colony-forming units/millilitre were detected. All strains were penicillin-sensitive. Pasteurella multocida respiratory infection is rare, although it is probably underestimated owing to the fact that it is difficult to identify when coexisting with oropharingeal flora. Characteristically, in affects old males with bronchial disease are involved and can be life threatening in severely immunosuppressed patients.


Progression of renal damage and tubular regeneration in pregnant and non-pregnant adult female rats inoculated with a sublethal dose of Shiga toxin 2.
Shiga toxin-producing Escherichia coli is the main cause of post-diarrheal hemolytic uremic syndrome (HUS) which produces acute kidney injury mainly in children, although it can also affect adults. The kidneys are the organs most affected by Shiga toxin type 2 (Stx2) in patients with HUS. However, previous studies in pregnant rats showed that a sublethal dose of Stx2 causes severe damage in the uteroplacental unit and induces abortion, whereas produces mild to moderate renal damage. The aim of the present work was to study the progression of renal injury caused by a sublethal dose of Stx2, as well as renal recovery, in pregnant and non-pregnant rats, and to investigate whether pregnancy physiology may affect renal damage progression mediated by Stx2. Renal function and histopathology was evaluated in pregnant rats intraperitoneally injected with a sublethal dose of Stx2 (0.5 ng/g bwt) at the early stage of gestation (day 8 of gestation), and results in these rats were compared over time with those observed in non-pregnant female rats injected with the same Stx2 dose. Hence, progression of cell proliferation and dedifferentiation in renal tubular epithelia was also investigated. The sublethal dose of Stx2 induced abortion in pregnant rats as well as a significant more extended functional and histological renal injury in non-pregnant rats than in pregnant rats. Stx2 also caused decreased ability to concentrate urine in non-pregnant rats compared to their controls. However, renal water handling in pregnant rats was not altered by Stx2, and was significantly different than in non-pregnant rats. The greatest renal injury in both pregnant and non-pregnant rats was observed at 4 days post-Stx2 injection, and coincided with a significant increase in tubular epithelial proliferation. Expression of mesenchymal marker vimentin in tubular epithelia was consistent with the level of tubular damage, being higher in non-pregnant rats than in pregnant rats. Recovery from Stx2-induced kidney injury was faster in pregnant rats than in non-pregnant rats. Adaptive mechanisms developed during pregnancy such as changes in water handle and renal hemodynamic may contribute to lessen the Stx2-induced renal injury, perhaps at the expense of fetal loss.


Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome.
Noonan syndrome (NS) is an autosomal dominant disorder presenting with characteristic facies, short stature, skeletal anomalies, and congenital heart defects. Mutations in protein-tyrosine phosphatase, nonreceptor-type 11 (PTPN11), encoding SHP-2, account for 33-50% of NS. This study screened for mutations in the PTPN11 gene in 34 Taiwanese patients with NS. Mutation analysis of the 15 coding exons and exon/intron boundaries was performed by polymerase chain reaction and direct sequencing of the PTPN11 gene. We identified 10 different missense mutations in 13 (38%) patients, including a novel missense mutation (855T>G, F285L). These mutations were clustered in exon 3 (n = 6) encoding the N-SH2 domain, exon 4 (n = 2) encoding the C-SH2 domain, and in exons 8 (n = 2) and 13 (n = 3) encoding the PTP domain. In conclusion, this study provides further support that PTPN11 mutations are responsible for Noonan syndrome in Taiwanese patients.


Hepatic caeruloplasmin-gene expression during development in the guinea-pig. Correlation with changes in hepatic copper metabolism.
Decreased amounts of the serum copper-binding protein caeruloplasmin (hypocaeruloplasminaemia) are one of the characteristic abnormalities of copper metabolism that are found in all neonatal mammals. In the present study we have investigated the mechanism responsible for hypocaeruloplasminaemia found in neonatal guinea pigs. Northern-blot analysis of guinea-pig liver RNA revealed the presence of two caeruloplasmin mRNA species. A marked developmental change in expression was observed, with no detectable mRNA before birth, when hepatic copper is elevated. Expression was initiated soon after birth, when copper levels in the liver are falling, and was closely linked to the rise in enzymic activity and protein levels in serum. There was no differential regulation of the two mRNA species; however, a marked inter-animal variation in mRNA levels was observed. Using gel-filtration chromatography we were able to show that, before birth, serum copper was associated with a low-molecular-mass species and that, with the advent of expression of the caeruloplasmin gene after birth, copper was increasingly associated with caeruloplasmin.


Predictions of Optic Nerve Traction Forces and Peripapillary Tissue Stresses Following Horizontal Eye Movements.
To use finite element (FE) analysis to predict the optic nerve sheath traction forces that act on the optic nerve head (ONH) following horizontal eye movements, and the resulting stress levels in the peripapillary connective tissues of the ONH (Bruch's membrane [BM] and sclera). An FE model of a healthy eye was reconstructed in primary gaze position that included details from the orbital and ONH tissues. Optic nerve sheath traction forces and peripapillary tissue stresses in both adduction and abduction (13°) were computed using FE analysis. Our models predicted that, following eye movements, the ONH was sheared in the transverse plane due to the pulling action of the optic nerve. The optic nerve sheath traction forces were 90 mN in abduction and 150 mN in adduction. Peripapillary tissue stresses were concentrated in the nasal and temporal quadrants. In adduction, scleral stresses were highest in the temporal region, and BM stresses were slightly higher in the nasal region. This trend was reversed in abduction. Following eye movements, our models predicted high optic nerve sheath traction forces of the same order of magnitude as extraocular muscle forces. Optic nerve traction resulted in significant peripapillary stresses, and thus may have a role to play in the development of peripapillary zones, glaucoma, and myopia.


Aminoglycoside ribosome interactions reveal novel conformational states at ambient temperature.
The bacterial 30S ribosomal subunit is a primary antibiotic target. Despite decades of discovery, the mechanisms by which antibiotic binding induces ribosomal dysfunction are not fully understood. Ambient temperature crystallographic techniques allow more biologically relevant investigation of how local antibiotic binding site interactions trigger global subunit rearrangements that perturb protein synthesis. Here, the structural effects of 2-deoxystreptamine (paromomycin and sisomicin), a novel sisomicin derivative, N1-methyl sulfonyl sisomicin (N1MS) and the non-deoxystreptamine (streptomycin) aminoglycosides on the ribosome at ambient and cryogenic temperatures were examined. Comparative studies led to three main observations. First, individual aminoglycoside-ribosome interactions in the decoding center were similar for cryogenic versus ambient temperature structures. Second, analysis of a highly conserved GGAA tetraloop of h45 revealed aminoglycoside-specific conformational changes, which are affected by temperature only for N1MS. We report the h44-h45 interface in varying states, i.e. engaged, disengaged and in equilibrium. Third, we observe aminoglycoside-induced effects on 30S domain closure, including a novel intermediary closure state, which is also sensitive to temperature. Analysis of three ambient and five cryogenic crystallography datasets reveal a correlation between h44-h45 engagement and domain closure. These observations illustrate the role of ambient temperature crystallography in identifying dynamic mechanisms of ribosomal dysfunction induced by local drug-binding site interactions. Together, these data identify tertiary ribosomal structural changes induced by aminoglycoside binding that provides functional insight and targets for drug design.


Aging and feature search: the effect of search area.
The preattentive system involves the rapid parallel processing of visual information in the visual scene so that attention can be directed to meaningful objects and locations in the environment. This study used the feature search methodology to examine whether there are aging-related deficits in parallel-processing capabilities when older adults are required to visually search a large area of the visual field. Like young subjects, older subjects displayed flat, near-zero slopes for the Reaction Time x Set Size function when searching over a broad area (30 degrees radius) of the visual field, implying parallel processing of the visual display. These same older subjects exhibited impairment in another task, also dependent on parallel processing, performed over the same broad field area; this task, called the useful field of view test, has more complex task demands. Results imply that aging-related breakdowns of parallel processing over a large visual field area are not likely to emerge when required responses are simple, there is only one task to perform, and there is no limitation on visual inspection time.


Fluorescent Imaging Evaluation of Lidocaine Distribution Following Bier Block in the Upper Extremity.
Bier block regional anesthesia has been used as an alternative to general anesthesia for years. Despite multiple theories and multiple techniques to delineate the location of the action of lidocaine during Bier block anesthesia, there has not been a consensus on the location of action. The purpose of this study was to use fluorescent imaging to further investigate the site of action of lidocaine during Bier block. Three patients with carpal tunnel syndrome underwent open carpal tunnel release with Bier block anesthesia performed in the standard fashion with 1cc of Indocyanine green (IcG) mixed with lidocaine. Fluorescent images were obtained at the time of injection and after 10 minutes to allow patients to reach the level of surgical anesthesia. Repeated imaging was obtained at the time of completion of the procedure or at 30 minutes of tourniquet time. At time 0, IcG was distributed along the superficial venous system of the hand and forearm. At 10 minutes, the distribution of IcG was within the capillary system and infiltrating the dermis. The distribution later saturated the capillary beds and remained present until release of the tourniquet. The authors demonstrate that some lidocaine action occurs at the cutaneous level during the administration of a Bier block. Due to limited field depth of view provided by the SPY® Elite System (Novadaq Technologies Inc., Mississauga, Canada), we are unable to draw any conclusions as to the distribution of the IcG or lidocaine at the level of the larger nerves at the site of the tourniquet.


Auraticoccus cholistanensis sp. nov., an actinomycete isolated from soil of the Cholistan Desert, and emended description of the genus Auraticoccus.
A Gram-stain-positive, aerobic, non-motile and non-spore-forming actinobacterium, designated as F435T, was isolated from soil sample collected from the Cholistan Desert, Pakistan. The taxonomic position of the strain was established by using a polyphasic taxonomic approach. The cells were coccoid-shaped and found in single or arrangement of pairs. The novel strain grew at 15‒37 °C (optimum, 25‒30 °C), pH 7‒11 (optimum, pH 7-8) and in the presence of 0‒8% (w/v) NaCl (optimum, 0 %). Results of blast analysis based on 16S rRNA gene sequences showed that Auraticoccus monumenti MON 2.2T was its closest relative with 97.4 % similarity followed by Desertihabitans aurantiacus CPCC 204711T (95.2 %). In phylogenetic trees, strain F435T formed a robust cluster with the only member of the genus Auraticoccus. The peptidoglycan isomer present in the cell wall was ll-diaminopimelic acid. The major fatty acid was determined to be anteiso-C15 : 0. Characteristic polar lipids of the strain were diphosphatidylglycerol, phosphatidylglycerol, phosphoglycolipids and glycolipids. The predominant menaquinone was MK-9(H4). The genomic G+C content was calculated as 73.5 mol%. The digital DNA-DNA hybridization (GGDC) and average nucleotide identity (ANI) values between strain F435T and A. monumenti MON 2.2T were 24.6 and 81.8 %, respectively. Based on the results of phenotypic, chemotaxonomic, phylogenetic and phylogenomic analyses, strain F435T represents a novel specie of the genus Auraticoccus, for which the name Auraticoccus cholistanensis sp. nov. is proposed. The type strain is F435T (=JCM 33648T=CGMCC 1.17443T). The description of the genus Auraticoccus has also been emended.


Computer simulation of an ideal lateral inhibition function.
A model for lateral inhibition is presented in the context of the auditory channel. The mechanical analyzing system of the inner ear cannot alone account for the frequency resolution of hearing. Some additional mechanism, possibly lateral inhibition located in the auditory neural network, is needed to achieve the frequency selectivity observed in electrophysiological and psychoacoustical experiments. In a computer simulation study, the shape of an ideal lateral inhibition function was obtained. Such a function is applicable to all sensory modalities. In hearing, this function permits the sharpest possible frequency resolution as it can completely remove the frequency desharpening effect of the mechanical properties of the basilar membrane. In vision, it can compensate for abberations caused by the imperfections of the optical system of the eye.


Clinical surveillance of thrombotic microangiopathies in Scotland, 2003-2005.
The prevalence, incidence and outcomes of haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopaenic purpura (TTP) are not well established in adults or children from prospective studies. We sought to identify both outcomes and current management strategies using prospective, national surveillance of HUS and TTP, from 2003 to 2005 inclusive. We also investigated the links between these disorders and factors implicated in the aetiology of HUS and TTP including infections, chemotherapy, and immunosuppression. Most cases of HUS were caused by verocytotoxin-producing Escherichia coli (VTEC), of which serotype O157 predominated, although other serotypes were identified. The list of predisposing factors for TTP was more varied although use of immunosuppressive agents and severe sepsis, were the most frequent precipitants. The study demonstrates that while differentiating between HUS and TTP is sometimes difficult, in most cases the two syndromes have quite different predisposing factors and clinical parameters, enabling clinical and epidemiological profiling for these disorders.