The role of genetics on migraine induction triggered by CGRP and PACAP38.
Migraine has a strong genetic component and is characterized by multiphasic events including an initial premonitory phase with premonitory symptoms (PS). Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide-38 (PACAP38) are endogenous neuropeptides that can trigger migraine attacks and have in recent years gained considerable interest in the migraine field. Yet, the exact pathophysiological mechanisms underlying CGRP- and PACAP38-induced attacks are not fully clarified. Human provocation models have shown that these peptides induce attacks in only two- thirds of migraine patients. Whether this diverse migraine response after CGRP or PACAP38 may be explained by genetic factors is unknown. The present thesis includes four studies that explore different factors that may be associated with the CGRP- and PACAP38-induced migraine response. In study I and II we investigated the role of familial predisposition (family load) and number of risk conferring gene variants on migraine attacks induced by CGRP or PA-CAP38. In study III, we investigated biochemical changes of CGRP, vasoactive intestinal peptide (VIP), S100B and TNF-alpha in the blood after PACAP38. Finally in study IV, we studied whether CGRP or PACAP38 may induce PS. Study I and II demonstrated that PACAP38 and CGRP induce migraine attacks in 63% and 72% of the patients, respectively. Moreover, we showed that patients with high family load or a high number of migraine associated gene variants did not report more migraine attacks after CGRP or PACAP38 than those with no familial predisposition or few gene variants. Study III showed that PACAP38 infusion caused changes in plasma concentrations for VIP and S100B, but not CGRP and TNF-alpha, suggesting activation of parasympathetic nerve endings. Study IV showed absence of PS after CGRP and lack of statistical difference in PS between patients who reported and not reported attacks after PACAP38 suggesting peripheral mechanisms of induction. In conclusion, the present thesis suggests that genetics factors such as family load and genetic variants do not contribute to susceptibility of migraine attacks induced by CGRP or PACAP38. Additionally, our data indicate that CGRP and PACAP38 primarily have a peripheral site of action. We believe that the acquired knowledge from this thesis on how CGRP and PACAP38 might be involved in migraine pathophysiology would contribute to the development of novel and better migraine treatments in the future.


Long-term impact of preventive proactivity on quality of life of the old-old.
This research explored the long-term benefits of engaging in proactive health promotion efforts among old-old residents of Sunbelt retirement communities to empirically test components of the Preventive and Corrective Proactivity (PCP) Model of Successful Aging. Specifically, we examined the contributions of exercise, tobacco use, moderate alcohol use, and annual medical checkups to multidimensional quality of life indicators of physical health, psychological well-being, and mortality. Data were obtained from a longitudinal study of adaptation to aging. Annual in-home interviews were conducted with 1000 older adults over a 9-year period. Whether health promotion behaviors at baseline predicted quality of life outcomes 8 years later was examined, controlling for the baseline outcome, sociodemographic variables, and, as an additional test, baseline health conditions. Exercise was predictive of fewer IADL limitations and greater longevity, positive affect, and meaning in life 8 years later. Avoiding tobacco was predictive of longevity. Before controlling for health conditions, exercise predicted decreased risk of basic activities of daily living limitations and having more goals; moderate alcohol use predicted longevity; annual health checkup predicted more IADL limitations; and having once smoked predicted having more IADL limitations and negative affect. Among the old-old, exercise had long-term and multifaceted benefits over an 8-year period. Tobacco avoidance also contributed to long-term positive outcomes. These results lend support to the long-term preventive value of health-promoting proactivity spontaneously engaged in by old-old persons proposed in the framework of the PCP model.


Speaking out.
DAVID OLIVER has been liberated. As a former national clinical director for older people's services, he adapted to the limitations imposed on clinicians who take on a government role. Now, though, he is free to speak his mind and does so frequently online and in print, often pointing out the contradictions and inconsistencies in the way older people's care is organised - or, in some cases, disorganised.


EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression.
Mutations in the EYS (eyes shut homolog) gene are a common cause of autosomal recessive (ar) retinitis pigmentosa (RP). Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT), and en face autofluoresence imaging, a cohort of 15 patients (ages 12-51 at first visit), some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK.


Probing the folding transition state of ubiquitin mutants by temperature-jump-induced downhill unfolding.
Crucial to revealing mechanistic details of protein folding is a characterization of the transition state ensemble and its structural dynamics. To probe the transition state of ubiquitin thermal unfolding, we examine unfolding dynamics and kinetics of wild-type and mutant ubiquitin using time-resolved nonlinear infrared spectroscopy after a nanosecond temperature jump. We observe spectral changes on two different time scales. A fast nonexponential microsecond phase is attributed to downhill unfolding from the transition state region, which is induced by a shift of the barrier due to the rapid temperature change. Slow millisecond changes arise from thermally activated folding and unfolding kinetics. Mutants that stabilize or destabilize beta strands III-V lead to a decreased or increased amplitude of the microsecond phase, indicating that the disruption or weakening of these strands occurs in the transition state. Unfolding features from microseconds to milliseconds can be explained by temperature-dependent changes of a two-dimensional free energy surface constructed by the native contacts between beta strands of the protein. In addition, the results support the possibility of an intermediate state in thermal unfolding.


[In vitro study of antimicrobial activity of lactoferrins from various sources].
Comparative antimicrobial activity of lactoferrins from various sources (native lactoferrin from Laprot, human hololactoferrin, recombinant human lactoferrin isolated from the cultural medium of permissive cell culture transfected using pseudoadenovirus nanostructure with the human lactoferrin gene, and native bovine lactoferrin) was studied to prove the possibility of their use for development of antimicrobial drugs. It was shown that all the substances were active against the Bacillus standard strains. The antibacterial activity was almost independent of the degree of saturation the lactoferrin molecules with Fe3+. The native human lactoferrin was more active than hololactoferrin against Candida when evaluated by the minimum inhibitory concentration (MIC). Fe(3+)-Non aturated recombinant human lactoferrin demonstrated the antimicrobial activity (by MIC) similar to that of the native human lactoferrin. The results showed that native and recombinant human lactoferrins might be used for the development of intravenous and intracavitary dosage forms, while the native bovine lactoferrin could be useful in development of oral drugs.


[Physical rehabilitation of patients with osteoporosis].
Osteoporosis is one of the most common diseases, which along with cardiovascular pathology, diabetes mellitus and oncological diseases has a leading place in the structure of morbidity and mortality of the population. The combination of pharmacological and non-pharmacological methods is fundamental for the treatment and prevention of osteopenia and osteoporosis. This article presents rehabilitation methods that are of great importance for improving the functioning of the musculoskeletal system, the quality of life of patients with osteoporosis. Physical rehabilitation is aimed at stopping the destruction of bone tissue, strengthening it, eliminating pain, reducing stress from the affected areas and restoring the normal function of joints and bones. The proposed types of physical activity not only increase bone strength and strengthen muscle mass, but also reduce the risk of falling - a leading cause of osteoporotic fractures. Exercise programs designed for patients with osteoporosis should include strength and exercise exercises, as well as exercises for flexibility, posture correction, coordination of movements and balance. Training should be regular, varied and of a certain duration. The article considers the advantages and disadvantages of each type of activity.


In situ immunoradiometric assay of fibrinogen adsorbed to artificial surfaces.
An in situ immunoradiometric assay was devised to quantitate human fibrinogen deposited on hemodialysis membrane, Cuprophane, from in vitro exposure to fibrinogen solution and from ex vivo extracorporally clinical use. The method requires a monospecific 125I-labeled antifibrinogen -IgG purified by DEAE chromatography and immunoadsorption. The labeled antifibrinogen IgG was shown to react specifically with fibrinogen adsorbed and immobilized (by glutaraldehyde) on Cuprophane. Other plasma proteins such as human albumin, IgG, or alpha-thrombin, adsorbed singly or coadsorbed with fibrinogen on the surface did not seem to affect the fibrinogen- antifibrinogen reaction. The presence of blood cells such as platelets and granulocytes with fibrinogen on Cuprophane reduced only slightly the uptake of 125I- antifibrinogen -IgG. The examination of fibrinogen-fibrin deposition on clinically used Cuprophane by this technique and by autoradiography of the same material following 125I- antifibrinogen -IgG conjugation indicated that the deposition of fibrinogen was heavy and heterogeneous. We concluded that this in situ method may be useful to monitor fibrinogen-fibrin deposition and adsorption of other plasma proteins that occur under in vitro, ex vivo, and in vivo conditions.


Mycosides C: behavior as receptor site substance for mycobacteriophage D4.
Interpretation of an earlier published infrared spectrum of Mycobacterium smegmatis lipids with receptor site activity for D4 phage led us to the inference that the active substance is very likely a mycoside C. This hypothesis was confirmed: the well-characterized mycosides C(s) and C(1217) elaborated by the heterologous strains M. scrofulaceum and Mycobacterium species 1217, respectively, are essentially indistinguishable from the smegmatis lipids in their behavior toward D4. Minute quantities adsorb and extensively inactivate the phage on appropriate incubations. In accord with derivative expectations, Mycobacterium species 1217 is a permissive host, attacked and lysed by D4. However, our current strains of M. butyricum, M. avium, and M. scrofulaceum, which reputedly produce various related mycosides C, are neither lysed by nor do they significantly adsorb the phage. Implications of these observations are discussed.


AutomAl 6000: Semi-automatic structural labelling of HAADF-STEM images of precipitates in Al-Mg-Si(-Cu) alloys.
When the Al-Mg-Si(-Cu) alloy system is subjected to age hardening, different types of precipitates nucleate depending on the composition and thermomechanical treatment. The main hardening precipitates extend as needles, laths or rods along the <100> directions in the aluminium matrix. It has been found that the structures of all metastable precipitates may be generalized as stacks of <100> columns, where most of these columns are replaced by solute elements. In the precipitates, a column relates to neighbour columns by a set of simple structural principles, which allows identification of species and relative longitudinal displacement over the (100) cross-section. Aberration-corrected high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) is an important tool for studying such precipitates. With the goal of analysing atomic resolution HAADF-STEM images of precipitate cross-sections in the Al-Mg-Si(-Cu) system, we have developed the stand-alone software AutomAl 6000, which features a column characterization algorithm based on the symbiosis of a statistical model and the structural principles formulated in a digraph-like framework. The software can semi-autonomously determine the 3D column positions in the image, as well as column species. In turn, AutomAl 6000 can then display, analyse and/or export the structure data. This paper describes the methodology of AutomAl 6000 and applies it on three different HAADF-STEM images, which demonstrate the methodology. The software, as well as other resources, are available at http://automal.org. The source code is also directly available from https://github.com/Haawk666/AutomAl-6000.


Ultrastructure of extracellular matrix of embryonic chick limb bud cartilage.
The ultrastructure of the extracellular matrix of chick limb buds at stages 24--36 was investigated with the electron microscope and with polarization microscopic evaluation of topo-optical reactions. Two types of extracellular matrix structures could be distinguished. In the primary matrix of presumptive cartilaginous areas at developmental stage 25, topo-optical reactions revealed polycarboxylated glycosaminoglycans oriented parallel to the cell surface. With the electron microscope few fine filaments and small matrix granules could be found. In the secondary cartilage matrix, from stage 26 on, topo-optical reactions demonstrated glycosaminoglycans and collagen being predominantly ordered parallel to each other. Their amount and the degree of their orientation gradually increased during the developmental period investigated. Electron microscopy demonstrated collagen filaments and matrix granules in increasing number at stages 26--36. While some parallel ordering of filaments was seen in the electron micrographs, no sign of spatial ordering of glycosaminoglycans could be found with this technique.


Pleuritis and peritonitis in a golden eagle.
A female Golden Eagle died despite intensive treatment after being struck by a vehicle. Necropsy revealed poor body condition, with no fat stores. The proventriculus and ventriculus contained a pellet of fur and bone fragments, at the center of which was the leg of a Red-Tailed Hawk. A talon on the leg had punctured the ventriculus, resulting in fatal pleuritis and peritonitis.


Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure.
The effects of GRK2 inhibition on myocardial metabolism in heart failure (HF) are unchartered. In this work, we evaluated the impact of pharmacological inhibition of GRK2 by a cyclic peptide, C7, on metabolic, biochemical, and functional phenotypes in experimental HF. C7 was initially tested on adult mice ventricular myocyte from wild type and GRK2 myocardial deficient mice (GRK2-cKO), to assess the selectivity on GRK2 inhibition. Then, chronic infusion of 2 mg/kg/day of C7 was performed in HF mice with cryogenic myocardial infarction. Cardiac function in vivo was assessed by echocardiography and cardiac catheterization. Histological, biochemical, and metabolic studies were performed on heart samples at time points. C7 induces a significant increase of contractility in wild type but not in adult ventricle myocytes from GRK2-cKO mice, thus confirming C7 selectivity for GRK2. In HF mice, 4 weeks of treatment with C7 improved metabolic features, including mitochondrial organization and function, and restored the biochemical and contractile responses. GRK2 is a critical molecule in the physiological regulation of cardiac metabolism. Its alterations in the failing heart can be pharmacologically targeted, leading to the correction of metabolic and functional abnormalities observed in HF.


Mode of action of the microbial metabolite GE23077, a novel potent and selective inhibitor of bacterial RNA polymerase.
GE23077, a novel microbial metabolite recently isolated from Actinomadura sp. culture media, is a potent and selective inhibitor of bacterial RNA polymerase (RNAP). It inhibits Gram-positive (Bacillus subtilis) and Gram-negative (Escherichia coli) RNAPs with IC50 values (i.e. the concentration at which the enzyme activity is inhibited by 50%) in the 10(-8) m range, whereas it is not active on E. coli DNA polymerase or on eukaryotic (wheat germ) RNAP II (IC50 values > 10(-4) m in both cases). In spite of its potent activity on purified bacterial RNAPs, GE23077 shows a narrow spectrum of antimicrobial activity on Gram-positive and Gram-negative bacteria. To investigate the molecular basis of this behaviour, the effects of GE23077 on macromolecular biosynthesis were tested in E. coli cells permeabilized under different conditions. The addition of GE23077 to plasmolyzed cells resulted in an immediate and specific inhibition of intracellular RNA biosynthesis, in a dose-response manner, strongly suggesting that cell penetration is the main obstacle for effective antimicrobial activity of the antibiotic. Biochemical studies were also conducted with purified enzymes to obtain further insights into the mode of action of GE23077. Interestingly, the compound displays a behaviour similar to that of rifampicin, an antibiotic structurally unrelated to GE23077: both compounds act at the level of transcription initiation, but not on the sigma subunit and not on the formation of the promoter DNA-RNAP complex. Tests on different rifampicin-resistant E. coli RNAPs did not show any cross-resistance between the two compounds, indicating distinct binding sites on the target enzyme. In conclusion, GE23077 is an interesting new molecule for future mechanistic studies on bacterial RNAP and for its potential in anti-infective drug discovery.


An overview of US coronary stent trials.
Since the introduction of coronary stent procedures in the US there has been a determined effort to understand appropriate clinical applications better through the use of carefully designed prospective clinical trials. These studies fall into the general categories of efficacy studies, pharmacology, studies, intravascular ultrasound studies, adjuvant stent therapy studies, stent versus stent studies and new stent registries. Most of the pivotal clinical trials have been randomized controlled studies, but there have also been several carefully performed registry analyses which have provided useful insights. There are ample data to support the use of stents for abrupt and threatened closure syndrome. STRESS (the STent REStenosis Study) helped to establish the 'anti-restenosis' efficacy of elective Palmaz-Schatz coronary stent placement in native coronary arteries, although secondary complications (subacute stent thrombosis, bleeding and vascular events) were disturbing owing to excessive systemic anticoagulation regimens. Subsequent studies, often using intravascular ultrasound guidance, have clearly indicated that optimal stent implantation requiring post-stent high-pressure dilatations combined with aggressive antiplatelet therapy (aspirin plus ticlopidine) provides the best early and late clinical outcomes. Many of these observations have now been extended to other lesion subsets including saphenous vein grafts. In the future, stent adjuvant therapies will be carefully evaluated, including pharmacological agents, intravascular irradiation, and pre-stent atheroablation. Finally, interstent comparisons of randomized clinical trials are ongoing and there are several new stent registries which will help to extend the frontiers of clinical applications and operator technique.


Daunomycin, cytosine arabinoside and 6-thioguanine (DAT) vs vincristine, cytosine arabinoside and 6-thioguanine (VAT) in the induction treatment of acute nonlymphocyte leukemia: a randomized collaborative study.
One hundred patients were entered in a cooperative study comparing the efficacy of two different regimens in the induction treatment of acute nonlymphocytic leukemia (ANLL). Patients were randomly allocated to receive either the DAT or VAT combination; half of the patients were also randomized to receive CNS prophylaxis including intrathecal methotrexate + prednisone and cranial irradiation. Consolidation and maintenance therapy were uniform in responding patients. Out of 82 evaluable patients 41 (50%) attained complete remission (CR) with no significant difference between the two regimens. Median remission duration was slightly longer in the DAT group (32.5 vs 22 weeks); median survival was 34 weeks for all evaluable patients with no difference between the two schedules. Meningeal relapse occurred only in two patients after 19 and 99 weeks of continuous remission. Fourteen patients are still alive after 61 to greater than or equal to 155 weeks, of whom seven are in their initial remission (six in the DAT and one in the VAT group). We conclude that 1) DAT and VAT are equally effective in inducing CR in a high proportion of ANLL patients; 2) until marrow remission can be prolonged significantly, preventing CNS leukemia will not have any significant impact of the course of ANLL.


A Bayesian spatio-temporal model for forecasting Anaplasma species seroprevalence in domestic dogs within the contiguous United States.
This paper forecasts the 2016 canine Anaplasma spp. seroprevalence in the United States from eight climate, geographic and societal factors. The forecast's construction and an assessment of its performance are described. The forecast is based on a spatial-temporal conditional autoregressive model fitted to over 11 million Anaplasma spp. seroprevalence test results for dogs conducted in the 48 contiguous United States during 2011-2015. The forecast uses county-level data on eight predictive factors, including annual temperature, precipitation, relative humidity, county elevation, forestation coverage, surface water coverage, population density and median household income. Non-static factors are extrapolated into the forthcoming year with various statistical methods. The fitted model and factor extrapolations are used to estimate next year's regional prevalence. The correlation between the observed and model-estimated county-by-county Anaplasma spp. seroprevalence for the five-year period 2011-2015 is 0.902, demonstrating reasonable model accuracy. The weighted correlation (accounting for different sample sizes) between 2015 observed and forecasted county-by-county Anaplasma spp. seroprevalence is 0.987, exhibiting that the proposed approach can be used to accurately forecast Anaplasma spp. seroprevalence. The forecast presented herein can a priori alert veterinarians to areas expected to see Anaplasma spp. seroprevalence beyond the accepted endemic range. The proposed methods may prove useful for forecasting other diseases.


Managing nurse practitioners in ambulatory care: what are the issues?
Current emphasis on cost containment of health care services has spurred interest in the expansion of primary care in ambulatory care centers. While nurse practitioners can contribute significantly to ambulatory care, their effectiveness depends on the climate in which they perform--nursing administrators play a key role in creating that climate. This article discusses the issues nursing administrators face in the selection, management, evaluation, and reimbursement of nursing practitioners.


Ischemic preconditioning stimulates anaerobic glycolysis in the isolated rabbit heart.
Preconditioning decreases ischemic injury, preserves tissue ATP content, and enhances the salutary effects of reperfusion. To evaluate whether preserved ATP is related to reduced utilization or increased production, 28 paced isolated rabbit hearts, perfused at constant flow, were subjected to 3 min of transient no-flow ischemia followed 12 min later by 1 h of low-flow ischemia and 45 min of reperfusion. Results were compared with those from 34 control hearts subjected to ischemia and reperfusion without preconditioning. Preconditioning delayed the onset of ischemic contracture and decreased its amplitude. At the end of ischemia, tissue ATP content was higher in hearts subjected to preconditioning (9.8 +/- 3.3 vs. 4.5 +/- 1.1 mumol/g dry wt; P < 0.01), accounted for by increased anaerobic ATP production using exogenous glucose. Preconditioning decreased ischemic damage (creatine kinase release 373 +/- 199 vs. 587 +/- 291 U/g dry wt; P < 0.05) and resulted in better functional recovery with reperfusion (74 +/- 11% of baseline developed pressure vs. 60 +/- 23%; P < 0.05). Thus preconditioning appears to protect ischemic myocardium by enhancing anaerobic glycolytic production of ATP using exogenous glucose.


The MADS transcription factor CmANR1 positively modulates root system development by directly regulating CmPIN2 in chrysanthemum.
Plant root systems are essential for many physiological processes, including water and nutrient absorption. MADS-box transcription factor (TF) genes have been characterized as the important regulators of root development in plants; however, the underlying mechanism is largely unknown, including chrysanthemum. Here, it was found that the overexpression of CmANR1, a chrysanthemum MADS-box TF gene, promoted both adventitious root (AR) and lateral root (LR) development in chrysanthemum. Whole transcriptome sequencing analysis revealed a series of differentially expressed unigenes (DEGs) in the roots of CmANR1-transgenic chrysanthemum plants compared to wild-type plants. Functional annotation of these DEGs by alignment with Gene Ontology (GO) terms and biochemical pathway Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that CmANR1 TF exhibited "DNA binding" and "catalytic" activity, as well as participated in "phytohormone signal transduction". Both chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) and gel electrophoresis mobility shift assays (EMSA) indicated the direct binding of CmPIN2 to the recognition site CArG-box motif by CmANR1. Finally, a firefly luciferase imaging assay demonstrated the transcriptional activation of CmPIN2 by CmANR1 in vivo. Overall, our results provide novel insights into the mechanisms of MADS-box TF CmANR1 modulation of both AR and LR development, which occurs by directly regulating auxin transport gene CmPIN2 in chrysanthemum.


VOLUME-RENDERED ANGIOGRAPHIC AND STRUCTURAL OPTICAL COHERENCE TOMOGRAPHY.
To demonstrate combined and integrated volume rendering of the retinal vasculature and selected structural abnormalities information derived from optical coherence tomography. The eyes were scanned using optical coherence tomography using split-spectrum amplitude-decorrelation techniques to derive flow information. Various sublayers could be color coded as needed. The corresponding structural optical coherence tomography information was segmented for salient anatomic structures of interest, such as areas of edema fluid or intraretinal lipid deposits. The angiographic and structural data were integrated on a plane-by-plane basis and used to create volume-rendered images. The combined volume-rendered angiographic and structural optical coherence tomography data could be rotated about three different axes for evaluation. Representative images from the eyes with diabetic macular edema, Type 1 macular telangiectasis, choroidal neovascularization, and retinal veno-occlusive disease are shown. The interrelationships between areas of cystoid fluid accumulation or intraretinal lipid accumulation could be visualized. Although structural and angiographic findings are typically shown in isolation, they can be integrated into a merged data set that is amenable to volume rendering. Using this new technique will allow investigation into the interrelationships between vascular and structural abnormalities of the retina and choroid.


Physiologic mechanisms underlying the failure of the "shock index" as a tool for accurate assessment of patient status during progressive simulated hemorrhage.
Shock index (SI), the ratio of heart rate (HR) to systolic arterial pressure (SAP), is a metric often used to diagnose patients at risk of impending cardiovascular instability and hemorrhagic shock. We hypothesized that if SI reflected impending cardiovascular instability and shock in an individual, then: (1) elevations in SI and HR would be greater in individuals with low tolerance (LT) to progressive lower-body negative-pressure (LBNP) compared with individuals with high tolerance (HT), and (2) LT would be associated with greater vagal withdrawal of the baroreflex sensitivity (BRS) compared with HT. A total of 187 healthy subjects (HT, 125; LT, 62) underwent exposure to LBNP until a SAP of less than 80 mm Hg (instability) was achieved. HR and SAP were used to calculate SI, and BRS was determined from spontaneous fluctuations in R-R interval and diastolic arterial pressure. Maximal cardiac vagal withdrawal was calculated as the difference between BRS at baseline and BRS at 100% LBNP tolerance. Contrary to our hypothesis, SI at 60%, 80%, and 100% LBNP tolerance in LT (0.59 ± 0.03, 0.73 ± 0.04, and 0.97 ± 0.06, respectively) was lower (p ≤ 0.002) than SI in HT subjects at the same levels (0.66 ± 0.03, 0.84 ± 0.04, and 1.24 ± 0.06, respectively). Maximal cardiac vagal withdrawal was less (p = 0.045) in LT subjects (11.3 ± 2.2 ms/mm Hg) compared with HT subjects (14.9 ± 2.5 ms/mm Hg). The sensitivity of SI in identifying impending instability (SI, 0.9) at 80% and 100% LBNP tolerance was 13% and 63% in LT subjects and 34% and 91% in HT subjects, respectively. The low sensitivity of the SI observed in LT individuals is associated with a lower capacity to withdraw cardiac vagal activity and can lead to an undertriage of those patients most likely to develop early hemorrhagic shock.


Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients.
Parkinson's disease, caused by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease characterized by bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-dopa) is the most effective treatment for the amelioration of Parkinson's disease signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-dopa -induced dyskinesias (LIDs). Studies in rat striatal slices have shown dopamine to be an essential component of activity-dependent synaptic plasticity at the input to the basal ganglia, but dopamine is also released from ventrally projecting dendrites of the substantia nigra pars compacta (SNc) on the substantia nigra pars reticulata (SNr), a major output structure of the basal ganglia. We characterized synaptic plasticity in the SNr using field potentials evoked with a nearby microelectrode (fEPs), in 18 Parkinson's disease patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN). High frequency stimulation (HFS--four trains of 2 s at 100 Hz) in the SNr failed to induce a lasting change in test fEPs (1 Hz) amplitudes in patients OFF medication (decayed to baseline by 160 s). Following oral L-dopa administration, HFS induced a potentiation of the fEP amplitudes (+29.3% of baseline at 160 s following a plateau). Our findings suggest that extrastriatal dopamine modulates activity-dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of Parkinson's disease.


M-mode echocardiographic parameters and indices in the normal German shepherd dog.
M-mode echocardiographic measurements were made from 50 healthy German Shepherd dogs (30 males and 20 females). The dogs were awake and unsedated, in right lateral recumbent position. The following parameters were measured on the echocardiographic images: interventricular septal thickness at end-diastole (IVSd), interventricular septal thickness at end-systole (IVSs), left ventricular internal dimension at end-diastole (LVIDd), left ventricular internal dimension at end-systole (LVIDs), left ventricular posterior wall thickness at end-diastole (LVPWd), left ventricular posterior wall thickness at end-systole (LVPWs), left atrial dimension (LAD), aortic root dimension (AOD), left atrial to aortic root ratio (LAD/AOD), right ventricular internal dimension at end-diastole (RVID), amplitude of mitral valve excursion (DE amplitude), velocity of mitral valve opening (D-E slope), and velocity of mitral valve closure (E-F slope). Fractional shortening (FS) was also calculated. The effect of gender and age on each echocardiographic parameter was analyzed and the relationship between body weight (BW) and each parameter was also investigated. There was a significant relationship between gender and LVPW in systole and diastole and FS. Significant association was also found between BW and IVS, LVID, and LVPW in systole and diastole, FS, LAD, AOD, RVID, DE amplitude, and D-E slope of the mitral valve.


Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors.
Recent evidence suggests that angiotensin II (Ang II) induces a variety of proinflammatory mediators including chemokines. Nuclear factor-kappaB (NF-kappaB) activation plays an important role in Ang II-mediated inflammation. The present study investigated which Ang II receptor subtype is involved in NF-kappaB activation. We focused particularly on the Ang II subtype 2 (AT2) receptor because we previously observed that Ang II-induction of the chemokine RANTES in vitro and in vivo is mediated through AT2 receptors. AT1 or AT2 receptors were selectively overexpressed in COS7 cells that normally do not express Ang II receptors. In addition, rat glomerular endothelial cells (GER) that express AT1 and AT2 receptors and PC12 cells that exclusively exhibit AT2 receptors were studied also. Ang II-receptor expression was confirmed by Western blots of membrane lysates. NF-kappaB DNA binding in vitro was detected by electrophoretic shift assays. In addition, in vivo transactivation of a reporter gene construct with kappa enhancer coupled to luciferase also was investigated. Expression of the inhibitor of kappaB alpha (IkappaB-alpha) was detected by Western blots. In AT1 or AT2 receptor transfected cells, but not untransfected COS7 cells, 10-7 mol/L Ang II induced NF-kappaB DNA binding in vitro, as detected by electrophoretic shift assays and in vivo transactivation of a reporter gene construct. The AT2 receptor antagonist PD 123319 but not losartan attenuated Ang II-mediated NF-kappaB activation in COS7 cells transfected with AT2 receptors. While Ang II also induced NF-kappaB activation in PC12 cells, this activation was blocked by PD 123319. Finally, stimulation of GERs with Ang II led to the activation of NF-kappaB through both subtypes of Ang II receptors. Nuclear extracts from COS7 cells transfected with AT2 receptors and PC12 cells with NF-kappaB DNA-binding activity consisted of p50/p65 complexes. There was no difference in subunit composition of nuclear proteins from Ang II-stimulated AT1 receptor transfected COS7 cells. An artificial peptide (p-Amino-Phe6-Ang II) with a high affinity for the AT2 receptor also activated NF-kappaB. Ang II-induced activation of NF-kappaB was associated with degradation of IkappaB-alpha in all studied cell lines. Our results clearly demonstrate in various cell lines that Ang II induces NF-kappaB activation through AT2 receptors. These data may have important therapeutic consequences, because potential Ang II-mediated proinflammatory renal and cardiovascular effects may not be totally antagonized by the currently increased clinical use of AT1 receptor antagonists.


Sympathoadrenal function in patients with paroxysmal hypertension: pseudopheochromocytoma.
The causes of paroxysmal hypertension in patients in whom pheochromocytoma has been excluded ('pseudopheochromocytoma') usually remain unclear. Blood pressure disturbances and symptoms of catecholamine excess in these patients may reflect activation of the sympathetic nervous and adrenal medullary systems. We therefore examined sympathoadrenal function in patients with pseudopheochromocytoma compared with age-matched control subjects in whom there was no suspicion of pheochromocytoma. Plasma catecholamines and hemodynamics were examined in response to intravenous glucagon, yohimbine, and trimethaphan in 11 patients with pseudopheochromocytoma and a comparison group of nine normotensive and five hypertensive volunteers. Adrenomedullary function was also assessed by abdominal F-fluorodopamine positron emission tomography and measurements of plasma metanephrine, the O-methylated metabolite of epinephrine. Compared with controls, patients with pseudopheochromocytoma had normal plasma concentrations of norepinephrine, but 120% higher (P < 0.05) baseline plasma concentrations of epinephrine, 80% higher (P < 0.01) baseline plasma concentrations of metanephrine, and sixfold larger (P < 0.05) increases in plasma epinephrine after glucagon. Adrenal 18F-fluorodopamine-derived radioactivity did not differ between groups. Compared with changes in plasma norepinephrine, falls in blood pressure after trimethaphan were 13-fold larger (P < 0.005) and increases in blood pressure after yohimbine were threefold larger (P < 0.01) in pseudopheochromocytoma patients than in controls. Patients with pseudopheochromocytoma exhibit a pattern of normal sympathetic noradrenergic outflow, adrenomedullary activation, and augmented blood pressure responses to changes in the sympathoneural release of norepinephrine.


The Arabidopsis hrl1 mutation reveals novel overlapping roles for salicylic acid, jasmonic acid and ethylene signalling in cell death and defence against pathogens.
Defence against pathogens in Arabidopsis is orchestrated by at least three signalling molecules: salicylic acid (SA), jasmonic acid (JA) and ethylene (ET). The hrl1 (hypersensitive response-like lesions 1) mutant of Arabidopsis is characterized by spontaneous necrotic lesions, accumulation of reactive oxygen species, constitutive expression of SA- and ET/JA-responsive defence genes, and enhanced resistance to virulent bacterial and oomycete pathogens. Epistasis analyses of hrl1 with npr1, etr1, coi1 and SA-depleted nahG plants revealed novel interactions between SA and ET/JA signalling pathways in regulating defence gene expression and cell death. RNA gel-blot analysis of RNA isolated separately from the lesion+ and the lesion- leaves of double mutants of hrl1 revealed different signalling requirements for the expression of defence genes in these tissues. Expression of the ET/JA-responsive PDF1.2 gene was markedly reduced in hrl1 npr1 and in SA-depleted hrl1 nahG plants. In hrl1 nahG plants, expression of PDF1.2 was regulated by benzathiadiazole in a concentration-dependent manner: induced at low concentration and suppressed at high concentration. The hrl1 etr1 plants lacked systemic PR-1 expression, and exhibited compromised resistance to virulent Pseudomonas syringae and Peronospora parasitica. Inhibiting JA responses in hrl1 coi1 plants lead to exaggerated cell death and severe stunting of plants. Finally, the hrl1 mutation lead to elevated expression of AtrbohD, which encodes a major subunit of the NADPH oxidase complex. Our results indicate that defence gene expression and resistance against pathogens in hrl1 is regulated synergistically by SA and ET/JA defence pathways.


[Effects of smoking on expressions of HIF-1α and HDAC2 in asthmatic mice].
To explore the effects of smoking on airway inflammation through the expressions of hypoxia-inducible factor-1α (HIF-1α) and histone deacetylase-2 (HDAC2) in asthmatic mice. A total of 30 female SPF BALB/c mice were divided randomly into 3 groups of control (C), asthma (A) and smoking asthma (S). The latter two groups were sensitized and challenged with ovalbumin (OVA) for asthmatic modeling. The mice of group S were placed into a self-made fumigating box for passive smoking. While group S was sensitized and challenged with normal saline instead of OVA. The pathological changes of different groups were observed. The different cell counts of bronchoalveolar fluid (BALF) were analyzed. The expressions of HIF-1α and HDAC2 were detected by immunohistochemistry. The level of interleukin (IL)-8 in BALF was detected by enzyme-linked immunosorbent assay (ELISA). And the levels of HIF-1α and HDAC2 in lung homogenate were measured by Western blot. The ratios of eosinophil (EOS) to total cell numbers of BALF in groups A and S were significantly higher than that in group C ((8.90 ± 1.60)%, (7.52 ± 0.63)% vs (0.60 ± 0.10)%, both P < 0.01), while the ratio of neutrophile (NEU) in group S was higher than that in group A ((18.24 ± 5.19)% vs (8.46 ± 1.58)%, P < 0.01). Western blot showed that HIF-1α expressions in lung homogenate of groups A and S were significantly elevated than that in groups C (0.144 ± 0.008, 0.238 ± 0.015 vs 0.081 ± 0.005, both P < 0.01). While the HIF-1α level of group S was higher than that of group A (P < 0.01). And the expressions of HDAC2 in groups A and S significantly decreased than that in group C (0.287 ± 0.008, 0.164 ± 0.015 vs 0.452 ± 0.041, both P < 0.01). While the HDAC2 level of group S was lower than that of group A (P < 0.01). The BALF level of IL-8 in group S was higher than those in groups A and C ((42.07 ± 4.54) vs (21.66 ± 2.78), (14.33 ± 3.73) pg/ml, both P < 0.01). There were significantly negative correlations between the expressions of HIF-1α and HDAC2 (r = -0.950, P < 0.01) in lung as well as HDAC2 in lung and IL-8 (r = -0.855, P < 0.01) in BALF. Cigarette smoking aggravates the airway inflammation through a down-regulated expression of HDAC2 by activating HIF-1α.


Criticality and market efficiency in a simple realistic model of the stock market.
We discuss a simple model based on the minority game which reproduces the main stylized facts of anomalous fluctuations in finance. We present the analytic solution of the model in the thermodynamic limit. Stylized facts arise only close to a line of critical points with nontrivial properties, marking the transition to an unpredictable market. We show that the emergence of critical fluctuations close to the phase transition is governed by the interplay between the signal to noise ratio and the system size. These results provide a clear and consistent picture of financial markets, where stylized facts and verge of unpredictability are intimately related aspects of the same critical systems.


The druggable genome and support for target identification and validation in drug development.
Target identification (determining the correct drug targets for a disease) and target validation (demonstrating an effect of target perturbation on disease biomarkers and disease end points) are important steps in drug development. Clinically relevant associations of variants in genes encoding drug targets model the effect of modifying the same targets pharmacologically. To delineate drug development (including repurposing) opportunities arising from this paradigm, we connected complex disease- and biomarker-associated loci from genome-wide association studies to an updated set of genes encoding druggable human proteins, to agents with bioactivity against these targets, and, where there were licensed drugs, to clinical indications. We used this set of genes to inform the design of a new genotyping array, which will enable association studies of druggable genes for drug target selection and validation in human disease.


Identification and characterization of a novel extracellular polyhydroxyalkanoate depolymerase in the complete genome sequence of Undibacterium sp. KW1 and YM2 strains.
Polyhydroxyalkanoate (PHA) is a biodegradable polymer that is synthesized by a wide range of microorganisms. One of the derivatives of PHA, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBH) has flexible material properties and low melting temperature. We have previously demonstrated that PHBH is degradable in a freshwater environment via the formation of biofilm on the surface of the PHBH film. Undibacterium sp. KW1 and YM2, which were isolated from the biofilm present on the PHBH film in the freshwater sample, were shown to have PHBH-degrading activity. In this study, the complete genome sequence of KW1 and YM2 revealed that the extracellular PHA depolymerase gene, designated as phaZUD, was present in their chromosomes. Sequence analysis revealed that PhaZUD contained four domains: a signal peptide, catalytic domain, linker domain, and substrate-binding domain. Escherichia coli harboring a PhaZUD-expressing plasmid showed PHBH-degrading activity in LB medium containing 1 wt% PHBH powder. The recombinant His-tagged PhaZUD from KW1 and YM2 was purified from the culture supernatant and shown to have PHBH-degrading activity at the optimum temperature of 35 and 40°C, respectively. When the degradation product in the PHBH solution was treated with PhaZUD and assayed by LC-TOF-MS, we detected various oligomer structures, but no more than pentamers, which consist of 3-hydroxybutyrate and 3-hydroxyhexanoate. These results demonstrated that PhaZUD may have an endo-type extracellular PHA depolymerase activity.


Management of Anxiety and Depressive Disorders in Patients ≥ 65 Years of Age by Homeopath General Practitioners versus Conventional General Practitioners, with Overview of the EPI3-LASER Study Results.
The increasing use of psychotropic drugs to treat anxiety and depressive disorders (ADDs) is concerning. According to the study, 'Etude Pharmacoépidémiologique de l'Impact de Santé Publique des modes de prise en charge pour 3 groupes de pathologies' (EPI3)-LASER, adult ADD patients who consult a general practitioner prescribing homeopathic medicines (GP-Ho) report less psychotropic drug use and are marginally more likely to experience clinical improvement than those receiving conventional care. We determined whether these observations also apply to patients ≥ 65 years old in the EPI3 cohort. The EPI3-LASER study, conducted in France between March 2007 and July 2008, was a nationwide, observational survey of the three most common reasons for primary care consultation, including ADD, and the impact of the GPs' prescribing preferences: homeopathy (GP-Ho), conventional medicines (GP-CM) or mixed prescriptions (GP-Mx). This sub-analysis included 110 patients ≥ 65 years old with ADD from the EPI3 cohort who consulted either a GP-CM or GP-Ho. Socio-demographic and medical data and details of any medications prescribed were collected at inclusion. Information regarding the patients' functional status (Hospital Anxiety and Depression Scale [HADS)]) was obtained via a telephone interview 72 hours after inclusion, and at 1, 3 and 12 months post-inclusion. Medication use and outcome were determined over the 12-month period. Differences between the GP-CM and GP-Ho groups were assessed by multivariate logistic regression analysis. One hundred and ten patients were recruited and 87 (79.1%) with ADD (HADS ≥ 9) at the 72-hour interview were evaluated (age range: 65-93 years, 82.8% female). Patients who consulted a GP-Ho were more likely (odds ratio [OR] = 10.38, 95% confidence interval [CI]: 1.33-81.07) to have clinical improvement (HADS < 9) after 12 months than those in the GP-CM group. Patients who consulted a GP-Ho reported less psychotropic drug use (OR = 22.31 [95% CI: 2.20-226.31]) and benzodiazepine use (OR = 60.63 [95% CI: 5.75-639.5]) than GP-CM patients. Management of ADD patients aged ≥ 65 years by GP-Ho appears to have a real public health interest in terms of effectiveness and lower psychotropic drug use.


Bridged Hybrid Monolithic Column Coupled to High-Resolution Mass Spectrometry for Top-Down Proteomics.
Top-down mass spectrometry (MS)-based proteomics has become a powerful tool for comprehensive characterization of intact proteins. However, because of the high complexity of the proteome, highly effective separation of intact proteins from complex mixtures prior to MS analysis remains challenging. Monolithic columns have shown great promise for intact protein separation due to their high permeability, low backpressure, and fast mass transfer. Herein, for the first time, we developed bridged hybrid bis(triethoxysilyl)ethylene (BTSEY) monolith with C8 functional groups (C8@BTSEY) for highly effective protein separation and coupled it to high-resolution MS for identification of intact proteins from complex protein mixtures. We have optimized mobile phase conditions of our monolith-based reverse-phase chromatography (RPC) for online liquid chromatography (LC)-MS analysis and evaluated separation reproducibility of the C8@BTSEY column. We further assessed the chromatographic performance of this column by separating a complex protein mixture extracted from swine heart tissue. Using our monolithic column (i.d. 100 μm × 35 cm), we separated over 300 proteoforms (up to 104 kDa) from 360 ng of protein mixture in an 80 min one-dimensional (1D) LC run. The highly effective separation and recovery of intact proteins from this monolithic column allowed unambiguous identification of ∼100 proteoforms including a large protein, αactinin2 (103.77 kDa), by online 1D LC-MS/MS analysis for the first time. As demonstrated, this C8@BTSEY column is reproducible and effective in separation of intact proteins, which shows high promise for top-down proteomics.


The Procedural and Clinical Outcomes of Rotational Atherectomy in Patients Presenting With Acute Myocardial Infarction.
Rotational atherectomy (RA) is an indispensable tool used for calcified lesion preparation in percutaneous coronary intervention (PCI). However, use of RA in the setting of acute myocardial infarction (AMI) is challenged with limited clinical data. This study aims to retrospectively investigate the procedural results, periprocedural complications, and clinical outcomes of RA in patients with AMI. All possible consecutive patients who received RA in AMI from January 2009 to March 2018 in a single tertiary center were analyzed retrospectively. Patients without AMI during the study period were also enrolled for comparison. A total of 121 patients with AMI (76.0 ± 10.8 years, 63.6% males) and 290 patients without AMI were recruited. Among the AMI group, 81% of patients had non-ST-elevation myocardial infarction (NSTEMI) and 14% presented with cardiogenic shock. RA could be completed in 98.8% of patients in the AMI group and 98.3% in the non-AMI group (p = 1.00). The periprocedural complication rates were comparable between the AMI and non-AMI groups. The risks of in-hospital, 30-day, 90-day, and 1-year cardiovascular major adverse cardiac events (CV MACE) were significantly higher in the AMI group compared with the non-AMI group (in-hospital 13.2 vs. 2.8%, p < 0.001; 30-day 14.2 vs. 4.5%, p < 0.001; 90-day 20.8 vs. 6.9%, p < 0.001; 1-year 30.8 vs. 19.1%, p = 0.01). AMI at initial presentation and cardiogenic shock were predictors for both in-hospital CV MACE and 1-year CV MACE in multivariable binary logistic regression analysis. Other predictors for 1-year CV MACE included serum creatinine level and triple vessel disease. RA in patients with AMI is feasible with a high procedural completion rate and acceptable periprocedural complications. Given unstable hemodynamics and complex coronary anatomy, the in-hospital and 1-year MACE rates remained higher in patients with AMI compared with patients without AMI.


Ozone degradation of residual carbon in biological samples using microwave irradiation.
In an attempt to produce complete oxidation of a biological matrix, bovine liver, ozone was investigated as an additional, potentially non-contaminating, oxidizing reagent after nitric acid digestion. Experiments were carried out to determine the decomposition efficiency of residual carbon species, primarily o-, m- and p-nitrobenzoic acids (NBAs), using ozone. The NBAs were degraded by purging sample digests with ozone, while heating the solutions with microwave energy at atmospheric pressure. The effects of the degradation temperature and solution pH on the ozonation of NBAs were determined. Solid phase extraction (C18) was used to extract NBAs from the acid digestate solutions prior to HPLC analysis. Reversed phase HPLC was used to determine NBA concentrations in digest solutions. After 2.5 h of purging ozone at 80 degrees C, 33.65 +/- 3.80% o-NBA degradation, 19.39 +/- 1.74% m-NBA degradation, and 26.47 +/- 3.36% p-NBA degradation were obtained.


Prevalence of Hepatitis B Virus, Hepatitis C Virus, and HIV Infections in Hemodialysis Patients at Kano Kidney Center.
Background Hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infections are more prevalent in hemodialysis patients compared to the general population. The objective of this study was to evaluate the prevalence of HBV, HCV, and HIV infections in hemodialysis patients dialyzing regularly at Kano Kidney Center (KKC) in the Eastern Health Cluster of Saudi Arabia in 2022. Methods This retrospective study included all hemodialysis patients who were dialyzed regularly at KKC during 2022. Their electronic medical records were reviewed for the results of HBV, HCV, and HIV along with the patient's demographics, comorbid conditions, and dialysis history. The study was approved and monitored by the Institutional Review Board of Dammam Medical Complex. Results A total of 239 regular hemodialysis patients were included, consisting of 142 males and 97 females (59.41% and 40.59%, respectively), with a mean age of 52.71±15.83 years. Most of the patients were Saudis (156 patients, 65.27%) with the non-Saudi patients being composed mostly of Arabian patients. Nine patients (3.77%) tested positive for hepatitis B surface antigen (HBsAg), the serologic hallmark of HBV infection. Two patients (0.84%) had resolved HBV infections as evidenced by positive hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs). However, the majority (226 patients, 94.56%) were never tested for anti-HBc. Anti-HBs, which can imply long-term immunity against HBV from prior immunizations or infections, were positive in 165 patients (69.04%). A protective anti-HBs level of ≥ 10 IU/L was detected in 158 patients (66.11%) including 104 patients (43.51%) having ≥ 100 IU/L. Eighteen patients (7.53%) had reactive HCV antibodies. Four patients (1.67%) had chronic HCV infection as they had detectable HCV RNA. The remaining 14 patients (5.86%) cleared HCV either spontaneously (seven patients, 2.93%) or by medications (seven patients, 2.93%). HIV screening tests were negative in all 239 patients (100%). HBsAg-positive patients did not have any statistically significant differences from HBsAg-negative patients. On the other hand, the patients who were positive for HCV antibodies were older than the patients who were negative for HCV antibodies (60.66 vs 52.05 years on average, p-value <0.05). They also contained a statistically larger proportion of non-Saudi patients than the patients with no evidence of prior infections (61.11% vs 32.13%, p-value <0.05). Conclusions The study found that the prevalence of HBV and HCV infections among hemodialysis patients in KKC at 3.77% and 1.67%, respectively, is higher than that reported in the general population in Saudi Arabia, with non-Saudis having a higher prevalence rate of HCV infection than Saudis. However, the current prevalence rate is lower compared to the previous studies that were conducted in Saudi Arabia in the first decade of the 21st century, and there were no cases of HIV infections. Nevertheless, a significant proportion of patients had unprotective or negative anti-HBs antibody titers, indicating the need for strict vaccination protocols and monitoring of antibody titers to ensure optimal protection.


Spinel Ferrite Core-Shell Nanostructures by a Versatile Solvothermal Seed-Mediated Growth Approach and Study of Their Nanointerfaces.
An easy, low-cost, repeatable seed-mediated growth approach in solvothermal condition has been proposed to synthesize bimagnetic spinel ferrite core-shell heterostructures in the 10-20 nm particle size range. Cobalt ferrite and manganese ferrite nanoparticles (CoFe2O4 and MnFe2O4) have been coated with isostructural spinel ferrites like maghemite/magnetite, MnFe2O4, and CoFe2O4 with similar cell parameters to create different heterostructures. The conventional study of the structure, morphology, and composition has been combined with advanced techniques in order to achieve details on the interface at the nanoscale level. Clear evidence of the heterostructure formation have been obtained (i) indirectly by comparing the 57Fe Mössbauer spectra of the core-shell samples and an ad hoc mechanical mixture and (ii) directly by mapping the nanoparticles' chemical composition by electron energy loss spectroscopy (EELS) and energy-dispersive X-ray spectroscopy (EDX) in the scanning transmission electron microscopy mode (STEM). In addition, chemical-sensitive electron tomography in STEM-EDX mode has been applied in order to obtain detailed 3D images with a sub-nanometer spatial resolution.


The role of external fixators in paediatric trauma.
We report a retrospective review of all paediatric trauma patients managed with an external fixator admitted to our institution over a 7-year period. We identified 30 fractures in 28 children. The fractures included 20 tibiae, 5 femurs, 2 humerii, 2 radii and 1 phalanx. The indications were 23 open fractures, 4 comminuted fractures and 3 closed fractures in poly-traumatised patients. It was the definitive treatment in 13 fractures. The mean length of total time with an external fixator was 9.6 weeks (range 1-38 weeks.) Difficulties encountered were eight problems, one obstacle and two true complications. There were no cases of re-fracture following removal of the external fixator. This review confirms that there is a role for the use of external fixation in selected paediatric fractures with a low complication rate.


Early reperfusion strategy improves the outcomes of surgery for type A acute aortic dissection with malperfusion.
The control of malperfusion is the key to improving the outcomes of surgery for type A acute aortic dissection. We revised our treatment strategy to reperfuse each ischemic organ before central repair. Our current early reperfusion strategy consists of percutaneous coronary artery intervention for coronary malperfusion, direct surgical fenestration for carotid artery occlusion, active perfusion of the superior mesenteric artery for visceral malperfusion, and external shunting from the brachial artery to the femoral artery for lower limb ischemia. Central repair is performed without delay after reperfusion therapy, but if irreversible organ damage is recognized, further aggressive treatment is discontinued. Among 438 patients who underwent initial treatment for type A acute aortic dissection, malperfusion in one or more organs was diagnosed in 108 patients (24%). We applied an early reperfusion strategy in 33 patients, (coronary, 14 patients; carotid, 4; visceral, 7; lower extremity, 8). Central repair was then performed in 28 patients. One patient (3.6%) died of pneumonia; 27 patients overcame the ischemic organ damage and survived. Among the 108 patients with malperfusion, 10 patients (9.3%) were treated medically without early reperfusion and central repair. During the same period, mortality from central repair procedures in patients with malperfusion who had not received early reperfusion therapy was 12 of 65 (18%), and the mortality of patients without malperfusion was 9 of 262 (3.4%). Malperfusion was a serious risk factor for hospital death, but the mortality rate of the patients with an early reperfusion strategy was significantly (P < .01) lower than the patients without early reperfusion. Our strategy might improve the outcomes of surgery for type A acute aortic dissection with malperfusion. This strategy enables us to avoid unproductive central repair procedures in irreversibly damaged patients.


Driven transport on open filaments with interfilament switching processes.
We study a two-filament driven lattice gas model with oppositely directed species of particles moving on two parallel filaments with filament-switching processes and particle inflow and outflow at filament ends. The filament-switching process is correlated with the occupation number of the adjacent site such that particles switch filaments with finite probability only when oppositely directed particles meet on the same filament. This model mimics some of the coarse-grained features observed in context of microtubule-(MT) based intracellular transport, wherein cellular cargo loaded and off-loaded at filament ends are transported on multiple parallel MT filaments and can switch between the parallel microtubule filaments. We focus on a regime where the filaments are weakly coupled, such that filament-switching rate of particles scale inversely as the length of the filament. We find that the interplay of (off-) loading processes at the boundaries and the filament-switching process of particles leads to some distinctive features of the system. These features includes occurrence of a variety of phases in the system with inhomogeneous density profiles including localized density shocks, density difference across the filaments, and bidirectional current flows in the system. We analyze the system by developing a mean field (MF) theory and comparing the results obtained from the MF theory with the Monte Carlo (MC) simulations of the dynamics of the system. We find that the steady-state density and current profiles of particles and the phase diagram obtained within the MF picture matches quite well with MC simulation results. These findings maybe useful for studying multifilament intracellular transport.


[The risk of bladder cancer in patients with prostatic hyperplasia and strategies to manage this combination].
The combination of bladder cancer with benign prostatic hyperplasia (BPH) occurs in 5-27% of cases. The link between these diseases has not yet been closely investigated. The main role in the pathogenesis of bladder cancer combined with BPH is played by the residual urine and prolonged exposure of urothelium to the urine carcinogens. The choice of surgical treatment modality for the combination of non-muscle invasive bladder cancer and BPH is still a matter of debate. There is no consensus on the safety and appropriateness of simultaneous transurethral resection of the bladder and prostate in these patients. On one hand, opponents of simultaneous surgery suggest sustained exposure to carcinogens and the spread of tumor cells in a transurethral resection through the prostate wound surface in the blood and lymphatic vessels. On the other hand, supporters refer to studies and meta-analyzes showing that the simultaneous resection neither increases the recurrence rate of bladder cancer nor causes metastasis and tumor progression.


Biorevitalizing effect of a novel facial serum containing apple stem cell extract, pro-collagen lipopeptide, creatine, and urea on skin aging signs.
Epithelial regeneration in skin is achieved by the constant turnover and differentiation of keratinocytes. Epidermal and dermal stem cells compartments are fundamental for the continuous renewal of the skin. Adult stem cells are the unique source for skin tissue renewal. Plants have stem cells and plant derived stem cell extracts are now used in topical products for their potential anti-ageing and anti-wrinkle effects. A new dermocosmetic product containing apple stem cell extract, urea, creatine and palmitoyl tripeptide-38 (Ureadin Fusion Serum Lift Antiarrugas, ISDIN S.A), has been recently developed to target different aspects involved in skin aging. To assess in vitro the effects of this new serum on the metabolic functions of human senescent fibroblasts and in vivo the anti-aging effects by clinical and instrumental evaluation. We evaluated the effects of the serum on the mitochondrial ROS (reactive oxygen species) production in human senescent cultured fibroblasts measured at 0.1% and 1% using the Mitoread AntiOx mtROS method. In addition we evaluated the anti-ageing in vivo effect of this new serum applied on the face twice daily for 28 consecutive days and assessed by clinical and instrumental evaluation in 32 women with sensitive skin bearing wrinkles on crow's feet. The tested serum both at 0.1% and 1% induces a significant increase in 02 consumption, cellular ATP level and a reduction in extra-cellular lactate concentration. The product reduces also significantly the mitochondrial ROS production. The clinical study shows a relevant anti-wrinkle effect in 71% of the treated women with visible effects in 68% of the subjects as soon as 7 days of treatment. A significant increase in dermal density and skin elasticity was also observed. The use of this novel anti-aging serum demonstrated a significant improvement of aging skin signs with first visible results achieved after one week of use. The product seemed to optimize the metabolic functions in human senescent cultured fibroblast restoring a more efficient cell metabolism therefore contributing to the anti-aging properties of the product.


Nutritional factors determine germ tube formation in Candida albicans.
Following a short (3 h) period of carbon starvation, exponential phase yeast cells of Candida albicans rapidly (T50 45 min) formed germ tubes in a glucose/ammonium ion solution. The presence of both a sugar (glucose, sucrose or galactose) and a nitrogen source (ammonium ion or an amino acid metabolized via glutamate) was critical for morphogenesis.


Pneumothorax as an Adverse Event in Patients with Lung Metastasis of Soft Tissue Sarcoma under Eribulin Treatment.
Pneumothorax has been reported as a pazopanib-associated adverse event in patients with lung metastases of soft tissue sarcoma (STS). However, pneumothorax triggered by eribulin treatment has never been reported. We herein report two cases of spontaneous pneumothorax in patients with STS treated with eribulin. Both patients experienced pneumothorax accompanied by sudden dyspnea on day 9 or 10 of eribulin treatment. These two cases suggest that spontaneous pneumothorax may occur as an adverse event of eribulin treatment in such patients. We should therefore be alert for the potential development of pneumothorax during eribulin treatment of patients with STS and lung metastases.


APOA-1 is a novel marker of erythroid cell maturation from hematopoietic stem cells in mice and humans.
The mechanism that regulates the terminal maturation of hematopoietic stem cells into erythroid cells is poorly understood. Therefore, identifying genes and surface markers that are restricted to specific stages of erythroid maturation will further our understanding of erythropoiesis. To identify genes expressed at discrete stages of erythroid development, we screened for genes that contributed to the proliferation and maturation of erythropoietin (EPO)-dependent UT-7/EPO cells. After transducing erythroid cells with a human fetal liver (FL)-derived lentiviral cDNA library and culturing the cells in the absence of EPO, we identified 17 candidate genes that supported erythroid colony formation. In addition, the mouse homologues of these candidate genes were identified and their expression was examined in E12.5 erythroid populations by qRT-PCR. The expression of candidate erythroid marker was also assessed at the protein level by immunohistochemistry and ELISA. Our study demonstrated that expression of the Apoa-1 gene, an apolipoprotein family member, significantly increased as hematopoietic stem cells differentiated into mature erythroid cells in the mouse FL. The Apoa-1 protein was more abundant in mature erythroid cells than hematopoietic stem and progenitor cells in the mouse FL by ELISA. Moreover, APOA-1 gene expression was detected in mature erythroid cells from human peripheral blood. We conclude that APOA-1 is a novel marker of the terminal erythroid maturation of hematopoietic stem cells in both mice and humans.


Betulinic acid induces DNA damage and apoptosis in SiHa cells.
Betulinic acid (BA) is a naturally occurring terpenoid found principally in the bark of birch trees as well as in numerous other plants. BA is reported to inhibit cancer progression and induce apoptosis in multiple tumor types. In the present study we have investigated the cytotoxicity and potential genotoxicity of BA in SiHa cells. The cell viability was measured by using MTT assay and the morphological changes, DNA damage, changes in cell cycle and mitochondrial membrane potential (MMP) were used for the assessment of apoptosis. BA was shown to destroy SiHa cells preferentially in a concentration dependent manner with a 50% inhibition of the cells at 39.83 μg/ml. The growth inhibition of the cells by BA was coupled with DNA strand breaks, morphological changes, disruption of MMP, reactive oxygen species (ROS) generation and the cell arrest at G0/G1 stage of cell cycle. BA induced apoptosis in SiHa cells was confirmed by positive Annexin V FITC-PI staining. Our results indicate that BA effectively induced DNA damage and apoptosis in SiHa cells. The mechanism of apoptosis was caspase independent and through mitochondrial pathways.


Vertically polarizing undulator with the dynamic compensation of magnetic forces for the next generation of light sources.
A short prototype (847-mm-long) of an Insertion Device (ID) with the dynamic compensation of ID magnetic forces has been designed, built, and tested at the Advanced Photon Source (APS) of the Argonne National Laboratory. The ID magnetic forces were compensated by the set of conical springs placed along the ID strongback. Well-controlled exponential characteristics of conical springs permitted a very close fit to the ID magnetic forces. Several effects related to the imperfections of actual springs, their mounting and tuning, and how these factors affect the prototype performance has been studied. Finally, series of tests to determine the accuracy and reproducibility of the ID magnetic gap settings have been carried out. Based on the magnetic measurements of the ID Beff, it has been demonstrated that the magnetic gaps within an operating range were controlled accurately and reproducibly within ±1 μm. Successful tests of this ID prototype led to the design of a 3-m long device based on the same concept. The 3-m long prototype is currently under construction. It represents R&D efforts by the APS toward APS Upgrade Project goals as well as the future generation of IDs for the Linac Coherent Light Source (LCLS).


Mechanisms of Change in Treatments of Personality Disorders: Commentary on the Special Section.
Personality disorders (PDs) come in a large variety of presentations, severely affect the individual's social and emotional functioning, and are notoriously complex to treat. To make treatments for individuals with PDs more potent, there is a need to better understand how and why these treatments work. The articles assembled for this special section propose potential mechanisms of change within PD patients that may be addressed in future process-outcome research. Although the studies are exploratory and were limited by their scope and heterogeneity of their samples, they illustrate the importance of process research as nomothetic and idiographic building blocks toward a multifaceted understanding of change processes in PDs and their treatment. In this discussion, the authors aim to foster interest in the potential mechanisms of change in PD treatments and inspire further research by providing several methodological considerations for future process-outcome research and its potential clinical implications.


Niche overlap and Hopfield-like interactions in generalized random Lotka-Volterra systems.
We study communities emerging from generalized random Lotka-Volterra dynamics with a large number of species with interactions determined by the degree of niche overlap. Each species is endowed with a number of traits, and competition between pairs of species increases with their similarity in trait space. This leads to a model with random Hopfield-like interactions. We use tools from the theory of disordered systems, notably dynamic mean-field theory, to characterize the statistics of the resulting communities at stable fixed points and determine analytically when stability breaks down. Two distinct types of transition are identified in this way, both marked by diverging abundances but differing in the behavior of the integrated response function. At fixed points only a fraction of the initial pool of species survives. We numerically study the eigenvalue spectra of the interaction matrix between extant species. We find evidence that the two types of dynamical transition are, respectively, associated with the bulk spectrum or an outlier eigenvalue crossing into the right half of the complex plane.


The evolution of gene expression, structure and function of transthyretin.
Thyroxine, the most abundant thyroid hormone in blood, partitions into lipid membranes. In a network-like system, thyroxine-binding plasma proteins counteract this partitioning and establish intravascular, protein-bound thyroxine pools. These are far larger than the free thyroxine pools. In larger eutherians, proteins specifically binding thyroxine are albumin, transthyretin, and thyroxine-binding globulin. Some binding of thyroxine can also occur to lipoproteins. During evolution, transthyretin synthesis first appeared in the choroid plexus of the stem reptiles, about 300 million years ago. Transthretin synthesis in the liver evolved much later, independently, in birds, eutherians and some marsupial species. Analysis of 57 human transthyretin variants suggests that most mutations in transthyretin are not compatible with its normal metabolism and lead to its deposition as amyloid. Analysis of transthyretin or its gene in 20 different species shows that evolutionary changes of transthyretin predominantly occurred near the N-termini. A change in RNA splicing between exon 1 and exon 2 led to a decrease in hydrophobicity and length of the N-termini. It is proposed that the selection pressure producing these changes was the need for a more effective prevention of thyroxine partitioning into lipids. Lipid pools increased during evolution with the increases in relative sizes of brains and internal organs and changes in lipid composition of membranes in ectothermic and endothermic species.


Abstinence duration modulates striatal functioning during monetary reward processing in cocaine patients.
Pre-clinical and clinical studies in cocaine addiction highlight alterations in the striatal dopaminergic reward system that subserve maintenance of cocaine use. Using an instrumental conditioning paradigm with monetary reinforcement, we studied striatal functional alterations in long-term abstinent cocaine-dependent patients and striatal functioning as a function of abstinence and treatment duration. Eighteen patients and 20 controls underwent functional magnetic resonance imaging during a Monetary Incentive Delay task. Region of interest analyses based on masks of the dorsal and ventral striatum were conducted to test between-group differences and the functional effects in the cocaine group of time (in months) with no more than two lapses from the first time patients visited the clinical service to seek treatment at the scanning time (duration of treatment), and the functional effects of the number of months with no lapses or relapses at the scanning session time (length of abstinence). We applied a voxel-wise and a cluster-wise FWE-corrected level (pFWE) at a threshold of P < 0.05. The patient group showed lower activation in the right caudate during reward anticipation than the control group. The regression analyses in the patients group revealed a positive correlation between duration of treatment and brain activity in the left caudate during reward anticipation. Likewise, length of abstinence negatively correlated with brain activity in the bilateral nucleus accumbens during monetary outcome processing. In conclusion, caudate and nucleus accumbens show a different brain response pattern to non-drug rewards during cocaine addiction, which can be modulated by treatment success.


[Quality of life in patients with hip bone fractures].
The aim of the study was to evaluate quality of life in patients who received surgical treatment of hip fracture. Fifty patients (mean age: 77,5) including 37 women and 13 men participated in the study. All patients filled in a questionnaire constructed specially for the study. Patients were investigated three times: first time during hospitalization after surgery, second time within one month, and the last time after one year since surgery. Patients were not diagnosed as osteoporotic, before fracture had occurred. The diagnosis of osteoporosis was done on the basis of risk factors analysis and occurrence of low-energy fracture. Eight percent of patients assesed their economical status as very good before the hip fracture has occurred. There were no such assessments after the hip fracture. Before hip fracture 28% of patients' assessed their economical status as low, after hip fracture there were 50% of low economical status assessments. Twenty two percent of patients need continuous care after one year since hip fracture in comparison to 16% of patients before hip fracture. Twenty eight percent of patients who suffered from hip fracture assessed their health condition as bad, in comparison to 16% of such assessments before hip fracture. Eight percent of patients stated that their quality of life is low, in comparison to 40% of such assessments after one year since hip fracture. All patients declared that pain ailments increased during last year. Mortality rate in investigated group, despite immediate treatment, was 40%. In investigated group 40% of patients died within one year since hip fracture, despite immediate treatment. In group of patients who died within one year 54% assessed their quality of life as low. Quality of life assessment is important indicator of overall health condition and treatment efficiency.


Association between community-level social trust and the risk of dementia: A retrospective cohort study in the Republic of Korea.
It is known that biological risk factors and lifestyle behaviors are important determinants of dementia. However, there has been yet to be sufficient evidence to prove that community-level social capital is one of the determinants of dementia. This retrospective cohort study is a large, long-term, population-based study that investigated the association between community-level social trust and the risk of dementia in the Republic of Korea. Data came from the Korean National Health Insurance Service database. The community-level social trust values were determined by the Korean Community Health Survey. The study population consisted of 1,974,944 participants over 50 years of age and was followed up from 1 January 2012 to 31 December 2019 with a latent period of 5 years from 1 January 2012 to 31 December 2016. Cox proportional hazards regression was utilized to obtain the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the risk of dementia according to social trust quintiles. Participants within the highest quintile of community-level social trust had a lower risk for overall dementia (aHR, 0.90; 95% CI, 0.86-0.94) and Alzheimer's disease (aHR, 0.90; 95% CI, 0.85-0.94) compared to those within the lowest quintile of community-level social trust. The alleviating trend association of high community-level social trust on dementia risk was maintained regardless of whether the participants had health examinations. Our findings suggest that higher community-level social trust is associated with a reduced risk of dementia. Community-level social trust is a crucial indicator of dementia and improving community-level social trust may lead to a lower risk of dementia.


Congenital mirror movement: report of a case.
We report the case of a 27-year-old woman who has had mirror movements in both hands since childhood. These synkinetic involuntary movements impair her performance in bimanual activities such as buttoning clothes, tying shoes, and washing dishes. Cranial magnetic resonance imaging disclosed only mild diffuse cortical atrophy. Although congenital mirror movements have been well-documented in the English literature, we herein report the first case of a Chinese patient in Taiwan.


Rapid increases in glial fibrillary acidic protein mRNA and protein levels in the copper-deficient, brindled mouse.
The brindled mouse (MObr/y) carries an X-linked mutation that produces severe copper deficiency. Affected males suffer profound deficits in oxidative metabolism. We have examined astrocyte pathology in MObr/y during development and have found marked changes in the metabolism of glial fibrillary acidic protein (GFAP). Immunocytochemistry with anti-GFAP antisera revealed a marked increase in staining at postnatal day 12 (P12), compared to heterozygous female and unaffected male littermates, particularly in neocortex and thalamus. Septum, hypothalamus, and striatum showed little change. Western blot analysis revealed increased levels of GFAP in MObr/y forebrain and cerebellum. Levels of GFAP mRNA were determined by Northern blotting with a mouse GFAP cDNA probe. At P10, mRNA levels were normal, but increased to 8-10 times normal by P12. Levels at P15 remained similarly elevated. Thus, immunostaining and protein determinations correlate with mRNA elevations. Astrocytes can alter GFAP mRNA and protein levels over a relatively short time. Counts of neocortical cells did not reveal differences in cell numbers between MObr/y and controls, indicating that the observed changes reflect increased cellular levels and not a large increase in the numbers of astrocytes.


Public thresholds for chlorinous flavors in U.S. tap water.
Considering this rapid growth in the purchasing of bottled water and home filtration devices, utilities are increasingly concerned about consumer dissatisfaction with tap water quality. This project aimed to characterize public perceptions of chlorinous flavors in drinking water, and how these impact customers' choices with respect to consumption of tap water alternatives. On-site taste tests at seven water utilities with 30 to 40 panelists at each site, were conducted using a forced-choice triangle test method (ASTM method E679-91) to measure public sensitivity to chlorine and chloramine in drinking water. The chlor(am)ine concentration increased from set to set. The best-estimate sensitivity limit for each panelist was the geometric mean of that concentration at which the last miss occurred and the next (adjacent) higher concentration. The measured sensitivity limit of average American populations to free chlorine (159 persons tested) and chloramine (93 persons tested) in tap water were 0.8 and 3.7 mg/L Cl2, respectively. These thresholds are much higher than those previously reported in the literature using trained FPA panels. No significant differences were observed between tap water users and users of tap water alternatives or between the various markets tested with respect to average sensitivity, though individual sensitivity varied widely.


In vitro cholinesterase inhibitory activity of some plants used in Iranian traditional medicine.
In this study, in vitro evaluation of cholinesterase inhibitory (ChEI) activity of various plants including betel nuts (Areca catechu L.), clove buds (Syzygium aromaticum L.), aerial parts of dodder (Cuscuta chinensis Lam.), common polypody rhizomes (Polypodium vulgare L.) and turpeth roots (Ipomoea turpethum R. Br.) which were recommended for the treatment of AD symptoms in Iranian Traditional Medicine (ITM) is reported. Among them, aqueous extract of A. catechu L. was found as the most potent anti-AChE (IC50 = 32.00 μg/mL) and anti-BChE (IC50 = 48.81 ± 0.1200 μg/mL) agent.


An improved remora optimization algorithm with autonomous foraging mechanism for global optimization problems.
The remora optimization algorithm (ROA) is a newly proposed metaheuristic algorithm for solving global optimization problems. In ROA, each search agent searches new space according to the position of host, which makes the algorithm suffer from the drawbacks of slow convergence rate, poor solution accuracy, and local optima for some optimization problems. To tackle these problems, this study proposes an improved ROA (IROA) by introducing a new mechanism named autonomous foraging mechanism (AFM), which is inspired from the fact that remora can also find food on its own. In AFM, each remora has a small chance to search food randomly or according to the current food position. Thus the AFM can effectively expand the search space and improve the accuracy of the solution. To substantiate the efficacy of the proposed IROA, twenty-three classical benchmark functions and ten latest CEC 2021 test functions with various types and dimensions were employed to test the performance of IROA. Compared with seven metaheuristic and six modified algorithms, the results of test functions show that the IROA has superior performance in solving these optimization problems. Moreover, the results of five representative engineering design optimization problems also reveal that the IROA has the capability to obtain the optimal results for real-world optimization problems. To sum up, these test results confirm the effectiveness of the proposed mechanism.


Preemptive Therapy for Cryptococcal Meningitis: A Valid Strategy for Latin America?
AIDS-related cryptococcal meningitis continues to cause a substantial burden of death in low and middle income countries. Better diagnostics allow detection of cryptococcosis in the asymptomatic phase and using these technologies to screen at-risk persons would likely reduce mortality. The World Health Organization recommends cryptococcal antigen screening among populations with a prevalence of cryptococcal antigenaemia (CRAG) > 3%. There is scarce data about CRAG prevalence in Latin America. Four studies (only one published as a full text) showed asymptomatic CRAG prevalence between 2.7% and 6.2% in several sub-sets of HIV-infected patients. The CRAG lateral flow assay (LFA) has several advantages over other techniques for actual implementation of a screening program. Although more studies are necessary to confirm available data, implementation of the CRAG screening strategy seems to be opportune in Latin America.


Use of genetic data, employment and insurance: an international perspective.
In this paper, I will say first of all a few words on what is novel in the potential exclusionary use of genetic information in the domains of work or insurance and to what extent legal protection specifically relating to genetic discrimination may be justified. Subsequently, I will briefly examine some of the proposed restrictions on the collection of genetic information for purposes of selection and the scope for international consensus on the issue; in doing so, I will deal separately with employment and private insurance. Finally, I will raise the question whether these issues require international handling and which international steps could be envisaged.


Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension.
Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) highly express the transcription factor hypoxia-inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we used a gain-of-function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared with PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia, there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared with SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic pulmonary arterial hypertension (IPAH). These findings highlight an SM22α-expressing cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.NEW & NOTEWORTHY In a mouse model wherein hypoxia-inducible factor 1 alpha (HIF-1α) is stabilized in vascular smooth muscle cells, we found that HIF-1α regulates vasoconstriction by limiting phosphorylation of myosin light chain and regulates vascular remodeling through p27 induction. These findings highlight a cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling.


Novel method of primary endoscopic realignment for high-grade posterior urethral injuries: A case report.
A male urethral disruption injury is a urological emergency. Primary endoscopic realignment (PER) refers to reestablishment of urethral alignment via indwelling urethral catheter by cystoscope, which is recommended as the optimal emergent treatment approach for reducing the likelihood of complications following injury. However, the prior literature suggests the success rate of PER to be relatively low due to complicated urethral disruption. We report a modified PER approach that serves to improve both the success rate and safety of the treatment. A 19-year-old male patient presented with multiple pelvic fractures and complete urethral disruption following a high-velocity traffic accident. The patient's abdominal computed tomography and retrograde urethrography results revealed complete urethral disruption at the bulbar urethra, with hematoma and contrast medium extravasation that extended into the extraperitoneal space. The conventional retrograde PER by cystoscope failed due to severe disruption and considerable hematoma. Modified simultaneous antegrade and retrograde PER was performed by means of semi-rigid ureteroscopy via a suprapubic Foley catheter and cystoscopy via the external urethra. An antegrade guidewire was passed through the bladder neck and then pulled out through the external urethral meatus with a cystoscope. Urethral continuity was achieved after a 16-Fr silicone Foley catheter was indwelled into the bladder along the guidewire. The patient recovered well, achieving voiding continence and avoiding further operation for urethral stricture. Modified PER via suprapubic Foley catheter represents a promising and safe treatment approach in patients with posterior urethral injuries.


[Sensitivity of corynebacterium diphtheriae strains to antibacterial preparations].
Study the prevalence and mechanisms of resistance in circulating C. diphtheriae strains. 664 C. diphtheriae strains isolated in 1987 - 2013 in various regions of Russia and sent to the reference center of Gabrichevsky Moscow Research Institute of Epidemiology and Microbiology were the object of the study. Antibiotic sensitivity of the strains was studied by disk-diffusion and E-test methods using 10 antimicrobial preparations. Nucleotide sequence analysis was carried out by using BLAST program and EMBL/GenBank database. Most of the studied strains turned out to be sensitive to all the antibacterial preparations used. 1.2% of C. diphtheriae strains turned out to be resistant to penicillin and 6.0% had intermediate level of resistance. 0.4 - 0.6% of the strains had intermediate level of resistance to macrolides, and 4.0 - 4.4% were resistant. 2.0% of the strains had multiple resistance. Erm(X)-specific PCR carried out in this study showed that all the C. diphtheriae strains resistant to macrolide antibiotics carry erm(X) gene. The results of the study indicate a fairly high level of prevalence for C. diphtheriae strains resistant to antibiotics.


Mobile Apps in Radiology.
Medical applications are being created in imaging with the goal that radiologists will be able to use them to interpret patient images. Mobile devices, such as the iPad, are able to display radiologic images in such a way that radiologists are able to use them successfully. The alternative approach of using mobile devices for viewing and making a diagnosis could prove to be immensely helpful in emergency situations where no workstations are available. The use of mobile devices would not replace workstations for radiologists, but rather it would advance their ability to expedite dictations for more effective patient care.


Tuberculosis of the large bowel. Report of two cases.
Two patients with primary tuberculosis of the ileocecal region and transverse colon were thought to be Crohn's disease or carcinoma of the colon. No pathognomonic symptoms or roentgenographic findings were present, and the diagnosis was made on the basis of histopathological features including the presence of alcohol/acid fast bacilli. In one case human tubercle bacilli were cultured. The involved bowel segments were resected and the patients received antituberculous chemotherapy postoperatively. Although tuberculosis of the colon is very rare it should however be considered in cases of vague bowel dysfunction.


CXCR4 chemokine receptors, histone deacetylase inhibitors and acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. The mechanism for selective homing of ALL cells to preferential sites has long been unclear. Recent reports indicate that the chemokine receptor CXCR4 is found on ALL cells and its ligand is highly expressed at sites associated with ALL-induced organ infiltration. This results in chemotaxis, or directed migration of leukemic cells from the bone marrow via the circulation to preferential sites of extramedullary organ infiltration. Because overexpression of CXCR4 on ALL cells is associated with high extramedullary organ infiltration and shorter disease-free survival, numerous pharmacological agents affecting CXCR4 have currently been investigated. The most promising data are available for histone deacetylase inhibitors (HDAIs), which have been shown to be safe and well tolerated in phase I clinical trials. In vitro, HDAIs extensively down-regulate CXCR4 protein and mRNA levels. As a result, the ability of CXCR4 ligand to induce cellular migration is impaired. Wider recognition of the role of CXCR4 in ALL and manipulation of this important mechanism may lead to novel approaches in the treatment and outcome of this disease.


Vitamin E in the genesis and prevention of cancer. A review.
A review of current literature reveals that the relationships between vitamin E and cancer is not yet fully understood though many experimental and clinical studies have shown that vitamin E can protect against carcinogenesis and tumour growth. This vitamin also appears to reduce toxicity of several anticancer therapies. Such effects are probably due to the antioxidant property and immunomodulatory function of vitamin E. The findings of different groups suggest that this vitamin may be helpful as a cancer chemopreventive agent.