Role for macrophage inflammatory protein-2 in lipopolysaccharide-induced lung injury in rats.
Macrophage inflammatory protein-2 (MIP-2) is a C-X-C chemokine that possesses chemotactic activity for neutrophils. Rat MIP-2 was cloned and expressed as a 7.9-kDa peptide that exhibited dose-dependent neutrophil chemotactic activity at concentrations from 10 to 250 nM. Rabbit polyclonal Ab to the 7.9-kDa peptide showed reactivity by western blot analysis and suppressed its in vitro chemotactic activity. Cross-desensitization chemotaxis experiments suggested that the chemotactic responses elicited by MIP-2 and the related chemokine, cytokine-induced neutrophil chemoattractant, may be mediated through a common receptor. Also, chemotactic responses to human GRO-alpha were blocked by exposure of human neutrophils to either GRO-alpha or rat MIP-2, suggesting conservation of this receptor-mediated response. After LPS instillation into rat lung, mRNA for MIP-2 was up-regulated in a time-dependent manner, peaking at 6 h. MIP-2 protein was detected in bronchoalveolar lavage fluids of these animals and a significant amount of chemotactic activity present in these fluids was attributed to MIP-2. On the basis of intrapulmonary instillation of Ab to MIP-2, neutrophil accumulation in lungs after airway instillation of LPS was found to be MIP-2-dependent. These data indicate that MIP-2 plays a significant role in LPS-induced inflammatory response in rat lungs and is required for the full recruitment of neutrophils.


Optimizing the inhalation flow and technique through metered dose inhalers of asthmatic adults and children attending a community pharmacy.
Despite training, many patients continue to misuse their metered dose inhaler (MDI). Research Ethics Committee approval was obtained to evaluate two different methods to help patients use a slow inhalation flow when they use their MDI. Asthmatic children (n = 17) and adults (n = 39) prescribed an MDI had their inhaler technique assessed. Those who achieved the recommended inhalation flow rate (IFR) of <90 l/min through their MDI formed the reference group (named (control--CT)). Others that had a poor inhaler technique with an IFR ≥ 90 l/min were randomized into either the verbal counseling (VC) group, who received verbal training on the correct MDI use with emphasis on using a slow IFR or into the 2ToneTrainer (2TT) group, who received the VC and a 2Tone Trainer to take home and use. 2TT is a training aid with audible feedback when the required slow inhalation flow is used. The participants were assessed on two occasions, 0 (baseline) and 6 weeks later. For the asthmatic adults, the median IFR at visit 1 was 68, 200, and 240 l/min for the CT, VC, and 2TT groups, respectively. Whereas on visit 2, the median IFR was 88, 48.5 (p < .001), and 65 (p < .001) l/min for the CT, VC, and 2TT groups, respectively. Improvements in asthma quality of life were achieved in VC and 2TT groups. The asthmatic children showed a similar trend. Training by VC and a training aid helps patients use a slow IFR with an MDI and improves asthma-related quality of life.


Postpartum Follow-up in Women Diagnosed with Subclinical Hypothyroidism during Pregnancy.
Management guidelines about the thyroid disease in pregnancy are silent about the postpartum course of new onset subclinical hypothyroidism (SCH). Hence, we analyzed the 2 years outcome of SCH diagnosed during pregnancy. We conducted this retrospective study using the medical records of patients with new onset SCH during pregnancy between 2010 and 2013 (n = 718). Patients who stopped their levothyroxine after delivery with a 2-year follow-up record were included. We excluded patients with known thyroid disorders and continuous use of drugs that affect the thyroid results. The patients were divided into two groups (Group 1 - euthyroid and Group 2 - hypothyroid) based on the final outcome after 2 years. The data were analyzed using appropriate statistical methods and a P < 0.05 was considered statically significant. A total of 559 (77.8%) women stopped levothyroxine after delivery, and the final follow-up data were available for 467 patients only. At the end of 2 years, 384 (82.2%) remained euthyroid, and the remaining 83 (17.8%) developed hypothyroidism. SCH and overt hypothyroidism were seen in 22 and 61 patients, respectively. Group 2 patients had higher mean age (25.5 vs. 23.6 years), goiter (51 vs. 2%), initial thyroid stimulating hormone (7.9 vs. 5.1 μIU/mL), and thyroid antibody positivity (76 vs. 13%) (P < 0.001). The majority of patients with SCH during pregnancy remain euthyroid after delivery. Advanced age, goiter, positive family history, and thyroid autoimmunity increase the future risk of hypothyroidism in patients with SCH diagnosed during pregnancy.


Chronic probable PTSD in police responders in the world trade center health registry ten to eleven years after 9/11.
Police enrolled in the World Trade Center Health Registry (WTCHR) demonstrated increased probable posttraumatic stress disorder (PTSD) after the terrorist attack of 9/11/2001. Police enrollees without pre-9/11 PTSD were studied. Probable PTSD was assessed by Posttraumatic Stress Check List (PCL). Risk factors for chronic, new onset or resolved PTSD were assessed using multinomial logistic regression. Half of police with probable PTSD in 2003-2007 continued to have probable PTSD in 2011-2012. Women had higher prevalence of PTSD than men (15.5% vs. 10.3%, P = 0.008). Risk factors for chronic PTSD included decreased social support, unemployment, 2+ life stressors in last 12 months, 2+ life-threatening events since 9/11, 2+ injuries during the 9/11 attacks, and unmet mental health needs. Police responders to the WTC attacks continue to bear a high mental health burden. Improved early access to mental health treatment for police exposed to disasters may be needed.


Dietary Diversity, Nutritional Status, and Associated Factors Among Pregnant Women in Their First Trimester of Pregnancy in Ambo District, Western Ethiopia.
Poor dietary diversity and undernutrition is a major public health concern for pregnant mothers. Optimal dietary diversity is essential during pregnancy since nutritional deficiencies may have a significant impact on both the mother's and the fetus's health. Pregnant women in Ambo district had inadequate dietary diversity and were undernourished, but their status during the first trimester of pregnancy was not known. As a result, the objective of this research was to assess the dietary diversity, nutritional status, and associated factors among pregnant women in the Ambo district. A community-based cross-sectional study design and a multi-stage sampling technique were used among 750 pregnant women. Data was gathered using a semi-structured questionnaire. The Food and Nutrition Technical Assistance questionnaire was modified to collect data on dietary diversity. The nutritional status of pregnant women was assessed by measuring the mid-upper arm circumference. First, descriptive statistics like mean, Standard deviation, frequency and percentage were used, then bivariable and, finally, multivariable logistic regression analysis was used to assess the association of the predictors with the outcome variable. The study revealed that 73.6% and 23.9% of pregnant women had low dietary diversity and were undernourished, respectively. Being in food secured household (AOR = 4.44, 95% CI: 2.14-9.15), having good knowledge (AOR = 3.32, 95% CI: 2.10-5.23) and favorable attitude toward nutrition and health (AOR = 1.71, 95% CI: 1.10-2.66) were significantly associated with dietary diversity, whereas household size (having 1-3 household members AOR = 6.59, 95% CI: 2.53-17.21, having 4-5 household members AOR = 5.62, 95% CI: 3.15-9.99), being in food secured household (AOR = 5.64, 95% CI: 2.79-11.38), having high dietary diversity (AOR = 8.49, 95% CI: 2.47-29.23), and having optimal practice on nutrition and health (AOR = 6.85, 95% CI: 3.23-14.55) were significantly associated with undernutrition (P < .05). The current study revealed that pregnant women in the study area had inadequate dietary diversity practices and a high prevalence of undernutrition. Knowledge and attitude, and households' food security status were the predictors of dietary diversity, while household size, household food security status, dietary diversity and nutrition and health practice were predictors of undernutrition. Hence, behavior change communication needs to be designed to improve the dietary diversity and nutritional status of pregnant women.


Anatomical targets and expected outcomes of catheter-based ablation of atrial fibrillation in 2020.
Anatomical-based approaches, targeting either pulmonary vein isolation (PVI) or additional extra PV regions, represent the most commonly used ablation treatments in symptomatic patients with atrial fibrillation (AF) recurrences despite antiarrhythmic drug therapy. PVI remains the main anatomical target during catheter-based AF ablation, with the aid of new technological advances as contact force monitoring to increase safety and effective radiofrequency (RF) lesions. Nowadays, cryoballoon ablation has also achieved the same level of scientific evidence in patients with paroxysmal AF undergoing PVI. In parallel, electrical isolation of extra PV targets has progressively increased, which is associated with a steady increase in complex cases undergoing ablation. Several atrial regions as the left atrial posterior wall, the vein of Marshall, the left atrial appendage, or the coronary sinus have been described in different series as locations potentially involved in AF initiation and maintenance. Targeting these regions may be challenging using conventional point-by-point RF delivery, which has opened new opportunities for coadjuvant alternatives as balloon ablation or selective ethanol injection. Although more extensive ablation may increase intraprocedural AF termination and freedom from arrhythmias during the follow-up, some of the targets to achieve such outcomes are not exempt of potential severe complications. Here, we review and discuss current anatomical approaches and the main ablation technologies to target atrial regions associated with AF initiation and maintenance.


[Anticoagulation therapy and the use of non-vitamin K antagonist oral anticoagulants in the elderly].
Anticoagulation indications do not differ between elderly and younger patients. However due to the changes with ageing some anticoagulants may increase the risk of bleeding. Therefore a dose adjustment might be needed for some anticoagulant drugs. Non-vitamin K antagonists are as safe and effective as vitamin K antagonists in the elderly.


Histopathologic alterations in the decidua in human spontaneous abortion: loss of cells with large cytoplasmic granules.
The histopathology of decidua obtained from the placental bed was evaluated by phloxine-tartrazine staining, which allows clear definition of cells with cytoplasmic granules. Mononuclear cells with large granules were seen in biopsy specimens taken from women at 8-31 weeks of normal pregnancy. In contrast, cells with large granules were missing in sections taken from the decidua of five women who were aborting or were destined to abort. Since the presence of suppressor cell activity in murine decidua correlates with the success of pregnancy and since this suppression is associated with small lymphocytes with cytoplasmic granules, the observations made using human placental bed biopsy material suggest that a possible suppressor cell deficiency might occur in the early stages of spontaneous abortion in human females.


Multiple cellular consequences of isocitrate dehydrogenase isozyme dysfunction.
To probe the functions of multiple forms of isocitrate dehydrogenase in Saccharomyces cerevisiae, mutants lacking three of the isozymes were constructed and analyzed. Results show that, while the mitochondrial NAD+-dependent enzyme, IDH (composed of Idh1p and Idh2p subunits) is not the major contributor to total isocitrate dehydrogenase activity under any growth condition, loss of IDH produces the most dramatic growth phenotypes. These include reduced growth in the absence of glutamate, as well as an increase in expression of Idp2p (the cytosolic NADP+-dependent enzyme) under some growth conditions. In this study, we have focused on another phenotype associated with loss of IDH, an elevated frequency of petite mutations indicating loss of functional mtDNA. Using mutant forms of IDH with altered active site residues, a correlation was observed between the high frequency of petite mutations and the loss of catalytic activity. Loss of Idp1p (the mitochondrial NADP+-dependent enzyme) and Idp2p contributes to the loss of functional mtDNA, but only in an IDH dysfunctional background. Surprisingly, overexpression of Idp1p, but not of Idp2p, was found to result in an elevated petite frequency independent of the functional state of IDH. This is the first phenotype associated with altered Idp1p. Finally, throughout this study we examined effects of loss of mitochondrial citrate synthase (Cit1p) on isocitrate dehydrogenase mutants, since defects in the CIT1 gene were previously shown to enhance growth of IDH dysfunctional strains on nonfermentable carbon sources. Loss of Cit1p was found to suppress the petite phenotype of strains lacking IDH, suggesting that these phenotypes may be linked.


Identification of intracellular factor XIII in human monocytes and macrophages.
Factor XIII is a blood protransglutaminase that is distributed in plasma and platelets. The extracellular and intracellular zymogenic forms differ in that the plasma zymogen contains A and B subunits, while the platelet zymogen has A subunits only. Both zymogens form the same enzyme. Erythrocytes, in contrast, contain a tissue transglutaminase that is distinct from Factor XIII. In this study other bone marrow-derived cells were examined for transglutaminase activity. Criteria that were used to differentiate Factor XIII proteins from erythrocyte transglutaminase included: (a) immunochemical and immunohistochemical identification with monospecific polyclonal and monoclonal antibodies to Factor XIII proteins, (b) requirement for thrombin cleavage to express activity, (c) pattern of fibrin cross-linking catalyzed by the enzyme, and (d) different electrophoretic mobilities in nondenaturing gel systems. By these criteria human peripheral blood monocytes, peritoneal macrophages, and monocytes maintained in culture contain an intracellular protransglutaminase that is the same as platelet Factor XIII. The monocyte-macrophage protein is thrombin-sensitive, and under appropriate conditions there is no enzyme expression without activation of the zymogen. Both the monocyte-macrophage zymogen and enzyme have the same electrophoretic mobilities as platelet Factor XIII zymogen and enzyme. Antibody to A protein reacts with the monocyte-macrophage protein. B protein is not associated with this intracellular zymogen. By immunoperoxidase staining monocyte-macrophage protein seems to be localized in the cytoplasm, similar to the known cytoplasmic distribution of platelet and megakaryocyte Factor XIII. These procedures were also used to study populations of human granulocytes and lymphocytes, and protransglutaminase activity was not observed in these cells.


Increased workload enhances force output during pedaling exercise in persons with poststroke hemiplegia.
A principle of poststroke rehabilitation is that effort should be avoided since it leads to increased spasticity and produces widespread associated abnormal reactions. Although weakness also contributes to movement dysfunction after a stroke, it has been feared that heightened activity levels during strength training will further exacerbate the abnormal tone imbalance present in spastic hemiplegia. The purpose of this study was to test this hypothesis by quantifying the effects of increased workload on motor performance during different speeds of pedaling exercise in persons with poststroke hemiplegia. Twelve healthy elderly subjects and 15 subjects with poststroke hemiplegia of greater than 6 months since onset were tested. The experimental protocol consisted of having subjects pedal at 12 randomly ordered workload and cadence combinations (45-J, 90-J, 135-J, and 180-J workloads at 25, 40, and 55 rpm). Pedal reaction forces were measured and used to calculate work done by each leg, including net positive and negative components. An electromyogram was recorded from seven leg muscles. The main finding was that net mechanical work done by the plegic leg increased as workload increased in 75 of 81 instances without increasing the percentage of inappropriate muscle activity. This study provides evidence that persons with hemiplegia increase force output by their plegic limb when pedaling against higher workloads without exacerbation of impaired motor control. Therefore, exertional pedaling exercise is a beneficial intervention for achieving gains in muscular force output without worsening motor control impairments.


Warm-night temperature alters paternal allocation strategy in a North temperate-zone butterfly.
Warming temperatures are greatly impacting wild organisms across the globe. Some of the negative impacts of climate change can be mitigated behaviorally, for example, by changes in habitat and oviposition site choice. Temperatures are reportedly warming faster at night than during the day, yet studies assessing the impacts of increasing night temperature are rare. We used the Finnish Glanville fritillary butterfly (Melitaea cinxia) as study species and exposed adult butterflies of both sexes to warmer night conditions. Under a seminatural outdoor enclosure, we assessed whether females base their oviposition choices primarily on habitat site characteristics (open, suggestive of dry meadows, versus covered by a coarse canopy, suggestive of pastures) or on plant condition (dry vs. lush), and if their choice is altered by the thermal conditions experienced at night. As exposure to warmer environmental conditions is expected to increase resting metabolic rate and potentially reduce life expectancy, we further assessed the fitness implications of warm-night temperatures. We found that females prefer open sites for oviposition and that females do not switch their oviposition strategy based on the thermal conditions they experienced at night prior to the reproductive event. Exposure to warm nights did not influence female lifespan, but the egg hatching success of their offspring was reduced. In addition, we found that males exposed to warm nights sired larger clutches with higher hatching rate. As warm-night exposure reduced male lifespan, this may imply a switch in male resource allocation strategy toward increased offspring quality. The present work adds on to the complex implications of climate warming and highlights the importance of the often-neglected role of males in shaping offspring performance.


Gorham-Stout syndrome in mainland China: a case series of 67 patients and review of the literature.
Gorham-Stout syndrome (GSS) is a rare disorder of uncertain etiology and unpredictable prognosis. This study aims to present a comprehensive understanding of this rare entity. A literature search in PubMed and three Chinese databases was performed to screen histologically proven GSS cases among Chinese residents in the mainland. We analyzed the patients' clinical characteristics, the value of different treatment modalities and their influence on the clinical outcome. Sixty-seven cases were finally enrolled. There were 43 men (64.2%) and 24 women (35.8%). The mean age at diagnosis was 28 years (1.5-71 years). The most common clinical symptoms included pain (n=40, 59.7%), functional impairment (n=13, 19.4%), and swelling (n=12, 17.9%). The radiographic presentation of 37 cases (55.2%) was disappearance of a portion of the bone. The others presented as radiolucent foci in the intramedullary or subcortical regions. A total of 42 cases provided data on therapy, these included surgery (n=27, 40.3%), radiation therapy (n=6, 9.0%), surgery combined with radiation therapy (n=2, 3.0%), and medicine therapy (n=7, 10.4%). For 30 of these 42 cases, follow-up data were available: 21 cases had the disorder locally controlled and 9 had a symptom progression. Fortunately, the disease is not fatal in the majority of cases. GSS has no specific symptoms and it should be taken into consideration when an unclear massive osteolysis occurs. The efficacies of different treatment modalities are still unpredictable and further research is required to assess the values of different treatments.


Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis.
Transgenic mice expressing the c-Myc oncogene driven by the immunoglobulin heavy chain enhancer (Emu) develop B-cell lymphoma and exhibit a mean survival time of approximately 6 months. The protracted latent period before the onset of frank disease likely reflects the ability of c-Myc to induce a p53-dependent apoptotic program that initially protects animals against tumor formation but is disabled when overtly malignant cells emerge. In cultured primary mouse embryo fibroblasts, c-Myc activates the p19(ARF)-Mdm2-p53 tumor suppressor pathway, enhancing p53-dependent apoptosis but ultimately selecting for surviving immortalized cells that have sustained either p53 mutation or biallelic ARF deletion. Here we report that p53 and ARF also potentiate Myc-induced apoptosis in primary pre-B-cell cultures, and that spontaneous inactivation of the ARF-Mdm2-p53 pathway occurs frequently in tumors arising in Emu-myc transgenic mice. Many Emu-myc lymphomas sustained either p53 (28%) or ARF (24%) loss of function, whereas Mdm2 levels were elevated in others. Its overexpression in some tumors lacking p53 function raises the possibility that Mdm2 can contribute to lymphomagenesis by interacting with other targets. Emu-myc transgenic mice hemizygous for ARF displayed accelerated disease (11-week mean survival), and 80% of these tumors lost the wild-type ARF allele. All ARF-null Emu-myc mice died of lymphoma within a few weeks of birth. About half of the tumors arising in ARF hemizygous or ARF nullizygous Emu-myc transgenic mice also overexpressed Mdm2. Therefore, Myc activation strongly selects for spontaneous inactivation of the ARF-Mdm2-p53 pathway in vivo, cancelling its protective checkpoint function and accelerating progression to malignancy.


The transition from conjugal development to the first vegetative cell division is dependent on RAD51 expression in the ciliate Tetrahymena thermophila.
Rad51p, the eukaryotic homolog of the prokaryotic recA protein, catalyzes strand exchange between single- and double-stranded DNA and is involved in both genetic recombination and double-strand break repair in the ciliate Tetrahymena thermophila. We have previously shown that disruption of the Tetrahymena RAD51 somatic macronuclear locus leads to defective germline micronuclear division and that conjugation of two somatic rad51 null strains results in an early meiotic arrest. We have constructed Tetrahymena strains that are capable of RAD51 expression from their parental macronuclei and are homozygous, rad51 nulls in their germline micronuclei. These rad51 null heterokaryons complete all of the early and middle stages of conjugation, including meiosis, haploid nuclear exchange, zygotic fusion, and the programmed chromosome fragmentations, sequence eliminations, and rDNA amplification that occur during macronuclear development. However, the rad51 null progeny fail to initiate the first vegetative cell division following conjugal development. Coincident with the developmental arrest is a disproportionate amplification of rDNA, despite the maintenance of normal total DNA content in the developing macronuclei. Fusion of arrested rad51 null exconjugants to wild-type cells is sufficient to overcome the arrest. Cells rescued by cytoplasmic fusion continue to divide, eventually recapitulating the micronuclear mitotic defects described previously for rad51 somatic nulls.


Quality of life in patients with neurocysticercosis in Mexico.
The objective of this study was to compare quality of life measures in patients with neurocysticercosis (NCC) to those of a matched control group. The NCC outpatients and their controls were recruited from two neurology referral hospitals in Mexico City, Mexico during 2007-2008. The quality of life of 224 NCC patients was compared with 224 age-sex-hospital-day matched controls using the short form 12 v2 (SF-12 v2) quality of life survey. Medical chart reviews were also conducted for the NCC outpatients to evaluate presenting clinical manifestations. Compared with the controls, NCC patients had a significantly lower score for each of the eight domains of health evaluated and significantly lower Physical and Mental Component Summary scores. Chart reviews indicated that hydrocephalus (48%), severe headaches (47%), and epilepsy (31%) were the most common clinical manifestations in these NCC outpatients.


Effect of air humidity on the egg viability of predatory mites (Acari: Phytoseiidae, Stigmaeidae) common on rubber trees in Brazil.
Rubber pest mites, Calacarus heveae and Tenuipalpus heveae, reach economic damage levels at the end of the rainy season and the beginning of the dry season in Brazil. Therefore, low humidity adaptation might be an important characteristic for predatory mites to successfully control pest organisms. This study determined the effect of the relative humidity (RH) levels of 30-100% on the hatching of larvae of Amblyseius acalyphus, Euseius citrifolius, Iphiseiodes zuluagai, Metaseiulus camelliae, Agistemus floridanus and Zetzellia malvinae at 25 +/- 0.5 degrees C. These predatory mites are common on rubber trees in the state of São Paulo and might be used for introduction in the major rubber tree production regions in the state of Mato Grosso. At 70% RH or higher, viability was 70% or higher for all species, indicating that their performance might be higher during the rainy season than during the dry season. Eggs of E. citrifolius and M. camelliae presented higher viability at the lower relative humidity levels than those of other species, indicating that these species might have higher chance to persist in the dry season. It is suggested that M. camelliae should be further evaluated for introduction in the state of Mato Grosso, considering that this mite is not yet present in that area.


The Role of Poly(Aspartic Acid) in the Precipitation of Calcium Phosphate in Confinement.
Many questions remain regarding the formation of ultrathin hydroxapatite (HAP) crystals within the confines of collagen fibrils of bones. These structures form through the interplay of the collagen matrix and non-collagenous proteins, and in vitro mineralization studies employing poly(aspartic acid) (PAsp) as a mimic of the non-collagenous proteins have generated mineralized fibrils with structures comparable to their biogenic counterparts. In this article, we employ the nanoscale cylindrical pores perforating track-etch filtration membranes to investigate the role of PAsp in controlling the infiltration and crystallization of calcium phosphate (CaP) within confined volumes. Oriented polycrystalline HAP and non-oriented octacalcium phosphate (OCP) rods precipitated within the membrane pores via an amorphous calcium phosphate (ACP) precursor, where PAsp increased the proportion of OCP rods. Further, ACP crystallized faster within the membranes than in bulk solution when PAsp was present, suggesting that PAsp inhibits crystallization in solution, but promotes it when bound to a substrate. Finally, in contrast to the collagen system, PAsp reduced the yield of intra-membrane mineral and failed to enhance infiltration. This suggests that a specific interaction between the collagen matrix and ACP/PAsp precursor particles drives effective infiltration. Thus, while orientation of HAP crystals can be achieved by confinement alone, the chemistry of the collagen matrix is necessary for efficient mineralisation with CaP.


Microhardness evaluations of CAD/CAM ceramics irradiated with CO2 or Nd:YAP laser.
The aim of this study was to measure the microhardness values of irradiated computer-aided design/computer-aided manufacturing (CAD/CAM) ceramics surfaces before and after thermal treatment. Sixty CAD/CAM ceramic discs were prepared and grouped by material, i.e. lithium disilicate ceramic (Emax CAD) and zirconia ceramic (Emax ZirCAD). Laser irradiation at the material surface was performed with a carbon dioxide laser at 5 Watt (W) or 10 W power in continuous mode (CW mode), or with a neodymium:yttrium aluminum perovskite (Nd:YAP) laser at 10 W on graphite and non-graphite surfaces. Vickers hardness was tested at 0.3 kgf for lithium disilicate and 1 kgf for zirconia. Emax CAD irradiated with CO2 at 5 W increased microhardness by 6.32 GPa whereas Emax ZirCAD irradiated with Nd:YAP decreased microhardness by 17.46 GPa. CO2 laser effectively increases the microhardness of lithium disilicate ceramics (Emax CAD).


Practical management of amblyopia.
Our knowledge on the mechanism of amblyopia has gained in recent years from concerted research efforts in basic science and clinical laboratories. Different clinical forms of amblyopia are reviewed and their diagnostic and therapeutic significance discussed. In spite of etiologic differences there are pathophysiological similarities. The value of the time proven constant occlusion treatment of the sound eye remains unchallenged even though minor modifications have become necessary to prevent occlusion amblyopia in infants and young children. Part-time occlusion and penalization are of ancillary value but cannot be considered equal in effectiveness to constant occlusion. Due to increasing public awareness there is a trend toward earlier diagnosis and thus successful treatment of amblyopia. However, more efforts must be directed toward including newborns in visual screening examinations.


Iris Chafing Syndrome Secondary to Iridociliary Adhesions in a Patient with a Single-Piece Acrylic Intraocular Lens: Case Report.
We present a unique case of iris chafing syndrome in a patient with a complex ophthalmologic history after successful placement of a single-piece in-the-bag intraocular lens (IOL) in an eye with healthy zonular support. A patient with a previous history of multiple retinal surgeries presented with pain and elevated intraocular pressure (IOP) secondary to retained viscoelastic material in the anterior chamber. Following removal of the viscoelastic material in clinic, the patient underwent a combined cataract and glaucoma surgery. Subsequently, the patient developed signs and symptoms of iris chafing syndrome. Anterior segment imaging revealed the cause to be iridociliary adhesion causing an elimination of the sulcus space. Iris chafing syndrome was suspected when the patient presented post-operatively with changes in vision and anterior chamber inflammation. New iris transillumination defects present at the edge of the optic and haptic of the 1-piece lens helped confirm the diagnosis of UGH. Upon further investigation with gonioscopy, ultrasound biomicroscopy and anterior segment optical coherence tomography, it was determined that the patient had iridociliary adhesions. These adhesions eliminated the sulcus space, which resulted in iris chafing. The patient opted for conservative medical management. Best-corrected distance visual acuity remained stable at 20/100 and IOP remained well controlled. A complex ocular history of multiple retinal surgeries and retained viscoelastic material in the anterior chamber resulted in adhesions of the ciliary processes to the iris, leading to UGH syndrome in a patient with an otherwise unremarkable placement of a single-piece in-the-bag IOL.


Oral administration of low doses of plant-based HBsAg induced antigen-specific IgAs and IgGs in mice, without increasing levels of regulatory T cells.
Plant-based oral vaccines run the risk of activating regulatory T cells (Tregs) and suppressing the antigen-specific immune response via oral tolerance. Mice humanized for two HLA alleles (HLA-A2.1 and HLA-DR1) were used to measure changes in Tregs and antigen-specific immune responses induced by the oral administration of tobacco (Nicotiana tabacum), expressing the hepatitis B surface antigen (HBsAg). Antigen-specific CD8+ T cell activation was not detected, but the plant-based oral immunization, without adjuvant, resulted in humoral responses comparable to those obtained by adjuvanted DNA immunization. Treg titers did not increase with DNA immunization. In contrast, with plant immunization, Tregs increased linearly to reach a plateau at high antigen doses. The highest humoral IgA and IgG responses correlated with the lowest plant antigen dose (0.5 ng), while for DNA immunization the best antibody responses were obtained at higher antigen doses. These experiments suggest that plant-based oral vaccines could be adjusted to minimize tolerance, while still inducing an immune response. Oral tolerance and adjuvant engineering in plants are discussed.


Research progress of natural products for the treatment of ischemic stroke.
Stroke is a leading cause of death and disability world-widely. The incidence rate of stroke has been increasing due to the aging population and lifestyle changes. At present, the only drug approved by the US Food and Drug Administration (FDA) for the treatment of ischemic stroke is tissue plasminogen activator (t-PA), but its clinical application is greatly limited because of its narrow time window and bleeding risk. Natural products have a long history of being used in traditional medicine with good safety, making them an important resource for the development of new drugs. Indeed, some natural products can target a variety of pathophysiological processes related to stroke, including oxidative stress, inflammation and neuronal apoptosis. Therefore, the development of high-efficiency, low-toxicity, safe and cheap active substances from natural products is of great significance for improving the treatment alternatives of patients with stroke. This article reviews the neuroprotective effects of 33 natural compounds by searching recent related literature. Among them, puerarin, pinocembrin, quercetin, epigallocatechin-3-gallate (EGCG), and resveratrol have great potential in the clinical treatment of ischemic stroke. This review will provide a powerful reference for screening natural compounds with potential clinical application value in ischemic stroke or synthesizing new neuroprotective agents with natural compounds as lead compounds.


Racing performance of Thoroughbreds with superficial digital flexor tendonitis treated with desmotomy of the accessory ligament of the superficial digital flexor tendon: 332 cases (1989-2003).
To assess postoperative probability of racing, career longevity, and convalescent time in Thoroughbred racehorses with moderate to severe superficial digital flexor tendonitis (SDFT) in the forelimbs treated by desmotomy of the accessory ligament of the superficial digital flexor tendon (ie, superior check ligament desmotomy [SCLD]). Retrospective case series. 332 Thoroughbred racehorses with SDFT consecutively treated by means of SCLD. Medical records and racing records were reviewed to assess return to racing, number of races completed, time to first race, and lifetime performance. The horses were categorized as raced or unraced prior to and after surgery. Descriptive statistics including age and treated limb were also recorded. Of 332 horses, 228 (69%) returned to racing following injury and treatment. Seventy-eight of 118 (66%) horses that had not raced prior to injury and 150 of 214 (70%) horses that had raced prior to injury raced after treatment. Seventeen of 39 (44%) horses ≥ 5 years old raced following injury and treatment and 211 of 293 (72%) horses ≤ 4 years old returned to racing. There was no difference in the percentages of horses returning to racing for 2-, 3-, or 4-year olds. Postoperative infections occurred in 6 of the 332 (2%) horses. Median time to first race for horses that raced after surgery was 302 days (range, 48 to 1,120 days; mean ± SD, 341 ± 153 days), with a median of 8 starts/horse after surgery (range, 1 to 109 starts; mean ± SD, 14 ± 15.8 starts). Of 228 horses that returned to racing, 159 (70%) raced ≥ 5 times after surgery. Sex and treated limb did not have a significant effect on return to racing. However, horses ≥ 5 years old were significantly less likely to return to racing, compared with younger horses. In horses with unilateral SDFT and < 5 starts, the affected and contralateral limbs were both treated, but return to racing was not significantly different between horses treated bilaterally versus unilaterally. 228 of 332 (69%) horses with SDFT of the forelimb treated with SCLD successfully returned to racing. Convalescent times were shorter, compared with previous recommendations, and treated horses had a longer racing career after surgery than has been described for other treatment modalities. The results of the present study support consideration of SCLD as part of a treatment plan for SDFT in Thoroughbred racehorses.


[Cyclosporin treatment in uveitis].
With Cyclosporin, a recently developed immunosuppressant drug, the authors treated eight patients with noninfectious chronic uveitis: intermediate uveitis (4), Behcet's disease (2), chorioiditis (1), and anterior uveitis (1). Therapy had to be discontinued in six patients who responded poorly or manifested severe side effects. In four cases the Cyclosporin concentration in the aqueous humor was determined. In spite of a concentration of about 900 ng/ml there was a deterioration in two cases with intermediate uveitis and Behcet's disease. Only one of the eight patients with intermediate uveitis responded well without any recurrence.


Analysis of Gene Expression Signatures in Cancer-Associated Stroma from Canine Mammary Tumours Reveals Molecular Homology to Human Breast Carcinomas.
Cancer-associated stroma (CAS) plays a key role in cancer initiation and progression. Spontaneously occurring canine mammary carcinomas are viewed as excellent models of human breast carcinomas. Considering the importance of CAS for human cancer, it likely plays a central role in canine tumours as well. So far, however, canine CAS lacks characterisation, and it remains unclear whether the biology between CAS from canine and human tumours is comparable. In this proof-of-principle study, using laser-capture microdissection, we isolated CAS and normal stroma from 13 formalin-fixed paraffin embedded canine simple mammary carcinomas and analysed the expression of seven known human CAS markers by RT-qPCR (Reverse Transcription quantitative PCR) and validated some targets by immunohistochemistry. We found that Col1a1 (Collagen1α1), αSMA (alpha Smooth Muscle Actin), FAP (Fibroblast activation protein), PDGFRβ (Platelet-derived growth factor receptor beta), and Caveolin-1 were significantly upregulated in canine CAS, and the expression of CXCL12 (Stromal cell derived factor 1) significantly decreased, whereas MMP2 (Matrix Metalloproteinase 1) and IL6 (Interleukin 6) did not change. Our results suggest strong similarities in CAS biology in canine and human mammary carcinomas but also reveal some differences. To the best of our knowledge, this is the first report to provide a comprehensive expression analysis of the most important CAS markers in canine simple mammary carcinomas and further supports the validity of the dog as model for human cancer.


The use of an occlusion perfusion catheter to deliver paclitaxel to the arterial wall.
Nonstent drug delivery platforms have recently emerged as an alternative treatment of peripheral arterial disease. Perfusion catheters have the potential to directly deliver antiproliferative agents to the medial arterial layer to prevent restenosis. The purpose of this study was to therefore determine the effectiveness of a perfusion catheter to deliver paclitaxel, a proven antiproliferative agent, to combat restenosis. A benchtop model was utilized to determine the varying parameters of a novel occlusion perfusion catheter to maximize paclitaxel delivery using pharmacokinetic evaluation and fluorescent microscopy. Parameters tested included concentration of paclitaxel, delivery pressure, duration of delivery, and the use of an excipient. In addition, bilateral rabbit iliac arteries were treated with the perfusion catheter and pharmacokinetic evaluation performed at 1 hour, 1 day and 3 days. Benchtop testing demonstrated uniform and circumferential penetration of paclitaxel within the treated arteries. The results of the ex vivo test identified two groups with and without an excipient with similar loading conditions (with excipient: 15.4±8.6 ng/mg vs without excipient: 8.9±6.9 ng/mg, P=.77). The in vivo pharmacokinetic analysis of these two groups demonstrated the use of contrast agent increased arterial paclitaxel levels and maintained initial paclitaxel dosing up to 3 days (With excipient: 1 hour: 107±62 ng vs 3 days: 40±23 ng, P=.824; No excipient: 1 hour: 247±120 ng vs 3 days: 2.92±2.9 ng, P=.009). These results demonstrate the feasibility to deliver paclitaxel directly to the medial layer of an artery via a perfusion catheter.


Pretreatment with the Gram-positive bacterial cell wall molecule peptidoglycan improves bacterial clearance and decreases inflammation and mortality in mice challenged with Staphylococcus aureus.
To determine whether tolerance and enhancement of innate immune function can be induced by the Gram-positive cell wall component peptidoglycan. Controlled, in vivo laboratory study. Male mice, 8-12 wks (C57BL6/J; C3H/HeJ; B6.129-Tlr2/J). Mice were given intraperitoneal injections of 1 mg peptidoglycan on two consecutive days. Mice were then challenged with an intravenous injection of live Staphylococcus aureus (1 x 10 colony-forming units) 2 days after the second pretreatment. Mice pretreated with peptidoglycan had diminished plasma concentrations of tumor necrosis factor-alpha and interferon-gamma in response to the bacterial challenge when compared with untreated controls. Plasma interleukin-10 after bacterial challenge was higher in peptidoglycan-pretreated mice than in controls. Clearance of bacteria after the staphylococcal challenge was improved in mice pretreated with peptidoglycan, and mortality in response to a subsequent Staphylococcus challenge was significantly attenuated. Peptidoglycan pretreatment of mice lacking intact toll-like receptor-4 signaling (C3H/HeJ) or toll-like receptor-2 signaling (toll-like receptor-2 knockouts) had similar effects on plasma cytokine balance, bacterial clearance, and mortality. Exposure to peptidoglycan significantly attenuated inflammation and enhanced bacterial clearance after a subsequent challenge with S. aureus. These results show that exposure to Gram-positive bacterial cell wall components can induce tolerance and enhance innate immune function and neither toll-like receptor-2 nor toll-like receptor-4 are necessary for this phenomenon. Further, although the altered cytokine balance is similar to that seen in septic patients, induced tolerance differs importantly from the clinical scenario of sepsis in that bacterial clearance and survival are improved compared with normal control animals.


Pathophysiology, prevention, and treatment of medication overuse headache.
Regular or frequent use of analgesics and acute antimigraine drugs can increase the frequency of headache, and induce the transition from episodic to chronic headache or medication overuse headache. The 1-year prevalence of this condition in the general population is between 1% and 2%. Medication overuse headache is more common in women and in people with comorbid depression, anxiety, and other chronic pain conditions. Treatment of medication overuse headache has three components. First, patients need education and counselling to reduce the intake of medication for acute headache attacks. Second, some patients benefit from drug withdrawal (discontinuation of the overused medication). Finally, preventive drug therapy and non-medical prevention might be necessary in patients at onset of treatment or in patients who do not respond to the first two steps. The optimal therapeutic approach requires validation in controlled trials.


Ionic immune suppression within the tumour microenvironment limits T cell effector function.
Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K+]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. Although the suppressive effect mediated by elevated [K+]e is independent of changes in plasma membrane potential (Vm), it requires an increase in intracellular potassium ([K+]i). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv1.3 lowers [K+]i and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy.


Implications of tristability in pattern-forming ecosystems.
Many ecosystems show both self-organized spatial patterns and multistability of possible states. The combination of these two phenomena in different forms has a significant impact on the behavior of ecosystems in changing environments. One notable case is connected to tristability of two distinct uniform states together with patterned states, which has recently been found in model studies of dryland ecosystems. Using a simple model, we determine the extent of tristability in parameter space, explore its effects on the system dynamics, and consider its implications for state transitions or regime shifts. We analyze the bifurcation structure of model solutions that describe uniform states, periodic patterns, and hybrid states between the former two. We map out the parameter space where these states exist, and note how the different states interact with each other. We further focus on two special implications with ecological significance, breakdown of the snaking range and complex fronts. We find that the organization of the hybrid states within a homoclinic snaking structure breaks down as it meets a Maxwell point where simple fronts are stationary. We also discover a new series of complex fronts between the uniform states, each with its own velocity. We conclude with a brief discussion of the significance of these findings for the dynamics of regime shifts and their potential control.


Variation in complex olfactory stimuli and its influence on odour recognition.
Natural olfactory stimuli are often complex and highly variable. The olfactory systems of animals are likely to have evolved to use specific features of olfactory stimuli for identification and discrimination. Here, we train honeybees to learn chemically defined odorant mixtures that systematically vary from trial to trial and then examine how they generalize to each odorant present in the mixture. An odorant that was present at a constant concentration in a mixture becomes more representative of the mixture than other variable odorants. We also show that both variation and intensity of a complex olfactory stimulus affect the rate of generalization by honeybees to subsequent olfactory stimuli. These results have implications for the way that all animals perceive and attend to features of olfactory stimuli.


[Wilms' tumor in adults].
Wilms' tumor occurs extremely rarely in adults. There is no consensus in the literature on the problems of clinical manifestations, diagnosis and treatment of the disease. Ten adult patients (aged 16-29) with Wilms' tumor formed the study group. They made up 0.9 per cent of the total number of kidney tumor patients. The peculiarities of the clinical course that distinguish adult nephroblastoma from renal cancer and Wilms' tumor of the infancy were analysed. The latent period appeared to be long. Problems of diagnosis are discussed. Angiography proved to be of the highest diagnostic value. Complex treatment including transperitoneal nephrectomy, radiation and chemotherapy was carried out in 7 cases, palliative chemotherapy and radiation treatment--in 3. Unlike pediatric nephroblastoma, Wilms' tumor in adults was resistant to radiation. Treatment results still remained unsatisfactory: 6 patients died 7-19 months after the beginning of treatment.


Suspended sediment regimes in contrasting reference-condition freshwater ecosystems: implications for water quality guidelines and management.
Suspended sediment (SS), ranging from nano-scale particles to sand-sized sediments, is one of the most common contributors to water quality impairment globally. However, there is currently little scientific evidence as to what should be regarded as an appropriate SS regime for different freshwater ecosystems. In this article, we compare the SS regimes of ten systematically-selected contrasting reference-condition temperate river ecosystems that were observed through high-resolution monitoring between 2011 and 2013. The results indicate that mean SS concentrations vary spatially, between 3 and 29 mg L(-1). The observed mean SS concentrations were compared to predicted mean SS concentrations based on a model developed by Bilotta et al. (2012). Predictions were in the form of probability of membership to one of the five SS concentration ranges, predicted as a function of a number of the natural environmental characteristics associated with each river's catchment. This model predicted the correct or next closest SS range for all of the sites. Mean annual SS concentrations varied temporally in each river, by up to three-fold between a relatively dry year (2011-2012) and a relatively wet year (2012-2013). This inter-annual variability could be predicted reasonably well for all the sites except the River Rother, using the model described above, but with modified input data to take into account the mean annual temperature (°C) and total annual precipitation (mm) in the year for which the mean SS prediction is to be made. The findings highlight the need for water quality guidelines for SS to recognise natural spatial and temporal variations in SS within rivers. The findings also demonstrate the importance of the temporal resolution of SS sampling in determining assessments of compliance against water quality guidelines.


CCR5 and p53 codon 72 gene polymorphisms: implications in breast cancer development.
The aim of this study was to investigate the CCR5 gene and p53 codon 72 polymorphisms in a Brazilian population with breast cancer compared with healthy control subjects and to associate the clinical stage with these genotypes. No differences were detected for the D32 allele between breast cancer patients and the normal healthy donors (p=0.270), although this allele was more often present in blood donors. For p53 genotype analysis, breast cancer patients presented a significant (p<0.05) over-representation of p53 Arg homozygosity (55.5%) compared with the healthy control group (33.3%). Although no statistical difference occurred, a very strong tendency in breast cancer patients in stage III (p=0.0503) presenting homozygous genotype for Arg was verified. Five breast cancer patients were D32 deletion carriers and two patients presenting metastasis showed homozygous genotype for Arg. It is possible that p53 Arg homozygosity is associated with breast cancer and may represent a potential risk factor for breast tumorigenesis. In the present study, a higher percentage of breast cancer patients presented homozygous genotype for Arg and wild-type for CCR5 than the control subjects.


Transoral and submental thyroidectomy using intraoperative nerve stimulation and indocyanin green fluorescence imaging.
There is a recent proliferation of clinical studies about the minimally invasive scarless thyroid surgery. The transoral endoscopic thyroidectomy vestibular approach (TOETVA) carries a great potential for being scarless surgery via a short dissection flap. However, TOETVA has limitations in extracting larger thyroid tumours via the transoral vestibular incision and due to its potential damage to the branches of the mental nerve. The rapidly evolving surgical innovations have now introduced transoral and submental thyroidectomy (TOaST) approach that allows extraction of large thyroid tumours with less flap dissection and minimal postoperative pain. We present a 39-year-old man with a large multinodular goitre. The patient was euthyroid with moderate to severe compression symptoms of difficulty in breathing and swallowing. We performed a TOaST procedure using intraoperative neuromonitoring and indocyanin green fluorescence imaging with an uneventful recovery. This is a first case report from the middle east region that will pave the way to large clinical trials to determine the efficacy and safety of TOaST.


Structure-Based Design of an RNase Chimera for Antimicrobial Therapy.
Bacterial resistance to antibiotics urges the development of alternative therapies. Based on the structure-function of antimicrobial members of the RNase A superfamily, we have developed a hybrid enzyme. Within this family, RNase 1 exhibits the highest catalytic activity and the lowest cytotoxicity; in contrast, RNase 3 shows the highest bactericidal action, alas with a reduced catalytic activity. Starting from both parental proteins, we designed a first RNase 3/1-v1 chimera. The construct had a catalytic activity much higher than RNase 3, unfortunately without reaching an equivalent antimicrobial activity. Thus, two new versions were created with improved antimicrobial properties. Both of these versions (RNase 3/1-v2 and -v3) incorporated an antimicrobial loop characteristic of RNase 3, while a flexible RNase 1-specific loop was removed in the latest construct. RNase 3/1-v3 acquired both higher antimicrobial and catalytic activities than previous versions, while retaining the structural determinants for interaction with the RNase inhibitor and displaying non-significant cytotoxicity. Following, we tested the constructs' ability to eradicate macrophage intracellular infection and observed an enhanced ability in both RNase 3/1-v2 and v3. Interestingly, the inhibition of intracellular infection correlates with the variants' capacity to induce autophagy. We propose RNase 3/1-v3 chimera as a promising lead for applied therapeutics.


Maternal Antibodies Provide Bank Voles with Strain-Specific Protection against Infection by the Lyme Disease Pathogen.
Multistrain microbial pathogens often induce strain-specific antibody responses in their vertebrate hosts. Mothers can transmit antibodies to their offspring, which can provide short-term, strain-specific protection against infection. Few experimental studies have investigated this phenomenon for multiple strains of zoonotic pathogens occurring in wildlife reservoir hosts. The tick-borne bacterium Borrelia afzelii causes Lyme disease in Europe and consists of multiple strains that cycle between the tick vector (Ixodes ricinus) and vertebrate hosts, such as the bank vole (Myodes glareolus). We used a controlled experiment to show that female bank voles infected with B. afzelii via tick bite transmit protective antibodies to their offspring. To test the specificity of protection, the offspring were challenged using a natural tick bite challenge with either the maternal strain to which the mothers had been exposed or a different strain. The maternal antibodies protected the offspring against a homologous infectious challenge but not against a heterologous infectious challenge. The offspring from the uninfected control mothers were equally susceptible to both strains. Borrelia outer surface protein C (OspC) is an antigen that is known to induce strain-specific immunity. Maternal antibodies in the offspring reacted more strongly with homologous than with heterologous recombinant OspC, but other antigens may also mediate strain-specific immunity. Our study shows that maternal antibodies provide strain-specific protection against B. afzelii in an ecologically important rodent reservoir host. The transmission of maternal antibodies may have important consequences for the epidemiology of multistrain pathogens in nature.IMPORTANCE Many microbial pathogen populations consist of multiple strains that induce strain-specific antibody responses in their vertebrate hosts. Females can transmit these antibodies to their offspring, thereby providing them with short-term strain-specific protection against microbial pathogens. We investigated this phenomenon using multiple strains of the tick-borne microbial pathogen Borrelia afzelii and its natural rodent reservoir host, the bank vole, as a model system. We found that female bank voles infected with B. afzelii transmitted to their offspring maternal antibodies that provided highly efficient but strain-specific protection against a natural tick bite challenge. The transgenerational transfer of antibodies could be a mechanism that maintains the high strain diversity of this tick-borne pathogen in nature.


Stereotactic body radiation therapy for colorectal liver metastases.
Stereotactic body radiation therapy (SBRT) is a treatment option for colorectal liver metastases. Local control, patient survival and toxicity were assessed in an experience of SBRT for colorectal liver metastases. SBRT was delivered with curative intent to 20 consecutively treated patients with colorectal hepatic metastases who were candidates for neither resection nor radiofrequency ablation (RFA). The median number of metastases was 1 (range 1-3) and median size was 2.3 (range 0.7-6.2) cm. Toxicity was scored according to the Common Toxicity Criteria version 3.0. Local control rates were derived on tumour-based analysis. Median follow-up was 26 (range 6-57) months. Local failure was observed in nine of 31 lesions after a median interval of 22 (range 12-52) months. Actuarial 2-year local control and survival rates were 74 and 83 per cent respectively. Hepatic toxicity grade 2 or less was reported in 18 patients. Two patients had an episode of hepatic toxicity grade 3. SBRT is a treatment option for patients with colorectal liver metastases who are not candidates for resection or RFA.


Increased proportions of outdoor feeding among residual malaria vector populations following increased use of insecticide-treated nets in rural Tanzania.
Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) represent the front-line tools for malaria vector control globally, but are optimally effective where the majority of baseline transmission occurs indoors. In the surveyed area of rural southern Tanzania, bed net use steadily increased over the last decade, reducing malaria transmission intensity by 94%. Starting before bed nets were introduced (1997), and then after two milestones of net use had been reached-75% community-wide use of untreated nets (2004) and then 47% use of ITNs (2009)-hourly biting rates of malaria vectors from the Anopheles gambiae complex and Anopheles funestus group were surveyed. In 1997, An. gambiae s.l. and An. funestus mosquitoes exhibited a tendency to bite humans inside houses late at night. For An. gambiae s.l., by 2009, nocturnal activity was less (p = 0.0018). At this time, the sibling species composition of the complex had shifted from predominantly An. gambiae s.s. to predominantly An. arabiensis. For An. funestus, by 2009, nocturnal activity was less (p = 0.0054) as well as the proportion biting indoors (p < 0.0001). At this time, An. funestus s.s. remained the predominant species within this group. As a consequence of these altered feeding patterns, the proportion (mean ± standard error) of human contact with mosquitoes (bites per person per night) occurring indoors dropped from 0.99 ± 0.002 in 1997 to 0.82 ± 0.008 in 2009 for the An. gambiae complex (p = 0.0143) and from 1.00 ± <0.001 to only 0.50 ± 0.048 for the An. funestus complex (p = 0.0004) over the same time period. High usage of ITNs can dramatically alter African vector populations so that intense, predominantly indoor transmission is replaced by greatly lowered residual transmission, a greater proportion of which occurs outdoors. Regardless of the underlying mechanism, the residual, self-sustaining transmission will respond poorly to further insecticidal measures within houses. Additional vector control tools which target outdoor biting mosquitoes at the adult or immature stages are required to complement ITNs and IRS.


Effects of clopidogrel on horses with experimentally induced endotoxemia.
To evaluate the effects of clopidogrel on clinical and clinicopathologic variables in healthy horses with experimentally induced endotoxemia. 12 adult mares. Procedures-Horses were assigned with a randomization procedure to receive clopidogrel (4 mg/kg, once, then 2 mg/kg, q 24 h; n = 6) or a placebo (6) through a nasogastric tube. After 72 hours of treatment, horses received lipopolysaccharide (LPS; 30 ng/kg, IV). Heart rate, respiratory rate, rectal temperature, CBC variables, plasma fibrinogen concentration, serum tumor necrosis factor-α concentration, plasma von Willebrand factor concentration, and measures of platelet activation (including ADP- and collagen-induced platelet aggregation and closure times, thrombelastography variables, and results of flow cytometric detection of platelet membrane P-selectin, phosphatidylserine, and microparticles) were determined at various times before and after LPS administration by investigators unaware of the treatment groups. Statistical analyses were performed with repeated-measures ANOVA. 4 of 6 clopidogrel-treated horses had significant decreases in ADP-induced platelet aggregation before and after LPS administration. Heart rate increased significantly after LPS administration only for the placebo group. No significant differences were detected between groups for CBC variables, closure time, and plasma concentration of fibrinogen or serum concentration of tumor necrosis factor-α, and no clinically relevant differences were detected for other hemostatic variables. In this study, administration of LPS did not induce platelet hyperreactivity in horses on the basis of measures of platelet adhesion, aggregation, degranulation, and procoagulant activity. Administration of clopidogrel was associated with variable platelet antiaggregatory activity and attenuated some clinical signs of endotoxemia.


Structure of NFAT1 bound as a dimer to the HIV-1 LTR kappa B element.
DNA binding by NFAT1 as a dimer has been implicated in the activation of host and viral genes. Here we report a crystal structure of NFAT1 bound cooperatively as a dimer to the highly conserved kappa B site from the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR). This structure reveals a new mode of dimerization and protein-DNA recognition by the Rel homology region (RHR) of NFAT1. The two NFAT1 monomers form a complete circle around the kappa B DNA through protein-protein interactions mediated by both their N- and C-terminal subdomains. The major dimer interface, formed by the C-terminal domain, is asymmetric and substantially different from the symmetric dimer interface seen in other Rel family proteins. Comparison to other NFAT structures, including NFAT5 and the NFAT1-Fos-Jun-ARRE2 complex, reveals that NFAT1 adopts different conformations and its protein surfaces mediate distinct protein-protein interactions in the context of different DNA sites.


Genome-wide association of anthropometric traits in African- and African-derived populations.
Genome-wide association (GWA) studies have identified common variants that are associated with a variety of traits and diseases, but most studies have been performed in European-derived populations. Here, we describe the first genome-wide analyses of imputed genotype and copy number variants (CNVs) for anthropometric measures in African-derived populations: 1188 Nigerians from Igbo-Ora and Ibadan, Nigeria, and 743 African-Americans from Maywood, IL. To improve the reach of our study, we used imputation to estimate genotypes at approximately 2.1 million single-nucleotide polymorphisms (SNPs) and also tested CNVs for association. No SNPs or common CNVs reached a genome-wide significance level for association with height or body mass index (BMI), and the best signals from a meta-analysis of the two cohorts did not replicate in approximately 3700 African-Americans and Jamaicans. However, several loci previously confirmed in European populations showed evidence of replication in our GWA panel of African-derived populations, including variants near IHH and DLEU7 for height and MC4R for BMI. Analysis of global burden of rare CNVs suggested that lean individuals possess greater total burden of CNVs, but this finding was not supported in an independent European population. Our results suggest that there are not multiple loci with strong effects on anthropometric traits in African-derived populations and that sample sizes comparable to those needed in European GWA studies will be required to identify replicable associations. Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations.


N-Acetylcysteine (NAC)-Induced Hyponatremia Caused by an Electronic Medical Record (EMR) Order Error.
Intravenous N-acetylcysteine (NAC) causes few adverse drug events, with mild anaphylactoid reactions being the most common. Hyponatremia as a complication of hypoosmolar NAC solution has been reported. We describe how a locally constructed electronic medical record (EMR) order set for IV NAC resulted in a seizure from hyponatremia due to excess free water administration. A 13-month-old female with no past medical history presented to a hospital after ingesting an unknown number of acetaminophen 500 mg tablets. The 4-h acetaminophen concentration was 343 mcg/mL, and she was started on IV NAC. 8.2 h into her 21-h IV NAC protocol, she developed a tonic-clonic seizure. Repeat serum sodium was 124 mEq/L, a decrease from 142 mEq/L at the time of admission. She was treated with hypertonic saline, lorazepam, and levetiracetam and had no further seizures. A brain MRI and EEG were both normal. After the seizure was stabilized, the providers noticed that the patient had receive a total of 900 mL of D5W (112.5 mL/kg) in the first 9 h of hospitalization. This was caused by a poorly constructed, restrictive, EMR order set that did not allow customization of the IV NAC preparation. Because the 21-h IV NAC administration involves preparation of 3 different doses infused over 3 different time intervals, an order set was developed to reduce ordering errors. However, error in its construction caused the pharmacist to prepare a solution containing too much free water, decreasing patient's intravascular sodium and resulting in a seizure. The purposes of our case report were to highlight the dangers of overreliance on EMR order sets and to recognize hyponatremic seizures as an adverse reaction of an inappropriately prepared IV NAC.


Clinical features of West Nile virus epidemic in Dallas, Texas, 2012.
In 2012, Texas has reported the highest number of West Nile virus (WNV) cases in the United States to the Centers for Disease Control and Prevention. In this report, we conducted a retrospective chart review of 57 patients with WNV disease and analyzed the clinical features of these patients. Our results revealed that 25 (44%) patients were diagnosed with West Nile fever and 32 (56%) with West Nile neuroinvasive disease (WNND). The median age for patients with WNND was 54.5 years, and those with encephalitis were more likely to be >60 years old. Pre-existing conditions such as hypertension and diabetes were more frequent in patients with WNND. Testing both serum and cerebrospinal fluid (CSF) for antibodies diagnosed more cases of WNND than just testing serum or CSF alone. The increasing number of WNV cases during this epidemic highlights the need to increase efforts to control mosquito populations and educate the general public.


Detecting Genomic Signatures of Natural Selection with Principal Component Analysis: Application to the 1000 Genomes Data.
To characterize natural selection, various analytical methods for detecting candidate genomic regions have been developed. We propose to perform genome-wide scans of natural selection using principal component analysis (PCA). We show that the common FST index of genetic differentiation between populations can be viewed as the proportion of variance explained by the principal components. Considering the correlations between genetic variants and each principal component provides a conceptual framework to detect genetic variants involved in local adaptation without any prior definition of populations. To validate the PCA-based approach, we consider the 1000 Genomes data (phase 1) considering 850 individuals coming from Africa, Asia, and Europe. The number of genetic variants is of the order of 36 millions obtained with a low-coverage sequencing depth (3×). The correlations between genetic variation and each principal component provide well-known targets for positive selection (EDAR, SLC24A5, SLC45A2, DARC), and also new candidate genes (APPBPP2, TP1A1, RTTN, KCNMA, MYO5C) and noncoding RNAs. In addition to identifying genes involved in biological adaptation, we identify two biological pathways involved in polygenic adaptation that are related to the innate immune system (beta defensins) and to lipid metabolism (fatty acid omega oxidation). An additional analysis of European data shows that a genome scan based on PCA retrieves classical examples of local adaptation even when there are no well-defined populations. PCA-based statistics, implemented in the PCAdapt R package and the PCAdapt fast open-source software, retrieve well-known signals of human adaptation, which is encouraging for future whole-genome sequencing project, especially when defining populations is difficult.


Concreteness and context availability in lexical decision tasks.
Three experiments were carried out to elucidate the origins of the concreteness (C) effect in a lexical decision task. The first experiment was a replication of the work of Schwanenflugel et al. (1988) and Van Hell and De Groot (1998), who presented the context availability (CA) hypothesis. In this experiment CA seemed to be a dominant factor. Familiarity (FAM) was not incorporated in the ANOVA, but a regression analysis and negative correlation between C and FAM in the groups matched on CA showed that FAM could explain the disappearance of the C effect. Experiment 2 controlled FAM and revealed a C effect, although concrete and abstract words were matched on CA. Experiment 3 controlled C and FAM and revealed a CA effect. The current data emphasize the importance of controlling FAM and CA in examining the C effect in a lexical decision task and support a revised version of the dual-coding theory.


Left lobe living donor liver transplantation in adults.
Adult left lobe (LL) living donor liver transplantation (LDLT) has not generally been recognized as a feasible procedure because of the problem of graft size. The objectives of this study were to assess the feasibility and short- and long-term results of adult LL LDLT in comparison with right lobe (RL) LDLT. Data on 200 consecutive LL LDLTs, including five retransplants, were retrospectively compared with those of 112 RL LDLTs, in terms of survival, complications and donor morbidity. The mean graft weight to standard volume ratio of LL grafts was 38.7% whereas that of RL grafts was 47.6% (p < 0.0001). The 1-, 5- and 10-year patient survival rates of LL LDLT were 85.6%, 77.9% and 69.5%, respectively, which were comparable to those of RL LDLT (89.8%, 71.3% and 70.7%, respectively). The incidence of small-for-size syndrome was higher in LL LDLT (19.5%) than in RL LDLT (7.1%) (p < 0.01). The overall donor morbidity rates were comparable between LL (36.0%) and RL (34.8%), whereas postoperative liver function tests and hospital stay were significantly better (p < 0.0001) in LL donors. In conclusion, adult LL LDLT has comparable outcomes to that of RL LDLT. LL LDLT is viable and is the first choice in adult LDLT.


CT Findings, Radiologic-Pathologic Correlation, and Imaging Predictors of Survival for Patients With Interstitial Pneumonia With Autoimmune Features.
The objective of this study is to determine the CT findings and patterns of interstitial pneumonia with autoimmune features (IPAF) and to assess whether imaging can predict survival for patients with IPAF. The study included 136 subjects who met the criteria for IPAF and had diagnostic-quality chest CT scans obtained from 2006 to 2015; a total of 74 of these subjects had pathologic samples available for review within 1 year of chest CT examination. CT findings and the presence of an usual interstitial pneumonitis (UIP) pattern of disease were assessed, as was the UIP pattern noted on pathologic analysis. Analysis of chest CT findings associated with survival was performed using standard univariate and multivariate Cox proportional hazards methods as well as the unadjusted log-rank test. Survival data were visually presented using the Kaplan-Meier survival curve estimator. Most subjects with IPAF (57.4%; 78/136) had a high-confidence diagnosis of a UIP pattern on CT. Substantially fewer subjects (28.7%; 39/136) had a pattern that was inconsistent with UIP noted on CT. The presence of a UIP pattern on CT was associated with smoking (p < 0.01), male sex (p < 0.01), and older age (p < 0.001). Approximately one-fourth of the subjects had a nonspecific interstitial pneumonitis pattern on CT. Of interest, nearly one-tenth of the subjects had a CT pattern that was most consistent with hypersensitivity pneumonitis rather than the customary CT patterns ascribed to lung disease resulting from connective tissue disease. Most subjects with a possible UIP pattern on CT (83.3%) had UIP diagnosed on the basis of pathologic findings. Focused multivariate analysis showed that honeycombing on CT (hazard ratio, 2.17; 95% CI, 1.05-4.47) and pulmonary artery enlargement on CT (hazard ratio, 2.08; 95% CI, 1.02-4.20) were independent predictors of survival. IPAF most often presents with a UIP pattern on CT and is associated with worse survival when concomitant honeycombing or pulmonary artery enlargement is present.


Hepatotoxicity of the Pesticide Avermectin Exposure to Freshwater-Farmed Carp: Evidence from In Vivo and In Vitro Research.
Avermectin (AVM) is presently one of the most extensively employed insecticides across the globe. A number of toxicity research studies of AVM have been carried out in freshwater-farmed carp; however, there are currently no toxicity studies on the liver. This investigation aims to replicate an acute liver injury model induced by AVM in carp, subsequently analyzing the adverse effects imposed on the nontarget species while delving into potential mechanisms underlying its toxicity. In this study, we found that AVM-exposed carp liver tissue showed cellular hydration degeneration and necrosis and reduced the viability of hepatocyte L8824. Second, AVM induced oxidative stress in carp, and AVM stimulation led to reactive oxygen species (ROS) accumulation and Ca2+ overload in hepatocyte L8824, suggesting that AVM exposure induces mitochondrial dysfunction in hepatocytes. AVM induced inflammation in carp liver tissue by inducing mitochondrial kinetic disruption, which triggered hepatic tissue injury. AVM induced autophagy and apoptosis in carp liver tissue and ROS mediated AVM-induced autophagy and apoptosis. The formation of autophagy attenuated the AVM-induced liver injury. In conclusion, the present study elucidated the hepatotoxicity and potential mechanisms of freshwater aquaculture carp exposed to the pesticide AVM, emphasized the importance of monitoring pesticide AVM contamination in freshwater aquaculture aquatic environments, and provided theoretical references for the targeted prevention of AVM-induced toxicity in carp.


Accuracy of microRNA discovery pipelines in non-model organisms using closely related species genomes.
Mapping small reads to genome reference is an essential and more common approach to identify microRNAs (miRNAs) in an organism. Using closely related species genomes as proxy references can facilitate miRNA expression studies in non-model species that their genomes are not available. However, the level of error this introduces is mostly unknown, as this is the result of evolutionary distance between the proxy reference and the species of interest. To evaluate the accuracy of miRNA discovery pipelines in non-model organisms, small RNA library data from a mosquito, Aedes aegypti, were mapped to three well annotated insect genomes as proxy references using miRanalyzer with two strict and loose mapping criteria. In addition, another web-based miRNA discovery pipeline (DSAP) was used as a control for program performance. Using miRanalyzer, more than 80% reduction was observed in the number of mapped reads using strict criterion when proxy genome references were used; however, only 20% reduction was recorded for mapped reads to other species known mature miRNA datasets. Except a few changes in ranking, mapping criteria did not make any significant differences in the profile of the most abundant miRNAs in A. aegypti when its original or a proxy genome was used as reference. However, more variation was observed in miRNA ranking profile when DSAP was used as analysing tool. Overall, the results also suggested that using a proxy reference did not change the most abundant miRNAs' differential expression profiles when infected or non-infected libraries were compared. However, usage of a proxy reference could provide about 67% of the original outcome from more extremely up- or down-regulated miRNA profiles. Although using closely related species genome incurred some losses in the number of miRNAs, the most abundant miRNAs along with their differential expression profile would be acceptable based on the sensitivity level of each project.


The European physical and rehabilitation medicine journal network: historical notes on national journals.
In the last 40 years, physical and rehabilitation medicine (PRM) has made significant steps forward in Europe with the foundation of the European Federation of Physical Medicine and Rehabilitation (EFPMR) (1963) which gave rise to the European Society of Physical and Rehabilitation Medicine (ESPRM) (2004) the European Academy of Rehabilitation Medicine (1970), the PRM Section of the European Union of Medical Specialists (1974), and the European Board of PRM (1991). Our journal, formerly Europa Medico-physica (1964), the official journal of the EFPMR, now European Journal of Physical and Rehabilitation Medicine (EJPRM) and official journal of the ESPRM since 2008, is distinct for its steadfast European vocation, long-standing Mediter-ranean interests and connections with various national scientific societies. Jointly with the ESPRM, efforts are under way to set up the European Physical and Rehabilitation Medicine Journal Network (EPRMJN). The aim of this article is to present a profile of the national journals in the EPRMJN so as to give a better overview of how the scientific part of PRM in Europe has developed within a national perspective. A profile of the following national journals is presented: Annals of Physical and Rehabilitation Medicine (France), Fizikalna i rehabilitacijska medicina (Physical and Rehabilitation Medicine) (Croatia), Neurorehabilitation (Bulgaria), Physical and Rehabilitation Medicine Portuguese Society Journal (Portugal), Physical Medicine, Rehabilitaton, Health (Bulgaria), Physikalische Medizin - Rehabilitationsmedizin - Kurort-medizin/Journal of Physical and Rehabilitation Medicine (Germany and Austria) Prevention and Rehabilitation (Bulgaria), Rehabilitacija (Rehabilitation) (Slovenia), Rehabilitación (Madr) (Spain), Turkish Journal of Physical Medicine and Rehabilitation (Turkey). Some national journals in Europe have a very long history and tradition of research and education. Having a better knowledge of these realities, usually hidden to the international readership owing to the English language barrier, could promote science in our specialty.


Coronavirus Disease 2019 Messenger RNA Vaccine Immunogenicity in Immunosuppressed Individuals.
Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-γ responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals.


Hepatitis B virus core and e antigen: immune recognition and use as a vaccine carrier moiety.
The hepatitis B virus (HBV) core gene codes for two partially colinear antigens: a secreted antigen (HBeAg) and the particulate core antigen (HBcAg), which assembles to form subviral particles and in virions contains the viral genome and polymerase. In this review we summarize data on the immune recognition of HBc/eA and recent progress in the use of HBcAg as a carrier moiety for heterologous epitopes. During HBV infection, HBcAg and HBeAg are important targets of antiviral immunity. HBcAg and HBeAg are serologically distinct but share all characterized T-cell epitopes. The particulate HBcAg can elicit T-cell-independent as well as T-cell-dependent antibody responses, HBeAg is a strictly T-cell-dependent antigen. Neonatal tolerance to maternally derived circulating HBeAg may facilitate chronic HBV infection after vertical transmission of HBV. In a murine transgenic model, HBc/eAg-specific Th1 cells were more readily anergized, whereas Th2 cells more easily escaped tolerization. In human HBV infection, acute adult HBV infection with subsequent virus elimination was characterized by Th1-like alpha-HBV serum IgG subtype distribution, whereas a Th2-like distribution of IgG subtypes was observed during chronic infection. During chronic infection, core gene mutants which abolish HBeAg synthesis were frequently observed. To exploit the unusual immunogenicity of particulate HBcAg as a vaccine carrier moiety, insertion sites for foreign epitopes were defined in recombinant expression systems. While fusion of epitopes to the N-terminus required a linker sequence for surface accessibility, both fusion to the N-terminus and to the C-terminus was compatible with particle assembly and preserved the native antigenicity and immunogenicity of HBcAg. Epitope insertion at an immunodominant internal site of HBcAg reduced the HBcAg immunogenicity and antigenicity and most drastically enhanced the immunogenicity of the inserted foreign epitopes. This internal site of HBcAg was used to express circumsporozoite antigen (CS) repeat epitopes of two rodent malaria parasites and of Plasmodium falciparum. Purified hybrid HBcAg-CS proteins were particulate and displayed CS antigenicity as well as reduced native HBc antigenicity. Immunization of several mouse strains with HBcAg-CS hybrid particles resulted in high-titered serum anti-CS antibodies representing all murine IgG isotypes and protected BALB/c mice against plasmodial challenge. Immunization of mice with HBcAg or HBcAg-CS particles formulated on alum, complete Freund's or incomplete Freund's adjuvant resulted in equivalent anti-CS and anti-HBc serum antibody titers. Preexisting immunity to HBcAg did not significantly alter the immunogenicity of hybrid HBcAg particles suggesting that carrier-specific immune suppression does not limit the use of hybrid HBcAg with internal insertions. Immunization with HBcAg-CS particles universally primed HBcAg-specific T cells and in addition CS-specific T cells were if the insert contained a CS-specific T-cell site for the corresponding murine MHC class II haplotype. The internal amino acid position in HBcAg is therefore permissive for the inclusion of heterologous T-helper as well as B-cell epitopes.


Innovative uses of communication technology for HIV programming for men who have sex with men and transgender persons.
Globally, overall rates of HIV are on the decline; however, rates among gay men and other men who have sex with men (MSM) and transgender persons are increasing. Meanwhile, there has been exponential growth in access to communication technology over the last decade. More innovative prevention and care technology-based programmes are needed to help address the growing numbers of MSM and transgender persons living with HIV and those at risk for infection. To address this need, a meeting was hosted by the U.S. Agency for International Development (USAID) through the President's Emergency Plan for AIDS Relief (PEPFAR) and co-sponsored by amfAR, The Foundation for AIDS Research and the National Institute of Mental Health (NIMH). The meeting brought together researchers, community implementers, advocates and federal partners to discuss the current landscape of technology-based interventions for MSM and transgender persons and to discuss key considerations. Presentations and discussions focused on the research gaps, facilitators and barriers to programme implementation and public-private partnerships. This article summarizes the meeting proceedings and outlines key considerations for future work in this area.


Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours.
Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.


Ectopic pregnancy early diagnosis markers.
Ectopic pregnancy (EP) is a high-risk medical condition with an incidence of 1.9% in reported pregnancies, and has proven to be the most common cause of pregnancy-related deaths in the first trimester. The clinical symptoms can mimic non-EP conditions, thus creating a challenge for developing diagnostic criteria and new diagnostic tools. Early diagnosis of ectopic pregnancy is essential in order to minimize the morbidity and to assess the need for urgent surgical intervention. Currently, ultrasound and serum biomarkers are used by clinicians for early detection and diagnosis. This review summarizes and comments on the available literature on the various markers including their utility and their statistical parameters.


The standardized-taper root canal preparation--Part 2. GT file selection and safe handpiece-driven file use.
To present guidelines on GT file selection, and safe operation. It is not necessary to remove excessive dentine for effective root canal preparation. GT files allow safe, standardized preparation, and should be selected to fit the case in hand. Small Root canals should be prepared with 0.06 and 0.08 taper GT files, whilst Large Root canals should be prepared with 0.10 GT or 0.12 Accessory GT files. The greatest challenge is un-learning habits acquired from traditional instrumentation methods. GT files should be used with light touch, and without up-down pumping motions. Spin speeds should be controlled below 300 r.p.m. for routine preparation. GT files are subject to fatigue and should be tracked to avoid overuse. It is recommended that GT files are discarded after the equivalent of five root canal preparations. For severe curvatures, GT files should be single-case tools. The standard GT file set comprises three instruments of 0.06, 0.08 and 0.10 taper. All are size 20 at the tip, and have a maximum diameter of 1 mm. Accessory GT files have a standard taper 0.12, and maximum diameter of 1.5 mm. They are available in tip sizes 35, 50 and 70. Large Roots are lower canines, upper anteriors, upper and lower single-rooted premolars, palatal roots of upper molars and distal roots of lower molars. They should be prepared with 0.10 GT or 0.12 Accessory GT files. Small Roots are lower incisors, multirooted premolars, buccal roots of upper molars and mesial roots of lower molars. They should be prepared with 0.06 or 0.08 GT files. All GT files should be used with light force and at the correct spin speed. GT files should be discarded after the equivalent of five root canal uses.


Sonographic classification of gallstones and outcome of extracorporeal shock wave lithotripsy.
The success of extracorporeal shock wave lithotripsy (ESWL) for gallstone elimination is dependent on the lithotripter's ability to reduce the stone to fragments less than 5 mm in diameter, but wide variation in successful fragmentation rates have been reported even with the same instrument. This variation is probably due in part to differences in stone composition. Tsuchiya et al. have recently related the pre-operative ultrasound properties of gallstones to their chemical compositions. In the present study, 138 patients with cholecystolithiasis were treated with ESWL and results were evaluated in light of the pre-treatment sonogram patterns as classified by the aforementioned authors. Complete fragmentation (CF), i.e., fragments less than 5 mm, was achieved in 90% of patients with type I a patterns (pure cholesterol stones); stone number, diameter, and volume had no effects on fragmentation. Significantly lower CF rates were obtained with I b and I c (mixed cholesterol), and type II (combination) stones (p less than 0.0003). No fragmentation at all was achieved in the six stones with type III (bilirubinate) patterns. Twelve months after treatment, 45%, 25%, and 9% of the patients with type 1 a, type I b, and types I c or II (the latter two combined), respectively, were stone-free. Pure and mixed cholesterol gallstones without calcification seem to respond best to ESWL; effective treatment can be expected even when stones are numerous (4-10) or large ( greater than 35 mm). We recommend the inclusion of ultrasound properties of gallstones in the selection criteria for candidates for ESWL.


The effect of expanded insurance coverage under the Affordable Care Act on emergency department utilization in New York.
One of the proposed benefits of expanding insurance coverage under the Affordable Care Act (ACA) was a reduction in emergency department (ED) utilization for non-urgent visits related to lack of health insurance coverage and access to primary care providers. The objective of this study was to estimate the effect of the 2014 ACA implementation on ED use in New York. We used the Healthcare Cost and Utilization Project State Emergency Department and State Inpatient Databases for all outpatient and all inpatient visits for patients admitted through an ED from 2011 to 2016. We focused on in-state residents aged 18 to 64, who were covered under Medicaid, private insurance, or were uninsured prior to the 2014 expansion. We estimated the effect of the expanded insurance coverage on average monthly ED visits volumes and visits per 1000 residents (rates) using interrupted time-series regression analyses. After ACA implementation, overall average monthly ED visits increased by around 3.0%, both in volume (9362; 95% Confidence Intervals [CI]: 1681-17,522) and in rates (0.80, 95% CI:0.12-1.49). Medicaid covered ED visits volume increased by 23,972 visits (95% CI: 16,240 -31,704) while ED visits by the uninsured declined by 13,297 (95% CI:-15,856 - -10,737), and by 1453 (95% CI:-4027-1121) for the privately insured. Medicaid ED visits rates per 1000 residents increased by 0.77 (95% CI:-1.96-3.51) and by 2.18 (95% CI:-0.55-4.92) for those remaining uninsured, while private insurance visits rates decreased by 0.48 (95% CI:-0.79 - -0.18). We observed increases in primary-care treatable ED visits and in visits related to mental health and alcohol disorders, substance use, diabetes, and hypertension. All estimated changes in monthly ED visits after the expansion were statistically significant, except for ED visit rates among Medicaid beneficiaries. Net ED visits by adults 18 to 64 years of age increased in New York after the implementation of the ACA. Large increases in ED use by Medicaid beneficiaries were partially offset by reductions among the uninsured and those with private coverage. Our results suggest that efforts to expand health insurance coverage only will be unlikely to reverse the increase in ED use.


D-aspartate modulates nociceptive-specific neuron activity and pain threshold in inflammatory and neuropathic pain condition in mice.
D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo (-/-)) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo (-/-) mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo (-/-) mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4-L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions.


Success rates, near-response patterns, and learning trends with free-fusion stereograms.
Free-fusion stereograms are routinely used for demonstrating various stereoscopic effects. Yet, untrained observers find it challenging to perform this task. This study showed that only less than 1/3rd of sixty-one pre-presbyopic adults with normal binocular vision could successfully free-fuse random-dot image pairs and identify the stereoscopic shapes embedded in these patterns. Another one-third of participants performed the task with poor success rates, while the remaining could not perform the task. There was a clear dissociation of vergence and accommodative responses in participants who were successful with free-fusion, as recorded using a dynamic infrared eye tracker and photorefractor. Those in the unsuccessful cluster either showed strong vergence and accommodation or weak vergence and strong accommodation during the task. These response patterns, however, were specific to the free-fusion task because all these participants generated good convergence/accommodation to real-world targets and to conflicting vergence and accommodative demands stimulated with prisms or lenses. Task performance of the unsuccessful cluster also improved significantly following pharmacological paralysis of accommodation and reached the performance levels of the successful cluster. A minority of participants also appeared to progressively learn to dissociate one of the two directions of their vergence and accommodation crosslinks with repeated free-fusion trials. These results suggest that successful free-fusion might depend upon how well participants generate a combination of volitional and reflex vergence responses to large differences in disparity with conflicting static accommodative demands. Such responses would require that only one direction of the vergence-accommodation crosslinks be active at any given time. The sequence of near-responses could also be learnt through repeated trials to optimize task performance.