Accidental epinephrine auto-injector-induced digital ischemia reversed by phentolamine digital block.
The use of epinephrine-containing auto-injectors as a prescription medication for treating routine to severe anaphylactic reactions is now widely accepted. Associated with this trend is an increasing number of accidental injections of epinephrine into digits, causing severe vasoconstriction and the risk of ischemic necrosis. When epinephrine is accidentally discharged into a digit, ischemic skin necrosis resulting from the alpha-adrenergic blocking effects of this agent can lead to the need for multiple operations, wound infection, and even loss of the digit. The alpha-adrenergic blocking characteristics of phentolamine administered by a variety of methods have proved effective in reversing the effects of epinephrine in these cases. The authors urge that the described treatment protocol become more widely disseminated among primary care and emergency physicians.


Weight loss in rats exposed to repeated acute restraint stress is independent of energy or leptin status.
Acute release of corticotropin-releasing factor (CRF) during repeated restraint (3-h restraint on each of 3 days) causes temporary hypophagia but chronic suppression of body weight in rats. Here we demonstrated that a second bout of repeated restraint caused additional weight loss, but continuing restraint daily for 10 days did not increase weight loss because the rats adapted to the stress. In these two studies serum leptin, which suppresses the endocrine response to stress, was reduced in restrained rats. Peripheral infusion of leptin before and during restraint did not prevent stress-induced weight loss, although stress-induced corticosterone release was suppressed. Restrained rats were hyperthermic during restraint, but there was no evidence that fever or elevated free interleukin-6 caused the sustained reduction in weight. Restraining food-restricted rats caused a small but significant weight loss. Food-restricted rats fed ad libitum after the end of restraint showed a blunted hyperphagia and slower rate of weight regain than their controls. These results indicate that repeated acute stress induces a chronic change in weight independent of stress-induced hypophagia and may represent a change in homeostasis initiated by repeated acute activation of the central CRF system.


Elucidating the Life History and Ecological Aspects of Allodero hylae (Annelida: Clitellata: Naididae), A Parasitic Oligochaete of Invasive Cuban Tree Frogs in Florida.
Given their ubiquitous nature, it is surprising that more oligochaete annelid worms (Annelida: Clitellata) have not adopted an endoparasitic lifestyle. Exceptions, however, are the understudied members of the genus Dero (Allodero) that parasitize the ureters of tree frogs and toads. This study experimentally explores the life cycle and host specificity of Allodero hylae, the worm's use of chemical cues in host searching, and its seasonal prevalence and abundance over a year-long collection period on the Florida Southern College campus. A total of 2,005 A. hylae was collected from the ureter, urinary bladder, or expressed urine of wild Osteopilus septentrionalis ; a significant positive correlation was found between host snout-vent length and parasite intensity for female but not male hosts. Monthly prevalence of A. hylae reached a peak of 58% in April, but never dropped below 20% in any month; mean abundance peaked March-May, whereas few worms were recovered in December and January. Confirming a parasitic lifestyle, wild-collected hosts with intense infections, typically >40 worms, showed obvious dilatation of the ureter wall, and some young-of-the-year O. septentrionalis exposed to A. hylae in the laboratory were killed by the apparent rupture of the host's ureter. The worm has a direct life cycle: worms expelled in the host's urine are capable of locating and re-infecting other hosts within aquatic microhabitats such as bromeliad tanks, and worms can survive for weeks in a free-living environment, even undergoing a morphological change. Further, chemotaxis assays found a positive response to a tree frog attractant for worms recently removed from hosts. Overall, this study provides the first multifaceted investigation on the life history and ecology of any Allodero spp., which offers new insights into an understudied endoparasitic oligochaete.


Maternal adjustment of egg size organizes alternative escape behaviors, promoting adaptive phenotypic integration.
Numerous integrated traits contribute to any aspect of organismal performance, but favorable trait combinations are difficult to maintain in the face of genetic recombination. We investigated the role of maternal effects in promoting integration of alternative reproductive strategies (throat colors) with antipredator traits (escape behaviors and dorsal patterns) in the side-blotched lizard (Uta stansburiana). Previously, we reported that maternally derived estradiol adaptively pairs dorsal patterns with progeny throat colors. Here we show adaptive maternal effects on escape behaviors within each throat color morph. Specifically, yellow-throated females and all females mated to yellow-throated sires lay larger eggs. Larger eggs produce stockier offspring, who remain stockier throughout life. Stockiness promotes evasive escape behaviors (e.g., reversals), which are adaptive in barred, yellow-throated offspring. Orange-throated females lay smaller eggs, producing leaner hatchlings who perform vertical escape behaviors (e.g., jumping). Vertical behaviors enhance survival in striped, orange-throated progeny. Escape behavior was not heritable, but was organized by natural or experimental egg size variation. Maternal effects on adaptive phenotypic integration are likely common in polymorphic species, because recombination otherwise breaks apart beneficial trait combinations. Furthermore, our results provide insight into the role of body shape in organizing (and constraining) evolution of integrated reproductive and antipredator strategies.


Promoting oral hygiene behavior in recruits in the Dutch Army.
To make practical recommendations for improving oral hygiene behavior (OHB) potential predictors based on the Theory of Planned Behavior (TPB) were assessed. Measurements of oral health knowledge (OHK) and the expected social effect for having healthy teeth were included. 216 recruits in the Dutch Army ground forces completed a questionnaire about oral hygiene behavior, attitudes, social norms, perceived behavioral control (PBC), intention to perform optimal OHB, OHK, and expected social outcomes. The multivariate regression analysis revealed that attitude and PBC explained 37.2% of the variance in intention to perform optimal oral hygiene behavior, which is a substantial proportion. Furthermore, actual oral hygiene behavior was only predicted by attitude, explaining 7.1% of the variance. The present findings suggest that recruits' oral hygiene behavior may be improved by promoting a more positive attitude and especially by enhancing perceived behavior control.


Quantitative analysis of hyperpolarized 129 Xe gas transfer MRI.
Hyperpolarized 129 Xe magnetic resonance imaging (MRI) using Dixon-based decomposition enables single-breath imaging of 129 Xe in the airspaces, interstitial barrier tissues, and red blood cells (RBCs). However, methods to quantitatively visualize information from these images of pulmonary gas transfer are lacking. Here, we introduce a novel method to transform these data into quantitative maps of pulmonary ventilation, and 129 Xe gas transfer to barrier and RBC compartments. A total of 13 healthy subjects and 12 idiopathic pulmonary fibrosis (IPF) subjects underwent thoracic 1 H MRI and hyperpolarized 129 Xe MRI with one-point Dixon decomposition to obtain images of 129 Xe in airspaces, barrier and red blood cells (RBCs). 129 Xe images were processed into quantitative binning maps of all three compartments using thresholds based on the mean and standard deviations of distributions derived from the healthy reference cohort. Binning maps were analyzed to derive quantitative measures of ventilation, barrier uptake, and RBC transfer. This method was also used to illustrate different ventilation and gas transfer patterns in a patient with emphysema and one with pulmonary arterial hypertension (PAH). In the healthy reference cohort, the mean normalized signals were 0.51 ± 0.19 for ventilation, 4.9 ± 1.5 x 10-3 for barrier uptake and 2.6 ± 1.0 × 10-3 for RBC (transfer). In IPF patients, ventilation was similarly homogenous to healthy subjects, although shifted toward slightly lower values (0.43 ± 0.19). However, mean barrier uptake in IPF patients was nearly 2× higher than in healthy subjects, with 47% of voxels classified as high, compared to 3% in healthy controls. Moreover, in IPF, RBC transfer was reduced, mainly in the basal lung with 41% of voxels classified as low. In healthy volunteers, only 15% of RBC transfer was classified as low and these voxels were typically in the anterior, gravitationally nondependent lung. This study demonstrates a straightforward means to generate semiquantitative binning maps depicting 129 Xe ventilation and gas transfer to barrier and RBC compartments. These initial results suggest that the method could be valuable for characterizing both normal physiology and pathophysiology associated with a wide range of pulmonary disorders.


Membrane progesterone receptor alpha as a potential prognostic biomarker for breast cancer survival: a retrospective study.
Classically, the actions of progesterone (P4) are attributed to the binding of nuclear progesterone receptor (PR) and subsequent activation of its downstream target genes. These mechanisms, however, are not applicable to PR- or basal phenotype breast cancer (BPBC) due to lack of PR in these cancers. Recently, the function of membrane progesterone receptor alpha (mPRα) in human BPBC cell lines was studied in our lab. We proposed that the signaling cascades of P4→mPRα pathway may play an essential role in controlling cell proliferation and epithelial mesenchymal transition (EMT) of breast cancer. Using human breast cancer tissue microarrays, we found in this study that the average intensity of mPRα expression, but not percentage of breast cancer with high level of mPRα expression (mPRα-HiEx), was significantly lower in the TNM stage 4 patients compared to those with TNM 1-3 patients; and both average intensities of mPRα expression and mPRα-HiEx rates were significantly higher in cancers negative for ER, as compared with those cancers with ER+. However, after adjusting for age at diagnosis and/or TNM stage, only average intensities of mPRα expression were associated with ER status. In addition, we found that the rates of mPRα-HiEx were significantly higher in cancers with epithelial growth factor receptor-1 (EGFR+) and high level of Ki67 expression, indicating positive correlation between mPRα over expression and EGFR or Ki67. Further analysis indicated that both mPRα-HiEx rate and average intensity of mPRα expression were significantly higher in HER2+ subtype cancers (i.e. HER2+ER-PR-) as compared to ER+ subtype cancers. These data support our hypothesis that P4 modulates the activities of the PI3K and cell proliferation pathways through the caveolar membrane bound growth factor receptors such as mPRα and growth factor receptors. Future large longitudinal studies with larger sample size and survival outcomes are necessary to confirm our findings.


Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation.
Sustained activation of the c-Jun NH(2)-terminal kinase (JNK) signaling pathway mediates the development and progression of experimental diet-induced nonalcoholic fatty liver disease (NAFLD). Delineating the mechanism of JNK overactivation in the setting of a fatty liver is therefore essential to understanding the pathophysiology of NAFLD. Both human and experimental NAFLD are associated with oxidative stress and resultant lipid peroxidation, which have been proposed to mediate the progression of this disease from simple steatosis to steatohepatitis. The ability of oxidants and the lipid peroxidation product 4-hydroxynonenal (HNE) to activate JNK signaling suggested that these two factors may act synergistically to trigger JNK overactivation. The effect of HNE on hepatocyte injury and JNK activation was therefore examined in cells under chronic oxidant stress from overexpression of the prooxidant enzyme cytochrome P450 2E1 (CYP2E1), which occurs in NAFLD. CYP2E1-generated oxidant stress sensitized a rat hepatocyte cell line to death from normally nontoxic concentrations of HNE. CYP2E1-overexpressing cells underwent a more profound depletion of glutathione (GSH) in response to HNE secondary to decreased gamma-glutamylcysteine synthetase activity. GSH depletion led to overactivation of JNK/c-Jun signaling at the level of mitogen-activated protein kinase kinase 4 that induced cell death. Oxidant stress and the lipid peroxidation product HNE cause synergistic overactivation of the JNK/c-Jun signaling pathway in hepatocytes, demonstrating that HNE may not be just a passive biomarker of hepatic oxidant stress but rather an active mediator of hepatocellular injury through effects on JNK signaling.


Patient education and consumer medicine information: a study of provision by Queensland rural and remote area Registered Nurses.
The aim of the larger study was to ascertain the medication practices of registered and enrolled nurses in rural and remote areas of Queensland after the introduction of the Health (Drugs and Poisons) Regulation. This paper reports on the findings of the role of registered nurses and their confidence in the ability to provide information on medications in a way that the client understands; the frequency of the provision of information to clients prior to discharge; and the frequency of Indigenous Health Workers or interpreters for people without English as a first language. Queensland employs approximately 17% of the Australian registered nurse workforce. In 1996 Queensland changed the Health (Drugs and Poisons) Regulation to allow specific registered nurses, who had undertaken approved postgraduate education and training programmes, to become endorsed for an expanded medication practice role. In particular, it allowed endorsed nurses to administer and supply (but not prescribe) drugs listed in a drug formulary to certain clients using protocols. It was not clear, however, whether the changes to the Regulation reflected the scope of practice, thereby providing adequate legal protection for the nurse. During 2001-02 an exploration of the medication practices of rural and remote area nurses was conducted by the use of a cross-sectional postal survey. Phase 1 of the study used a facility audit to ascertain facility medication practices and phase 2 of the study used a postal survey to ascertain nurses' medication practices. All nurses employed in rural and remote health facilities in Queensland were eligible to participate in the study. The nurse registering authority's (the Queensland Nursing Council) register was used to generate a non-proportional stratified random sample. Of the 1999 questionnaires sent, there were 668 respondents. Of these, 520 were registered nurses. The data indicated that there was a difference between endorsed and unendorsed registered nurses' medication practice. In particular, it was apparent that endorsed registered nurses were more likely to believe they could explain the side-effects of medication to clients in a way the patient understood; provided medication education to clients on discharge; and used Indigenous Health Workers or interpreters to explain medications to those clients for whom English was not a first language. However, it was apparent that <50% of all Registered Nurses were providing client medication education or using Indigenous Health Workers or interpreters. It is apparent that the changes to the Regulation have ensured that Registered Nurses who have undergone postgraduate education to enhance their medication practice are more likely to provide client education and consumer medication information. However, the results suggest that the majority of registered nurses in Queensland, whilst believing they have sufficient knowledge of pharmacology to provide client education, often do not provide appropriate medication advice to clients, particularly on discharge from the acute setting. It is well recognized that the provision of medication education to clients has several benefits to both the client and the health care system. The lack of client medication education indicated in this study compromises patient's safety as well as their compliance with their medication regime.


Effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on serum hormones and bone characteristics in a preclinical tumor model for breast cancer.
The purpose of this study was to evaluate and compare the effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on tumor growth, serum hormones, uterine weight, body composition, and bone characteristics in mice. Human estrogen-dependent breast cancer cells stably transfected with the aromatase gene (MCF-7CA cells) were inoculated in Matrigel subcutaneously into ovariectomized nude mice. This model represents postmenopausal breast cancer in many respects, including the fact that estrogen is no longer produced by the ovaries and is not under feedback regulation by gonadotropins. Mice that received subcutaneously implanted MCF-7CA cancer cells were then treated with tamoxifen or letrozole for 7 weeks. As reported previously, tumor growth was markedly inhibited by both tamoxifen (100 microg/day) and letrozole (10 microg/day). Tamoxifen treatment led to increased bone mineral density (BMD) and hyperplastic uteri. Mice treated with letrozole had significantly smaller uteri than the controls and tamoxifen-treated mice. Letrozole did not affect BMD. There was no significant difference in systemic leptin and insulin-like growth factor I levels as a result of tamoxifen or letrozole treatment. Tamoxifen treatment inhibited breast cancer cell growth and increased BMD but caused uterine hypertrophy in this preclinical model of postmenopausal breast cancer. Letrozole inhibited tumor growth without inducing uterine hypertrophy. In addition, letrozole had no effect on BMD. These findings provide experimental evidence that letrozole is an effective and safe (in terms of risk of endometrial cancer risk and osteoporosis) alternative or complement to tamoxifen treatment for breast cancer.


A novel neuregulin - jagged1 paracrine loop in breast cancer transendothelial migration.
The interaction of breast cancer cells with other cells in the tumor microenvironment plays an important role in metastasis. Invasion and intravasation, two critical steps in the metastatic process, are influenced by these interactions. Macrophages are of particular interest when it comes to studying tumor cell invasiveness. Previous studies have shown that there is paracrine loop signaling between breast cancer cells and macrophages involving colony stimulating factor 1 (CSF-1) produced by tumor cells and epidermal growth factor (EGF) production by macrophages. In this paper, we identify a novel paracrine loop between tumor cells and macrophages involving neuregulin (NRG1) and notch signaling. The aim of this study was to determine the role of NRG1, a ligand of the ErbB3 receptor, in macrophage stimulation of tumor cell transendothelial migration and intravasation. We used fluorescence-activated cell sorting (FACS) and western blot to determine ErbB3 and NRG1 expression, respectively. An in vitro transendothelial migration (iTEM) assay was used to examine the effects of short hairpin (sh)RNA targeting NRG1 in tumor cells and clustered regularly interspaced short palindromic repeats (CRISPR) knockout of jagged 1 (JAG1) in macrophages. Orthotopic xenograft injections in mice were used to confirm results in vivo. In our system, macrophages were the primary cells showing expression of ErbB3, and a blocking antibody against ErbB3 resulted in a significant decrease in macrophage-induced transendothelial migration of breast cancer cells. Stimulation of macrophages with NRG1 upregulated mRNA and protein expression of JAG1, a ligand of the Notch receptor, and JAG1 production by macrophages was important for transendothelial migration of tumor cells. This study demonstrates that stimulation of macrophages by tumor cell NRG1 can enhance transendothelial migration and intravasation. We also demonstrate that this effect is due to induction of macrophage JAG1, an important ligand of the Notch signaling pathway.


Visual restoration and transplant connectivity in degenerate rats implanted with retinal progenitor sheets.
The aim of this study was to determine whether retinal progenitor layer transplants form synaptic connections with the host and restore vision. Donor retinal sheets, isolated from embryonic day 19 rat fetuses expressing human placental alkaline phosphatase (hPAP), were transplanted to the subretinal space of 18 S334ter-3 rats with fast retinal degeneration at the age of 0.8-1.3 months. Recipients were killed at the age of 1.6-11.8 months. Frozen sections were analysed by confocal immunohistochemistry for the donor cell label hPAP and synaptic markers. Vibratome slices were stained for hPAP, and processed for electron microscopy. Visual responses were recorded by electrophysiology from the superior colliculus (SC) in 12 rats at the age of 5.3-11.8 months. All recorded transplanted rats had restored or preserved visual responses in the SC corresponding to the transplant location in the retina, with thresholds between -2.8 and -3.4 log cd/m(2). No such responses were found in age-matched S334ter-3 rats without transplants, or in those with sham surgery. Donor cells and processes were identified in the host by light and electron microscopy. Transplant processes penetrated the inner host retina in spite of occasional glial barriers between transplant and host. Labeled neuronal processes were found in the host inner plexiform layer, and formed apparent synapses with unlabeled cells, presumably of host origin. In conclusion, synaptic connections between graft and host cells, together with visual responses from corresponding locations in the brain, support the hypothesis that functional connections develop following transplantation of retinal layers into rodent models of retinal degeneration.


Does perceptual learning require consciousness or attention?
It has been proposed that visual attention and consciousness are separate [Koch, C., & Tsuchiya, N. Attention and consciousness: Two distinct brain processes. Trends in Cognitive Sciences, 11, 16-22, 2007] and possibly even orthogonal processes [Lamme, V. A. F. Why visual attention and awareness are different. Trends in Cognitive Sciences, 7, 12-18, 2003]. Attention and consciousness converge when conscious visual percepts are attended and hence become available for conscious report. In such a view, a lack of reportability can have two causes: the absence of attention or the absence of a conscious percept. This raises an important question in the field of perceptual learning. It is known that learning can occur in the absence of reportability [Gutnisky, D. A., Hansen, B. J., Iliescu, B. F., & Dragoi, V. Attention alters visual plasticity during exposure-based learning. Current Biology, 19, 555-560, 2009; Seitz, A. R., Kim, D., & Watanabe, T. Rewards evoke learning of unconsciously processed visual stimuli in adult humans. Neuron, 61, 700-707, 2009; Seitz, A. R., & Watanabe, T. Is subliminal learning really passive? Nature, 422, 36, 2003; Watanabe, T., Náñez, J. E., & Sasaki, Y. Perceptual learning without perception. Nature, 413, 844-848, 2001], but it is unclear which of the two ingredients-consciousness or attention-is not necessary for learning. We presented textured figure-ground stimuli and manipulated reportability either by masking (which only interferes with consciousness) or with an inattention paradigm (which only interferes with attention). During the second session (24 hr later), learning was assessed neurally and behaviorally, via differences in figure-ground ERPs and via a detection task. Behavioral and neural learning effects were found for stimuli presented in the inattention paradigm and not for masked stimuli. Interestingly, the behavioral learning effect only became apparent when performance feedback was given on the task to measure learning, suggesting that the memory trace that is formed during inattention is latent until accessed. The results suggest that learning requires consciousness, and not attention, and further strengthen the idea that consciousness is separate from attention.


Functional mapping in pea, as an aid to the candidate gene selection and for investigating synteny with the model legume Medicago truncatula.
The identification of the molecular polymorphisms giving rise to phenotypic trait variability-both quantitative and qualitative-is a major goal of the present agronomic research. Various approaches such as positional cloning or transposon tagging, as well as the candidate gene strategy have been used to discover the genes underlying this variation in plants. The construction of functional maps, i.e. composed of genes of known function, is an important component of the candidate gene approach. In the present paper we report the development of 63 single nucleotide polymorphism markers and 15 single-stranded conformation polymorphism markers for genes encoding enzymes mainly involved in primary metabolism, and their genetic mapping on a composite map using two pea recombinant inbred line populations. The complete genetic map covers 1,458 cM and comprises 363 loci, including a total of 111 gene-anchored markers: 77 gene-anchored markers described in this study, 7 microsatellites located in gene sequences, 16 flowering time genes, the Tri gene, 5 morphological markers, and 5 other genes. The mean spacing between adjacent markers is 4 cM and 90% of the markers are closer than 10 cM to their neighbours. We also report the genetic mapping of 21 of these genes in Medicago truncatula and add 41 new links between the pea and M. truncatula maps. We discuss the use of this new composite functional map for future candidate gene approaches in pea.


MK-801 and related compounds in monkeys: discriminative stimulus effects and effects on a conditional discrimination.
MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate] and related compounds were studied in monkeys discriminating between 0.032 mg/kg of (+)-MK-801 and saline and in a separate group of monkeys responding under a multiple schedule of repeated acquisition and performance of conditional discriminations. In the drug discrimination study, small doses of (+)-MK-801 occasioned saline-lever responding whereas larger doses occasioned responding on the MK-801 lever. Dexoxadrol substituted completely (greater than or equal to 90%) for the MK-801 discriminative stimulus in all subjects whereas dextrorphan and phencyclidine (PCP) substituted in only two of three subjects. Neither ketamine, (+)-N-allylnormetazocine, dextromethorphan nor the competitive excitatory amino acid antagonist CGS 19755 [cis-4-phosphonomethyl-2-piperidine-carboxylic acid] substituted for MK-801 in any of the monkeys. PCP, dextrorphan, dextromethorphan, (+)- and (-)-MK-801 decreased rates of lever pressing and increased errors in both components of the multiple acquisition, performance schedule. For each compound errors were increased in the acquisition component with doses smaller than doses required to increase errors in the performance component. In both procedures (+)-MK-801 was 10 times more potent than (-)-MK-801, although qualitatively similar results were obtained with the two enantiomers. PCP-like drugs have many effects in common, including their effects on learning and performance; however, with regard to discriminative stimulus effects this does not appear to be a homogenous pharmacological class, suggesting that change in excitatory amino acid-mediated neurotransmission might not be the only mechanism by which MK-801 and related compounds exert behavioral effects in nonhuman primates.


UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy.
Unique Molecular Identifiers (UMIs) are random oligonucleotide barcodes that are increasingly used in high-throughput sequencing experiments. Through a UMI, identical copies arising from distinct molecules can be distinguished from those arising through PCR amplification of the same molecule. However, bioinformatic methods to leverage the information from UMIs have yet to be formalized. In particular, sequencing errors in the UMI sequence are often ignored or else resolved in an ad hoc manner. We show that errors in the UMI sequence are common and introduce network-based methods to account for these errors when identifying PCR duplicates. Using these methods, we demonstrate improved quantification accuracy both under simulated conditions and real iCLIP and single-cell RNA-seq data sets. Reproducibility between iCLIP replicates and single-cell RNA-seq clustering are both improved using our proposed network-based method, demonstrating the value of properly accounting for errors in UMIs. These methods are implemented in the open source UMI-tools software package.


Evaluation of a portable prothrombin time monitor for home use by patients who require long-term oral anticoagulant therapy.
The anticoagulant activity of warfarin sodium is monitored by the prothrombin time (PT). The introduction of a portable PT monitor has raised the possibility that patients could reduce the inconvenience of anticoagulant therapy by measuring their PT at home. We performed this study to determine the feasibility and accuracy of home use of the portable PT monitor. A prospective cohort study was performed in consecutive eligible patients who required long-term anticoagulant therapy. Patients performed multiple measurements of their PT at home by means of the portable monitor and at their usual laboratory within a 4-hour interval. The accuracy of the portable monitor was evaluated by two criteria for agreement. Standard agreement was achieved if the portable monitor and laboratory results were both either within or outside the patient's targeted therapeutic range or if the two results were within 0.4 international normalized ratio units of each other. Expanded agreement was achieved if both the portable monitor and laboratory results were within +/- 0.4 international normalized ratio units of the targeted therapeutic range. Forty patients (19 men and 21 women, aged 25 to 74 years) were followed up for 6 to 24 months by means of the portable PT monitor. The mean level of agreement achieved per patient was 83% (95% confidence interval, 79% to 87%) by the standard criteria and 96% (95% confidence interval, 94% to 98%) by the expanded criteria. Twenty-seven patients (68%) and 39 patients (98%) achieved more than 80% agreement by the standard and the expanded criteria, respectively. Questionnaire results revealed that 97% of the patients preferred using the portable monitor to measure their PT. Patients receiving long-term anticoagulant therapy achieved a high rate of clinically important agreement between self-measurements of the PT with the use of a portable monitor and laboratory PT results. Patients strongly preferred using the portable monitor to measure their PT levels. The use of the portable monitor as the primary method for measuring the PT can be recommended in selected patients receiving long-term anticoagulant treatment.


COVID-19 Disease, Women's Predominant Non-Heparin Vaccine-Induced Thrombotic Thrombocytopenia and Kounis Syndrome: A Passepartout Cytokine Storm Interplay.
Coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitute one of the deadliest pandemics in modern history demonstrating cardiovascular, gastrointestinal, hematologic, mucocutaneous, respiratory, neurological, renal and testicular manifestations and further complications. COVID-19-induced excessive immune response accompanied with uncontrolled release of cytokines culminating in cytokine storm seem to be the common pathogenetic mechanism of these complications. The aim of this narrative review is to elucidate the relation between anaphylaxis associated with profound hypotension or hypoxemia with pro-inflammatory cytokine release. COVID-19 relation with Kounis syndrome and post-COVID-19 vaccination correlation with heparin-induced thrombocytopenia with thrombosis (HITT), especially serious cerebral venous sinus thrombosis, were also reviewed. A current literature search in PubMed, Embase and Google databases was performed to reveal the pathophysiology, prevalence, clinical manifestation, correlation and treatment of COVID-19, anaphylaxis with profuse hypotension, Kounis acute coronary syndrome and thrombotic events post vaccination. The same key immunological pathophysiology mechanisms and cells seem to underlie COVID-19 cardiovascular complications and the anaphylaxis-associated Kounis syndrome. The myocardial injury in patients with COVID-19 has been attributed to coronary spasm, plaque rupture and microthrombi formation, hypoxic injury or cytokine storm disposing the same pathophysiology with the three clinical variants of Kounis syndrome. COVID-19-interrelated vaccine excipients as polysorbate, polyethelene glycol (PEG) and trometamol constitute potential allergenic substances. Better acknowledgement of the pathophysiological mechanisms, clinical similarities, multiorgan complications of COVID-19 or other viral infections as dengue and human immunodeficiency viruses along with the action of inflammatory cells inducing the Kounis syndrome could identify better immunological approaches for prevention, treatment of the COVID-19 pandemic as well as post-COVID-19 vaccine adverse reactions.


Direct optical switching of bistable cholesteric textures in chiral azobenzene-doped liquid crystals.
The direct optical switching of bistable cholesteric textures (i.e., planar and focal conic textures) in chiral azobenzene-doped liquid crystals (LCs) is demonstrated. Chiral azobenzene is a chiral dopant with optically tuned helical twisting power that results from the photo-isomerization between trans- and cis- isomers via exposure to UV or visible light. The pitch length of the material can be optically and repeatedly elongated and shortened. With regard to free energy, LCs tend to be stable at planar (focal conic) textures when pitch length is elongated (shortened) by exposure to UV (visible) light. Thus, direct optical switchable LC displays are investigated.


Perceptual effects of social salience: evidence from self-prioritization effects on perceptual matching.
We present novel evidence showing that new self-relevant visual associations can affect performance in simple shape recognition tasks. Participants associated labels for themselves, other people, or neutral terms with geometric shapes and then immediately judged whether subsequent label-shape pairings were matched. Across 4 experiments there was a reliable self-prioritization benefit on response times and perceptual sensitivity that remained across different presentation contexts (with self, best friend, and unfamiliar others in Experiment 1; with self, best friend, and neutral terms, and with self, mother, and neutral terms in Experiments 2A and 2B, respectively. Control studies in Experiment 3 indicated that the results did not reflect the length, concreteness, or familiarity of the words. The self-prioritization effect on shape matching also increased when stimuli were degraded (self shapes showing weaker effects of degradation) in Experiment 4A, consistent with self-information modulating perceptual processing. A similar effect was found when people associated different reward values to the shape in Experiment 4B. The results indicate that associating a stimulus to the self modulates its subsequent perceptual processing, and this may operate by self-associated shapes automatically evoking the reward system.


Disability Measurement in the Health and Retirement Study.
The Health and Retirement Study (HRS) has provided extensive and detailed national data on disability since it began in 1992, and has been used extensively in studies of disability trends and trajectories. We summarize conceptual frameworks used to characterize disability and review the HRS measures of functioning, work disability, and employer accommodations. HRS survey questions have experienced changes in wording, skip logic, or other design features over the life of the study, and we comment on the analytic challenges posed by those changes. Among our conclusions are (1) work disability and benefit eligibility are important concepts that should be considered for redesign to better reflect current concepts and policy issues; (2) methodological studies of changes in wording or skip logic should be undertaken; and (3) minor additions to survey content in areas such as temporal reference periods or changes in social-participation activities would improve measurement.


Expression of c-Met in laryngeal carcinoma.
Expression of c-Met, a gene for the hepatocyte growth factor/scatter factor (HGF/SF) receptor, is known to be associated with tumour development in several human carcinomas. The expression of c-Met was examined using immunohistochemistry in 82 cases of primary laryngeal carcinoma to evaluate the tissue distribution of c-Met and the clinicopathological significance of c-Met expression. In normal larynx, c-Met expression was observed only in some minor salivary glands. Positive reaction for c-Met in neoplastic epithelium was noted in 45 out of 82 (54.9%) cases. In 44 cases, structures adjacent to the carcinoma (noncancerous squamous epithelium, some stromal fibroblastic cells, and endothelial cells) showed positive reaction for c-Met. c-Met expression in cancerous epithelium was significantly correlated with lymph node status (P<0.04) and proliferating activity expressed by the Ki-67 labelling index (P<0.02). There was no correlation between c-Met expression and age, sex, histological type, T category, distant metastasis or clinical stage. The data suggest that overexpression of c-Met in laryngeal carcinomas represents a growth advantage for cancer cells, which may be conferred by the mitogenic effect of HGF/SF. Simultaneous c-Met expression in noncancerous components of the larynx may represent a paracrine modification of c-Met.


Tularemia in Alaska, 1938 - 2010.
Tularemia is a serious, potentially life threatening zoonotic disease. The causative agent, Francisella tularensis, is ubiquitous in the Northern hemisphere, including Alaska, where it was first isolated from a rabbit tick (Haemophysalis leporis-palustris) in 1938. Since then, F. tularensis has been isolated from wildlife and humans throughout the state. Serologic surveys have found measurable antibodies with prevalence ranging from < 1% to 50% and 4% to 18% for selected populations of wildlife species and humans, respectively. We reviewed and summarized known literature on tularemia surveillance in Alaska and summarized the epidemiological information on human cases reported to public health officials. Additionally, available F. tularensis isolates from Alaska were analyzed using canonical SNPs and a multi-locus variable-number tandem repeats (VNTR) analysis (MLVA) system. The results show that both F. t. tularensis and F. t. holarctica are present in Alaska and that subtype A.I, the most virulent type, is responsible for most recently reported human clinical cases in the state.


Negative reinforcement reveals non-evoked ongoing pain in mice with tissue or nerve injury.
Patients with chronic pain experience spontaneous or ongoing pain as well as enhanced sensitivity to evoked stimuli. Spontaneous or ongoing pain is rarely evaluated in preclinical studies. In fact, it remains controversial whether ongoing or spontaneous pain even develops in mice after tissue or nerve injury. This study tested a hypothesis that negative reinforcement can be used to unmask the presence of pain in mice with tissue or nerve injury. We found that spinal administration of clonidine or lidocaine did not elicit conditioned place preference (CPP) in uninjured or sham-operated mice. However, these agents produced CPP in mice with chronic inflammation induced by complete Freund's adjuvant (CFA) or following L5/L6 spinal nerve ligation (SNL). These data indicate the presence of non-evoked (ie, stimulus-independent) ongoing pain in mice with chronic inflammation (CFA) or following nerve injury (SNL). In addition, this study validates the use of negative reinforcement to unmask non-evoked ongoing pain in mice. Given the existence of a large collection of transgenic and knockout mice, our data show the application of this approach to elucidate molecular mechanisms underlying non-evoked pain and to contribute to drug discovery for pain. We demonstrated the presence of non-evoked ongoing pain in mice with chronic inflammation or following nerve injury. The study also validates the use of negative reinforcement to unmask non-evoked pain in mice. We propose to apply this approach to identify molecular mechanisms and effective drugs for chronic pain.


Effects on abstinence of nicotine patch treatment before quitting smoking: parallel, two arm, pragmatic randomised trial.
To examine the effectiveness of a nicotine patch worn for four weeks before a quit attempt. Randomised controlled open label trial. Primary care and smoking cessation clinics in England, 2012-15. 1792 adults who were daily smokers with tobacco dependence. 899 were allocated to the preloading arm and 893 to the control arm. Participants were randomised 1:1, using concealed randomly permuted blocks stratified by centre, to either standard smoking cessation pharmacotherapy and behavioural support or the same treatment supplemented by four weeks of 21 mg nicotine patch use before quitting: "preloading." The primary outcome was biochemically confirmed prolonged abstinence at six months. Secondary outcomes were prolonged abstinence at four weeks and 12 months. Biochemically validated abstinence at six months was achieved by 157/899 (17.5%) participants in the preloading arm and 129/893 (14.4%) in the control arm: difference 3.0% (95% confidence interval -0.4% to 6.4%), odds ratio 1.25 (95% confidence interval 0.97 to 1.62), P=0.08 in the primary analysis. There was an imbalance between arms in the frequency of varenicline use as post-cessation treatment, and planned adjustment for this gave an odds ratio for the effect of preloading of 1.34 (95% confidence interval 1.03 to 1.73), P=0.03: difference 3.8% (0.4% to 7.2%). At four weeks, the difference in prolonged abstinence unadjusted for varenicline use was odds ratio 1.21 (1.00 to 1.48), difference 4.3% (0.0% to 8.7%), P=0.05, and adjusted for varenicline use was 1.32 (1.08 to 1.62) P=0.007. At 12 months the odds ratio was 1.28 (0.97 to 1.69), difference 2.7% (-0.4% to 5.8%), P=0.09 unadjusted for varenicline use and after adjustment was 1.36 (1.02 to 1.80) P=0.04. 5.9% of participants discontinued preloading owing to intolerance. Gastrointestinal symptoms-chiefly nausea-occurred in 4.0% (2.2% to 5.9%) more people in the preloading arm than control arm. Eight serious adverse events occurred in the preloading arm and eight in the control arm (odds ratio 0.99, 0.36 to 2.75). Evidence was insufficient to confidently show that nicotine preloading increases subsequent smoking abstinence. The beneficial effect seems to have been masked by a concurrent reduction in the use of varenicline in people using nicotine preloading, and future studies should explore ways to mitigate this unintended effect. Current Controlled Trials ISRCTN33031001.


Long-term exposure to ambient air pollution and incidence of brain tumor: the European Study of Cohorts for Air Pollution Effects (ESCAPE).
Epidemiological evidence on the association between ambient air pollution and brain tumor risk is sparse and inconsistent. In 12 cohorts from 6 European countries, individual estimates of annual mean air pollution levels at the baseline residence were estimated by standardized land-use regression models developed within the ESCAPE and TRANSPHORM projects: particulate matter (PM) ≤2.5, ≤10, and 2.5-10 μm in diameter (PM2.5, PM10, and PMcoarse), PM2.5 absorbance, nitrogen oxides (NO2 and NOx) and elemental composition of PM. We estimated cohort-specific associations of air pollutant concentrations and traffic intensity with total, malignant, and nonmalignant brain tumor, in separate Cox regression models, adjusting for risk factors, and pooled cohort-specific estimates using random-effects meta-analyses. Of 282194 subjects from 12 cohorts, 466 developed malignant brain tumors during 12 years of follow-up. Six of the cohorts also had data on nonmalignant brain tumor, where among 106786 subjects, 366 developed brain tumor: 176 nonmalignant and 190 malignant. We found a positive, statistically nonsignificant association between malignant brain tumor and PM2.5 absorbance (hazard ratio and 95% CI: 1.67; 0.89-3.14 per 10-5/m3), and weak positive or null associations with the other pollutants. Hazard ratio for PM2.5 absorbance (1.01; 0.38-2.71 per 10-5/m3) and all other pollutants were lower for nonmalignant than for malignant brain tumors. We found suggestive evidence of an association between long-term exposure to PM2.5 absorbance indicating traffic-related air pollution and malignant brain tumors, and no association with overall or nonmalignant brain tumors.


An ethnobotanical survey of traditionally used plants on Suva planina mountain (south-eastern Serbia).
This study documents the ethnobotanical and ethnomedicinal importance of plants in the Suva planina mountain region (south-eastern Serbia). It is reflected in their high diversity and their wide range of uses in the treatment of the local population. The aim of this study was a comparative analysis of data collected in the Suva planina region with relevant data from the Western Balkans, which included identifying the 'most popular' plants, as well as those species which are used specifically for treatment solely in the research area. Ethnobotanical research was carried out between 2012 and 2014 and data was collected through both open and semi-structured interviews with locals. A total of 66 people were interviewed (37 women and 29 men), aged between 49 and 90 (with a mean age of 71). This study identified 128 plants and 2 fungi which are used in ethnomedicine, 5 plant species used in ethnoveterinary medicine, and 16 plants used for 'other' purposes. Lamiaceae (20), Asteraceae (17), Rosaceae (16), Brassicaceae (5), Alliaceae (4) and Apiaceae (4) have the greatest diversity of species. Results showed that Achillea mellefolium, Allium cepa, Allium sativum, Arctostaphyllos uva-ursi, Gentiana lutea, Hypericum perforatum, Juglans regia, Matricaria chamomilla, Mentha piperita, Plantago lanceolata, Plantago major, Salvia officinalis, Sempervivum tectorum, Tilia cordata and Thymus sepyllum are the 'most popular' medicinal plants (UV=1). Those plants with the most phytotherapeutic uses are Gentiana cruciata (14), H. perforatum (11) and A. sativum (10), while the most common conditions treated with medicinal plants are respiratory (79), urogenital (53), gastrointestinal (51), skin (43) and those relating to the circulatory system (35). A comparative analysis of the data collected in the research area and that from other parts of the Western Balkans showed that there are great similarities within Serbia between Suva planina and the Zlatibor region (37.2%) and Kopaonik Mt. (32.3%), while further afield it is most similar to Bosnia and Herzegovina (40.9%) and Bulgaria (40.6%). Moreover, it was established that 14 plant species and 2 fungi are used only in the Suva planina region, which points to the specificity of the diversity and the sound knowledge of medicinal plants in this region. Our results confirm that medicinal plants are an invaluable resource of the research area and need to be protected as they contribute to an improvement in living standards and the survival of people threatened by unfavourable demographic trends. However, due to over-exploitation, some plants have become exceptionally rare and are under threat, leading to the need for their rational use and protection so as to ensure they are still around for future generations.


Genetic parameters of colostrum traits in Holstein dairy cows.
The main objective of this study was to assess the genetic background of colostrum yield and quality traits after calving in Holstein dairy cows. The secondary objective was to investigate genetic and phenotypic correlations among laboratory-based and on-farm-measured colostrum traits. The study was conducted in 10 commercial dairy herds located in northern Greece. A total of 1,074 healthy Holstein cows with detailed pedigree information were examined from February 2015 to September 2016. All cows were clinically examined on the day of calving and scored for body condition. All 4 quarters were machine-milked, and a representative and composite colostrum sample was collected and examined. Colostrum total solids (TS) content was determined on-farm using a digital Brix refractometer. Colostrum fat, protein, and lactose contents were determined using an infrared milk analyzer, and energy content was calculated using National Research Council (2001) equations. Dry period length (for cows of parity ≥2), milk yield of previous 305-d lactation (for cows of parity ≥2), age at calving, parity number, season of calving, time interval between calving and first colostrum milking, and milk yield were recorded. Each trait (colostrum yield and quality traits) was analyzed with a univariate mixed model, including fixed effects of previously mentioned factors and the random animal additive genetic effect. All available pedigrees were included in the analysis, bringing the total animal number to 5,662. Estimates of (co)variance components were used to calculate heritability for each trait. Correlations among colostrum traits were estimated with bivariate analysis using the same model. Mean percentage (±SD) colostrum TS, fat, protein, and lactose contents were 25.8 ± 4.7, 6.4 ± 3.3, 17.8 ± 4.0, and 2.2 ± 0.7%, respectively; mean energy content was 1.35 ± 0.3 Mcal/kg and mean colostrum yield was 6.18 ± 3.77 kg. Heritability estimates for the above colostrum traits were 0.27, 0.21, 0.19, 0.15, 0.22, and 0.04, respectively. Several significant genetic and phenotypic correlations were derived. The genetic correlation of TS content measured on-farm with colostrum protein was practically unity, whereas the correlation with energy content was moderate (0.61). Fat content had no genetic correlation with TS content; their phenotypic correlation was positive and low. Colostrum yield was not correlated genetically with any of the other traits. In conclusion, colostrum quality traits are heritable and can be amended with genetic selection.


Pornography consumption and non-marital sexual behaviour in a sample of young Indonesian university students.
Using a sample of Indonesian university students and a cross sectional design, this study investigated prevalence rates and patterns of pornography consumption in Indonesia, a religious, sexually conservative, Muslim-majority nation with strict anti-pornography laws. Further, the association between pornography consumption and common non-marital sexual behaviours was explored. The study found that in this sample, pornography is as widely and readily consumed as in comparable international studies predominantly utilising Western background samples from more sexually liberal and less religious countries with very few laws on pornography. Gender differences in patterns of pornography consumption were pronounced and comparable with findings in international counterpart studies. For men only, pornography consumption was found to significantly predict common sexual behaviours in non-marital relations. The study is the first to provide insights into prevalence rates and patterns of pornography consumption and its association with common non-marital sexual behaviours in a sexually conservative, Muslim-majority nation with strict anti-pornography laws.


The social process of international migration.
The social process of network growth helps to explain the rapid increase in the migration of Mexicans to the United States during the 1970s. Migrant networks are webs of social ties that link potential migrants in sending communities to people in receiving societies, and their existence lowers the costs of international movement. With each person that becomes a migrant, the cost of migration is reduced for a set of friends and relatives, inducing them to migrate and further expanding the network. As a result of this dynamic interaction, network connections to the United States have become widespread throughout Mexico, and the probability of international migration from that country is high.


Effect of meningitis in infancy on school-leaving examination results.
To determine whether having had meningitis in infancy adversely affects academic achievement at age 16. A case-control study in England and Wales of 461 teenagers who had bacterial meningitis in infancy and 289 GP matched controls recruited when the index cases were aged 5. Comparison between index cases and controls of the type of school attended; the number of GCSE examinations attempted; the number of examinations passed (grades A*-C) and achievement in five key subjects. Assessment of examination results according to the age at which meningitis occurred. The effect of meningitis-associated disability on GCSE results. 36/461 (7.8%) index cases compared with none of the controls were in special schools. Significantly more index cases (117/461 (25.4%)) than controls (19/289 (6.6%)) did not pass any GCSE examinations. Significantly more index cases (184/385 (47.8%)) than controls (59/232 (25.4%)) attending comprehensive schools failed to achieve the national educational standard of five passes at grade C. Pupils attending comprehensive schools who did not have meningitis-associated disability also passed significantly fewer GCSE examinations than the controls. The age at which meningitis had occurred was not associated with subsequent academic achievement. After meningitis in infancy a quarter of survivors failed to pass any GCSE examinations; nearly half of those attending state schools did not attain the national educational standard. "Healthy" survivors of bacterial meningitis in infancy pass significantly fewer GCSE examinations than the controls. All cases of bacterial meningitis in infancy should have a full postinfection assessment and continuing supervision.


Antilymphoma treatments given subsequent to Yttrium 90 ibritumomab tiuxetan are feasible in patients with progressive non-Hodgkin's lymphoma: a review of the literature.
Yttrium 90-labeled ibritumomab tiuxetan is approved for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). To date, the efficacy of repeated courses of radioimmunoconjugate treatment in patients whose disease has progressed has not been studied as a formal endpoint in a clinical trial setting. However, several clinical studies have been conducted in patients with progressive NHL who had previously received 90Y ibritumomab tiuxetan. A retrospective review of these studies has shown that clinical responses have been achieved with all types of subsequent treatment with no apparent impact on their efficacy. In addition, no significant differences in toxicities with subsequent therapies have been observed between patients who had previously received 90Y ibritumomab tiuxetan therapy and those who had not. These findings suggest that patients previously treated with 90Y ibritumomab tiuxetan can feasibly undergo other forms of treatment for progressive NHL, and that a clinical response to further treatment options is not precluded by administration of 90Y ibritumomab tiuxetan.


SERUM ACUTE-PHASE PROTEINS IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS) AND CORRELATION WITH COMMONLY UTILIZED INFLAMMATORY INDICES.
Acute-phase proteins (APP) are the foundation to the innate immune response and valuable biomarkers that increase with inflammation, infection, neoplasia, stress, and trauma.2,4,16 Little is known about the acute-phase response in cetaceans and if these proteins can be used for health monitoring in individuals and free-ranging populations. The purpose of this study was to characterize serum concentrations of haptoglobin (Hp) and serum amyloid A (SAA), as well as electrophoretic profiles of common bottlenose dolphins (Tursiops truncatus) in free-ranging (n = 33) and professional care (n = 27) settings. Results were correlated to commonly utilized inflammatory indices including erythrocyte sedimentation rate (ESR), fibrinogen, total white blood cell count (WBC), and absolute neutrophil count. SAA levels, measured with a dolphin-specific enzyme linked immunosorbent assay (ELISA), were significantly higher (P = 0.05) in free-ranging dolphins (mean = 4.26; SE = 1.12) when compared with those under professional care (mean = 1.82; SE = 0.45). For dolphins under professional care, a statistically significant correlation was identified between ESR and Hp (P < 0.001; r = 0.69), ESR and SAA (P < 0.001; r = 0.67), fibrinogen and Hp (P = 0.001; r = 0.58), and fibrinogen and SAA (P = 0.002; r = 0.56). In addition, there was a significant correlation between WBC and SAA (P = 0.01; r = 0.38) and absolute neutrophil count and SAA (P = 0.04; r = 0.32). There were no significant correlations between study variables observed in free-ranging dolphins. The variable correlation of APPs with commonly utilized inflammatory indices demonstrates that these proteins are independent measures of inflammation with unique sensitivity, specificity, and timeline of expression. The results of this study contribute to improved health monitoring of dolphins and have the potential to assist in identification of compromised health.


Auditory brainstem response (ABR) and effects of furosemide on ABR in conscious F344 rats.
The present study was conducted to evaluate the variations in the normal auditory brainstem response (ABR) between the F344 and Wistar rats. It was also investigated whether strain differences exist in the ABR profiles of each strain of rat given furosemide, which induced ototoxicity. The typical waveform of ABRs in the F344 rats were similar to those observed in the Wistar rats. There were no significant differences between the strains in almost all parameters, but peak latencies from P1 to P3 in the F344 rats tended to be longer than those in the Wistar rats. After a single intravenous injection of furosemide, the minimum effective dosage levels, at which each peak of the ABR disappeared, were 53.3 +/- 8.2 and 70.0 +/- 8.9 mg/kg in the F344 and Wistar rats, respectively. A single intravenous injection of 100 mg/kg furosemide delayed the reversal of decrease in amplitude, prolongation of peak latency and the reappearance time in F344 rats. Thus, the normal waveform of ABR was comparable in the F344 and Wistar rats, but a tendency towards a prolongation in each latency was noted in the F344 rat. The results also suggested that the ABR of F344 rats were more vulnerable to furosemide ototoxicity than that of Wistar rats.


Autism, attachment and parenting: a comparison of children with autism spectrum disorder, mental retardation, language disorder, and non-clinical children.
Children with Autism Spectrum Disorder (ASD) have severe and pervasive impairments in the development of social interaction, which may affect the attachment relationship with their parents and may have an impact on parenting. In the current investigation 89 families with young children (mean age 26.5 months) were involved, who were diagnosed as ASD, mentally retarded (MR), or language delayed (LD), or part of a non-clinical comparison group. Attachment security was observed with the Brief Attachment Screening Questionnaire, and several parental self-report questionnaires assessed the parenting style, parental efficacy, parental experiences of daily hassles, social support, and psychological problems. Children with ASD were rated as less secure compared to the other clinical and normal comparison groups. Parents of non-clinical children reported higher levels of authoritative parenting than parents in the ASD group and in the total clinical group, and they also received less social support. Parents of children with ASD coped remarkably well with the challenges of raising a child with ASD.


Amniotic membrane can be a valid source for wound healing.
Amniotic membrane (AM) can promote proper epithelialization with suppression of excessive fibrosis by creating a supportive milieu for regeneration of chronic ulcer bed. The objective of this study is to investigate whether AM scaffold can modulate the healing of a wound by promoting tissue reconstruction rather than promoting scar tissue formation. AM was obtained and prepared and then applied to patients with chronic leg ulcers who were randomly divided into two different groups. Group I (control group) included eleven patients in whom ulcers were treated with conventional wound dressings that were changed daily for 8 weeks. Group II (study group) included 14 patients in whom the AM was placed in contact with the ulcer and held in place with a secondary dressing, which was changed daily. Follow-up was done to detect healing rate and detection of ulcer size, assessment of pain, and to take ulcer images (days 0, 7, 14, 21, 30, 45, and 60). In group I, all ulcers showed no reduction in their size, and ulcer floor remained the same. Healthy granulations were present in two ulcers (18.2%) and absent in nine ulcers (81.8%). There was no improvement of pain level in the eleven ulcers. In group II, complete healing of 14 ulcers occurred in 14-60 days with a mean of 33.3±14.7; healing rate range was 0.064-2.22 and the mean 0.896±0.646 cm(2)/day. Healthy granulations were present in 13 ulcers (92.9%) and absent in one ulcer (7.1%). Three ulcers (21.4%) were of mild severity (grade 1 ulcers) while eleven ulcers (78.6%) were of moderate severity (grade 2 ulcers). The healing rate was faster in ulcers of mild severity (1.7±0.438 cm(2)/day) in comparison to ulcers of moderate severity (0.673±0.498 cm(2)/day). Eleven cases (78.6%) showed improvement in their pain level on a scale from 0 to 10. AM graft can be of value in wound healing. Further studies are needed to confirm these findings.


Efficacy of live attenuated vaccines against 2009 pandemic H1N1 influenza in ferrets.
The advent of the H1N1 influenza pandemic (pH1N1) in 2009 triggered the rapid production of pandemic influenza vaccines, since seasonal influenza vaccines were expected and demonstrated not to provide significant cross-protection against the newly emerged pandemic virus. To increase vaccine production capacity and further evaluate the effectiveness of different candidate pandemic influenza vaccines, the World Health Organization stimulated the evaluation of different vaccination concepts including the use of live attenuated influenza vaccines (LAIVs). Therefore, we have immunized ferrets intranasally with a single dose of pH1N1-LAIV from different manufacturers. They all induced adequate serum HI antibody titers in the ferrets and protected them against intratracheal wild-type pH1N1 virus challenge: pH1N1 virus replication in the upper respiratory tract and lungs was reduced and no disease signs or severe broncho-interstitial pneumonia were observed in any of the vaccinated ferrets. These data together with the relatively efficient production process emphasize the potential of the LAIV concept for pandemic preparedness.


The development of chromatography for the characterization of protein interactions: a personal perspective.
This article reviews the progress of a personal endeavour to develop chromatography as a quantitative procedure for the determination of reaction stoichiometries and equilibrium constants governing protein interactions. As well as affording insight into an aspect of chromatography with which many protein chemists are unfamiliar, it shows the way in which minor adaptations of conventional chromatographic practices have rendered the technique one of the most powerful methods available for the characterization of interactions. That pathway towards quantification is followed from the introduction of frontal gel filtration for the study of protein self-association to the characterization of ligand binding by the biosensor variant of quantitative affinity chromatography.


Are attitudes towards economic risk heritable? Analyses using the Australian twin study of gambling.
Abstract This study employs multiple regression models based on DeFries and Fulker (1985), and a large sample of twins, to assess heritability in attitudes towards economic risk, and the extent to which this heritability differs between males and females. Consistent with Cesarini et al. (2009), it is found that attitudes towards risk are moderately heritable, with about 20 percent of the variation in these attitudes across individuals being linked to genetic differences. This value is less than one-half the estimates reported by Zyphur et al. (2009) and Zhong et al. (2009). While females are more risk averse than males, there is no evidence that heritability in attitudes towards risk differs between males and females. Even though heritability is shown to be important to economic risk-taking, the analyses suggest that multivariate studies of the determinants of attitudes towards risk which to not take heritability into consideration still provide reliable estimates of the partial effects of other key variables, such as gender and educational attainment.


Relation between QT and RR intervals in patients with bradyarrhythmias.
To investigate the relation between QT and RR intervals in the sick sinus syndrome or high degree atrioventricular block. 32 patients with episodes of prolonged RR intervals (> or = 2.6 s) on Holter electrocardiographic recordings. QT and RR intervals were measured manually every 100 to 150 beats on electrocardiographic strips reprinted from the Holter tape over 24 hours. The slope of the QT/RR relation was determined by the linear regression equation for RR intervals < or = 1.4 s (slope 1) and > 1.4 s (slope 2). Slope 2 (0.0068 (0.0030)) was significantly lower than slope 1 (0.0824 (0.0059), P < 0.0001) in the overall patient population. Slopes 1 and 2 were significantly lower (P < 0.001) in the 23 patients with QT intervals at the preceding RR interval of 1 s (QT1s) of < 0.44 s (0.0692 (0.0053) and 0.0019 (0.0030), respectively) than in the nine patients with QT1s intervals > or = 0.44 s (0.1159 (0.0091) and 0.0194 (0.0055), respectively). Slopes 1 and 2 correlated positively with QT1s interval in all patients. The QT/RR relation was comparatively flat when the RR interval was prolonged. Patients with prolonged QT intervals showed exaggerated prolongation of the QT interval with prolonged cycle lengths when compared with patients with normal QT intervals.


Hormonal and neuromuscular responses during a singles match in male professional tennis players.
We sought to measure the response of cortisol concentrations around a professional tennis match and its association with hydration status and neuromuscular performance. Nine professional male tennis players were tested in a rest day, and 2-week after, during the first match of a professional tournament played in a clay-court. Salivary concentrations of cortisol (SalCC) were measured in a resting day (9:00 am and 8:00 pm), at the match day (9:00 am and 8:00 pm) and immediately before and after the match. Hydration status was assessed before the match (urine specific gravity; USG) while fluid turnover was tracked during the match. Finally, counter movement jump (CMJ) and handgrip isometric strength (HS) were measured before and after the match. SalCC, either in the morning (P = 0.161) and afternoon (P = 0.683) was similar in rest and match days. However, SalCC increased after the match (P = 0.033). Participants started the match hypohydrated (USG = 1.026±0.002) and during the match lost 1.0±0.3% of body weight despite 1.035±0.124 L/h of fluid ingested. CMJ and HS did not change post-match (P = 0.210 and P = 0.881, respectively). Correlations between the elevations in SalCC and dehydration (% BW loss) during the match were significant (r = -0.632; P = 0.034). Professional male tennis players did not show an anticipatory increase in SalCC the day of the match and neither signs of neuromuscular fatigue after it. During the match, the mild dehydration (i.e., <1.5%) was associated with the increases in cortisol levels which suggests that dehydration may be an added stress to be considered.


Contextual Information Modulates Pupil Size in Autistic Children.
Recent Bayesian models suggest that perception is more "data-driven" and less dependent on contextual information in autistic individuals than others. However, experimental tests of this hypothesis have given mixed results, possibly due to the lack of objectivity of the self-report methods typically employed. Here we introduce an objective no-report paradigm based on pupillometry to assess the processing of contextual information in autistic children, together with a comparison clinical group. After validating in neurotypical adults a child-friendly pupillometric paradigm, in which we embedded test images within an animation movie that participants watched passively, we compared pupillary response to images of the sun and meaningless control images in children with autism vs. age- and IQ-matched children presenting developmental disorders unrelated to the autistic spectrum. Both clinical groups showed stronger pupillary constriction for the sun images compared with control images, like the neurotypical adults. However, there was no detectable difference between autistic children and the comparison group, despite a significant difference in pupillary light responses, which were enhanced in the autistic group. Our report introduces an objective technique for studying perception in clinical samples and children. The lack of statistically significant group differences in our tests suggests that autistic children and the comparison group do not show large differences in perception of these stimuli. This opens the way to further studies testing contextual processing at other levels of perception.


Metabolic Engineering of Wheat Provitamin A by Simultaneously Overexpressing CrtB and Silencing Carotenoid Hydroxylase (TaHYD).
Increasing the provitamin A content in staple crops via carotenoid metabolic engineering is one way to address vitamin A deficiency. In this work a combination of methods was applied to specifically increase β-carotene content in wheat by metabolic engineering. Endosperm-specific silencing of the carotenoid hydroxylase gene (TaHYD) increased β-carotene content 10.5-fold to 1.76 μg g(-1) in wheat endosperm. Overexpression of CrtB introduced an additional flux into wheat, accompanied by a β-carotene increase of 14.6-fold to 2.45 μg g(-1). When the "push strategy" (overexpressing CrtB) and "block strategy" (silencing TaHYD) were combined in wheat metabolic engineering, significant levels of β-carotene accumulation were obtained, corresponding to an increase of up to 31-fold to 5.06 μg g(-1). This is the first example of successful metabolic engineering to specifically improve β-carotene content in wheat endosperm through a combination of methods and demonstrates the potential of genetic engineering for specific nutritional enhancement of wheat.


Identification of the cAMP response element that controls transcriptional activation of the insulin-like growth factor-I gene by prostaglandin E2 in osteoblasts.
Insulin-like growth factor-I (IGF-I), a multifunctional growth factor, plays a key role in skeletal growth and can enhance bone cell replication and differentiation. We previously showed that prostaglandin E2 (PGE2) and other agents that increase cAMP activated IGF-I gene transcription in primary rat osteoblast cultures through promoter 1 (P1), the major IGF-I promoter, and found that transcriptional induction was mediated by protein kinase A. We now have identified a short segment of P1 that is essential for full hormonal regulation and have characterized inducible DNA-protein interactions involving this site. Transient transfections of IGF-I P1 reporter genes into primary rat osteoblasts showed that the 328-base pair untranslated region of exon 1 was required for a full 5.3-fold response to PGE2; mutation in a previously footprinted site, HS3D (base pairs +193 to +215), reduced induction by 65%. PGE2 stimulated nuclear protein binding to HS3D. Binding, as determined by gel mobility shift assay, was not seen in nuclear extracts from untreated osteoblast cultures, was detected within 2 h of PGE2 treatment, and was maximal by 4 h. This DNA-protein interaction was not observed in cytoplasmic extracts from PGE2-treated cultures, indicating nuclear localization of the protein kinase A-activated factor(s). Activation of this factor was not blocked by cycloheximide (Chx), and Chx did not impair stimulation of IGF-I gene expression by PGE2. In contrast, binding to a consensus cAMP response element (CRE; 5'-TGACGTCA-3') from the rat somatostatin gene was not modulated by PGE2 or Chx. Competition gel mobility shift analysis using mutated DNA probes identified 5'-CGCAATCG-3' as the minimal sequence needed for inducible binding. All modified IGF-I P1 promoterreporter genes with mutations within this CRE sequence also showed a diminished functional response to PGE2. These results identify the CRE within the 5'-untranslated region of IGF-I exon 1 that is required for hormonal activation of IGF-I gene transcription by cAMP in osteoblasts.


Geographical and demographic clustering of gonorrhoea in London.
Gonorrhoea is an important cause of sexual ill health and is concentrated in geographical areas and demographic groups. This study explores the distribution of gonorrhoea across London. Epidemiological data on all gonorrhoea cases were collected from 13 major genitourinary clinics in London between 1 June and 30 November 2004. Samples were stored centrally and typed using NG-MAST. The postcode of each case's main residence was used to calculate incidence of gonorrhoea by borough using data from the UK 2001 census and a population survey on residence of men who have sex with men (MSM). 2,891 cases were confirmed, 1,822 of which had postcode data, resided in London, and had their strain successfully typed. There was a very high incidence of gonorrhoea in MSM (1,834 per 100,000 population) and heterosexuals of black ethnicity (392 per 100,000). The incidence among heterosexuals was highest in City of London (390 per 100,000, 95% CI 213 to 566), Southwark (308 per 100,000, 95% CI 280 to 336), Hackney (284 per 100,000, 95% CI 254 to 313), and Lambeth (216 per 100,000, 95% CI 194 to 239) and was not associated with measures of social deprivation (correlation coefficient = 0.0008, p = 0.97) but was strongly associated with black ethnicity (correlation coefficient = 0.48, p = 0.01). 45% of cases had one of the 21 major strains; eight of these strains were significantly clustered geographically and persisted for a shorter duration than those that were not clustered. Patients travelled a mean of 7.7 km from their home to the clinic. High gonorrhoea incidence in London is observed in MSM and heterosexuals of black ethnicity. Endemic strains in both MSM and heterosexuals are diagnosed at multiple clinics. Interventions, including partner notification, must therefore operate between clinics.


Emergency Medical Services Outcomes Project (EMSOP) IV: pain measurement in out-of-hospital outcomes research.
The purpose of the Emergency Medical Services Outcomes Project (EMSOP) is to develop a foundation and framework for out-of-hospital outcomes research. In prior work (EMSOP I), discomfort had the highest weighted score among outcome categories for the top 3 adult conditions (ie, minor trauma, respiratory distress, chest pain) and the first and third highest rankings for children's conditions (ie, minor trauma, respiratory distress). In this fourth article in the EMSOP series, we discuss issues relevant to the measurement of pain in the out-of-hospital setting, recommended pain measures that require evaluation, and implications for outcomes research focusing on pain. For adults, adolescents, and older children, 2 verbal pain-rating scales are recommended for out-of-hospital evaluation: (1) the Adjective Response Scale, which includes the responses "none," "slight," "moderate," "severe," and "agonizing," and (2) the Numeric Response Scale, which includes responses from 0 (no pain) to 100 (worst pain imaginable). The Oucher Scale, combining a visual analog scale with pictures, seems most promising for out-of-hospital use among younger children. Future research in out-of-hospital care should be conducted to determine the utility and feasibility of these measures, as well as the effectiveness of interventions for pain relief.


A comparative study of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine and dapsone) as chemoprophylactics against malaria in Gambian children.
A comparison has been made of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine +dapsone) as malaria chemoprophylactics when given every two weeks for 3 years to Gambian children under the age of 5 years. Both drugs produced falls in spleen and malaria parasite rates and an increase in packed cell volume. Maloprim, but not chlorproguanil, significantly reduced the incidence of episodes of fever accompanied by malaria parasitaemia. Children who received Maloprim, but not those who received chlorproguanil, grew better than children in the placebo group. This finding suggests that brief clinical episodes of malaria are more important in impairing growth than more prolonged periods of asymptomatic parasitaemia. No serious side-effect attributable to either drug was observed. After chemoprophylaxis had been given for 3 malaria transmission seasons the level of resistance of Plasmodium falciparum to pyrimethamine and to chlorproguanil was about 10%.


Association of Body Mass Index Changes during Neoadjuvant Chemotherapy with Pathologic Complete Response and Clinical Outcomes in Patients with Locally Advanced Breast Cancer.
The purpose of this study was to determine the association between body mass index (BMI) measurements (baseline BMI and changes in BMI during neoadjuvant systemic treatment [NST]) and clinical efficacy (pathologic complete response [pCR] rate and survival outcomes) in locally advanced breast cancer (LABC). We hypothesized that high baseline BMI and increases in BMI during NST are associated with lower pCR rates and poorer clinical outcomes in LABC. We retrospectively reviewed the medical records of 1002 patients, 204 with primary inflammatory breast cancer (IBC) and 798 with stage III non-IBC, who underwent standard NST and definitive surgery between November 1, 2006, and December 31, 2012. The median follow-up time for the survivors was 19.6 months (0.4 - 67.8 months). The pCR rates of patients whose BMI increased or decreased were 23.2% and 18.1%, respectively, (p=0.048). The unadjusted overall survival (OS) was significantly better in the group with increased BMI (p=0.006). However, increased BMI was not an independent predictor of pCR and clinical outcomes (recurrence-free survival and OS) after adjusting for other clinical variables. In subset analyses, increased BMI as a continuous variable was an independent predictor of higher pCR rates in the normal BMI/underweight group (odds ratio [OR]=1.35, 95% confidence interval [CI]: 1.06-0.71, p=0.015). Increased BMI (BMI change ≥0 vs. <0) was also an independent predictor of pCR (OR=1.65, 95% CI: 1.00-2.72, p=0.049) in the postmenopausal group. Our results show that increasing BMI shows improved clinical outcome in terms of better pCR rates in normal BMI/underweight group and in the postmenopausal group. These results contradict previously reported findings on the association between high BMI and poor clinical efficacy regarding pCR rate and survival outcomes in early-stage breast cancer. Thus, the role of BMI in breast cancer may depend on patients' clinical characteristics such as advanced stage.


The value of immunofluorescence in the study of human renal disease.
Immunofluorescence is a useful technique in the study of human renal diseases, both from the point of view of elucidating pathogenic mechanisms and as a diagnostic tool. The finding of characteristic staining patterns for immunoglobulins and complement indicates that many forms of glomerulonephritis are immune complex diseases and that a few are due to anti-GBM antibodies. On the other hand, in lipoid nephrosis and toxemia of pregnancy, deposits of immunoglobulins and complement are generally absent, indicating that immunologic mechanisms are probably not responsible for these glomerular diseases. The finding of fibrin or other fibrinogen derivatives in glomeruli in toxemia of pregnancy and in certain forms of glomulonephritis supports the interpretation that these substances play a pathogenic role in certain glomerular diseases. The use of immunofluorescence has led to the recognition of two previously unrecognized renal diseases: nephropathy with mesangial IgA-IgG deposits (Berger), and a tubular disorder with deposits of immunoglobulins and complement along the basement membrane.


Molecular Aspects of Varicella-Zoster Virus Latency.
Primary varicella-zoster virus (VZV) infection causes varicella (chickenpox) and the establishment of a lifelong latent infection in ganglionic neurons. VZV reactivates in about one-third of infected individuals to cause herpes zoster, often accompanied by neurological complications. The restricted host range of VZV and, until recently, a lack of suitable in vitro models have seriously hampered molecular studies of VZV latency. Nevertheless, recent technological advances facilitated a series of exciting studies that resulted in the discovery of a VZV latency-associated transcript (VLT) and provide novel insights into our understanding of VZV latency and factors that may initiate reactivation. Deducing the function(s) of VLT and the molecular mechanisms involved should now be considered a priority to improve our understanding of factors that govern VZV latency and reactivation. In this review, we summarize the implications of recent discoveries in the VZV latency field from both a virus and host perspective and provide a roadmap for future studies.


Characteristics of sudden potential drop in bullfrog gastric mucosa.
An unusual sudden potential drop (SPD) has been described by Kidder in bullfrog gastric mucosa exposed to anoxia and a serosal pH less than or equal to 7.1. We found that anoxia was not a prerequisite, since under fully oxygenated conditions the SPD occurred reliably in metiamide-treated tissues when the pH of the nutrient solution (pHN) was below 7.1. The SPD was observed also in metiamide-treated tissues exposed to 20 mM luminal or nutrient acetylsalicylic acid (ASA) with pHN = 7.3, an effect that was abolished by increased nutrient HCO3- concentration. The SPD occurred when NO3- but not isethionate or acetate replaced Cl- in the bathing media. A marked increase in potential difference in response to changing luminal Cl- concentration was observed after the SPD, uptake of Cl- from the luminal solution into the tissue increased, but transmural fluxes of Cl- decreased bidirectionally. Permeability to H+ was unaltered in the post-SPD state. An SPD never occurred in antrum under conditions causing SPD in fundus, suggesting that oxyntic cells are prerequisite. We conclude that, under conditions which cause tissue or cellular acidosis and cessation of H+ secretion, fundic mucosae respond with an anion-selective increase in apical permeability manifest as the SPD.


Noise-induced modulation of the relaxation kinetics around a non-equilibrium steady state of non-linear chemical reaction networks.
Stochastic effects from correlated noise non-trivially modulate the kinetics of non-linear chemical reaction networks. This is especially important in systems where reactions are confined to small volumes and reactants are delivered in bursts. We characterise how the two noise sources confinement and burst modulate the relaxation kinetics of a non-linear reaction network around a non-equilibrium steady state. We find that the lifetimes of species change with burst input and confinement. Confinement increases the lifetimes of all species that are involved in any non-linear reaction as a reactant. Burst monotonically increases or decreases lifetimes. Competition between burst-induced and confinement-induced modulation may hence lead to a non-monotonic modulation. We quantify lifetime as the integral of the time autocorrelation function (ACF) of concentration fluctuations around a non-equilibrium steady state of the reaction network. Furthermore, we look at the first and second derivatives of the ACF, each of which is affected in opposite ways by burst and confinement. This allows discriminating between these two noise sources. We analytically derive the ACF from the linear Fokker-Planck approximation of the chemical master equation in order to establish a baseline for the burst-induced modulation at low confinement. Effects of higher confinement are then studied using a partial-propensity stochastic simulation algorithm. The results presented here may help understand the mechanisms that deviate stochastic kinetics from its deterministic counterpart. In addition, they may be instrumental when using fluorescence-lifetime imaging microscopy (FLIM) or fluorescence-correlation spectroscopy (FCS) to measure confinement and burst in systems with known reaction rates, or, alternatively, to correct for the effects of confinement and burst when experimentally measuring reaction rates.


Modelling survival: exposure pattern, species sensitivity and uncertainty.
The General Unified Threshold model for Survival (GUTS) integrates previously published toxicokinetic-toxicodynamic models and estimates survival with explicitly defined assumptions. Importantly, GUTS accounts for time-variable exposure to the stressor. We performed three studies to test the ability of GUTS to predict survival of aquatic organisms across different pesticide exposure patterns, time scales and species. Firstly, using synthetic data, we identified experimental data requirements which allow for the estimation of all parameters of the GUTS proper model. Secondly, we assessed how well GUTS, calibrated with short-term survival data of Gammarus pulex exposed to four pesticides, can forecast effects of longer-term pulsed exposures. Thirdly, we tested the ability of GUTS to estimate 14-day median effect concentrations of malathion for a range of species and use these estimates to build species sensitivity distributions for different exposure patterns. We find that GUTS adequately predicts survival across exposure patterns that vary over time. When toxicity is assessed for time-variable concentrations species may differ in their responses depending on the exposure profile. This can result in different species sensitivity rankings and safe levels. The interplay of exposure pattern and species sensitivity deserves systematic investigation in order to better understand how organisms respond to stress, including humans.


Gender differences in biometry prediction error and intra-ocular lens power calculation formula.
To analyze changes over time in biometry prediction error (BPE) after cataract surgery with special reference to the impact of gender and the intra-ocular lens (IOL) calculation formula. About 65% of Swedish cataract surgery units participating in the outcome registration of the National Cataract Register (NCR) were included in this prospective register study. Data for planned and postoperative refraction and keratometry during the month of March 2004-2013 were analyzed, divided by gender. The newly introduced variables axial length and IOL calculation formula were analyzed for March 2013. Gender differences in BPE with correct sign (BPESign ) and absolute biometry prediction error (BPEAbs ) were compared for the Haigis' and Sanders-Retzlaff-Kraff T (SRK/T) formulas. The BPEAbs decreased throughout the study period. In 2004-2006, the BPEAbs was larger in women than in men (p < 0.05), but this difference disappeared from 2007. For 2004 through 2009, the mean BPESign was -0.105 ± 0.79D for women, but -0.003 ± 0.73D for men. After 2009, this myopic error for women gradually diminished. The Haigis' formula performed better in women than the SRK/T formula (p < 0.001); the SRK/T formula rendered a BPESign similar to that from 2004 to 2009 in women. Women had steeper corneas and shorter axial lengths than men (p < 0.001). The myopic BPE in women - associated with steeper corneas and shorter axial lengths - is decreasing, possibly owing to an increased use of the Haigis' formula. Using the Haigis' formula to a higher extent can potentially further reduce the BPEs after cataract surgery.


MetaCyto: A Tool for Automated Meta-analysis of Mass and Flow Cytometry Data.
While meta-analysis has demonstrated increased statistical power and more robust estimations in studies, the application of this commonly accepted methodology to cytometry data has been challenging. Different cytometry studies often involve diverse sets of markers. Moreover, the detected values of the same marker are inconsistent between studies due to different experimental designs and cytometer configurations. As a result, the cell subsets identified by existing auto-gating methods cannot be directly compared across studies. We developed MetaCyto for automated meta-analysis of both flow and mass cytometry (CyTOF) data. By combining clustering methods with a silhouette scanning method, MetaCyto is able to identify commonly labeled cell subsets across studies, thus enabling meta-analysis. Applying MetaCyto across a set of ten heterogeneous cytometry studies totaling 2,926 samples enabled us to identify multiple cell populations exhibiting differences in abundance between demographic groups. Software is released to the public through Bioconductor (http://bioconductor.org/packages/release/bioc/html/MetaCyto.html).


Congenital blindness is associated with large-scale reorganization of anatomical networks.
Blindness is a unique model for understanding the role of experience in the development of the brain's functional and anatomical architecture. Documenting changes in the structure of anatomical networks for this population would substantiate the notion that the brain's core network-level organization may undergo neuroplasticity as a result of life-long experience. To examine this issue, we compared whole-brain networks of regional cortical-thickness covariance in early blind and matched sighted individuals. This covariance is thought to reflect signatures of integration between systems involved in similar perceptual/cognitive functions. Using graph-theoretic metrics, we identified a unique mode of anatomical reorganization in the blind that differed from that found for sighted. This was seen in that network partition structures derived from subgroups of blind were more similar to each other than they were to partitions derived from sighted. Notably, after deriving network partitions, we found that language and visual regions tended to reside within separate modules in sighted but showed a pattern of merging into shared modules in the blind. Our study demonstrates that early visual deprivation triggers a systematic large-scale reorganization of whole-brain cortical-thickness networks, suggesting changes in how occipital regions interface with other functional networks in the congenitally blind.


Stereotactic radiosurgery for intracranial hemangioblastomas: a retrospective international outcome study.
The purpose of this study was to evaluate the role of stereotactic radiosurgery (SRS) in the management of intracranial hemangioblastomas. Six participating centers of the North American Gamma Knife Consortium and 13 Japanese Gamma Knife centers identified 186 patients with 517 hemangioblastomas who underwent SRS. Eighty patients had 335 hemangioblastomas associated with von Hippel-Lindau disease (VHL) and 106 patients had 182 sporadic hemangioblastomas. The median target volume was 0.2 cm(3) (median diameter 7 mm) in patients with VHL and 0.7 cm(3) (median diameter 11 mm) in those with sporadic hemangioblastoma. The median margin dose was 18 Gy in VHL patients and 15 Gy in those with sporadic hemangioblastomas. At a median of 5 years (range 0.5-18 years) after treatment, 20 patients had died of intracranial disease progression and 9 patients had died of other causes. The overall survival after SRS was 94% at 3 years, 90% at 5 years, and 74% at 10 years. Factors associated with longer survival included younger age, absence of neurological symptoms, fewer tumors, and higher Karnofsky Performance Status. Thirty-three (41%) of the 80 patients with VHL developed new tumors and 17 (16%) of the106 patients with sporadic hemangioblastoma had recurrences of residual tumor from the original tumor. The 5-year rate of developing a new tumor was 43% for VHL patients, and the 5-year rate of developing a recurrence of residual tumor from the original tumor was 24% for sporadic hemangioblastoma patients. Factors associated with a reduced risk of developing a new tumor or recurrences of residual tumor from the original tumor included younger age, fewer tumors, and sporadic rather than VHL-associated hemangioblastomas. The local tumor control rate for treated tumors was 92% at 3 years, 89% at 5 years, and 79% at 10 years. Factors associated with an improved local tumor control rate included VHL-associated hemangioblastoma, solid tumor, smaller tumor volume, and higher margin dose. Thirteen patients (7%) developed adverse radiation effects (ARE) after SRS, and one of these patients died due to ARE. When either sporadic or VHL-associated tumors were observed to grow on serial imaging studies, SRS provided tumor control in 79%-92% of tumors.


Cost-effectiveness of alternative strategies for use of 13-valent pneumococcal conjugate vaccine (PCV13) in Canadian adults.
The Canadian National Advisory Committee on Immunization (NACI) recommends use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in a sequential schedule (PCV13 → PPV23) among adults aged ≥ 65 years and those aged ≥ 18 years who are immunocompromised. In light of recent PCV13 efficacy data from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), and new sero-epidemiology data on community-acquired pneumonia (CAP), we examined the economic implications of funding an expanded adult pneumococcal immunization program in Canada. A microsimulation model depicting expected lifetime risks, consequences, and costs of invasive pneumococcal disease (IPD) and CAP was developed. PPV23 effectiveness was based on published literature, and PCV13 effectiveness was based on CAPiTA; all other model parameters were based on published data or secondary sources. Herd effects from the PCV13 pediatric program were considered. Outcomes and costs were evaluated assuming use of PPV23 alone, and alternatively, use of PCV13 → PPV23 among (1) all adults aged ≥ 65 years (n = 5.4 M) and (2) immunocompromised and high-risk adults aged ≥ 65 years (n = 3.0 M). For population no. 1, PCV13 → PPV23 reduced IPD cases by 1100, CAP cases by 7000, and disease costs by $135.8M; vaccination costs increased by $254.3M, and cost per QALY gained was $35,484. For population no. 2, PCV13 → PPV23 reduced IPD cases by 900, CAP cases by 6000, and disease costs by $120.3M; vaccination costs increased by $149.8M, and cost per QALY gained was $10,728. Expanding use of PCV13 → PPV23 by funding PCV13 among Canadian adults aged ≥ 65 would be a cost-effective use of healthcare resources.


First results of a uniform regional treatment protocol and registration for acute prosthetic join infection in the South-East of the Netherlands.
Introduction: Prosthetic joint infection (PJI) is a relatively uncommon (average incidence 0.5-2%) but devastating complication, with significant morbidity and leading to tremendously increased health care costs. In 2013, delegates from nine hospitals covering a large region in the South-East Netherlands composed one combined treatment protocol for acute PJI of total hip and knee arthroplasty (THA and TKA). This protocol was based on the definition of acute PJI according to Workgroup of the American Musculoskeletal Infection Society (MSIS) and the principles of debridement, antibiotics, irrigation and retention (DAIR). Methods: Patients with a THA or TKA treated with DAIR because of suspicion of PJI were selected from the online PJI database. PJI was defined as at least two phenotypically identical pathogens, isolated in cultures from at least two separate tissues, obtained from the affected prosthetic joint. Acute PJIs, occurring within 90 days after primary implantation, between January 2014 and December 2016, were analyzed. We analyzed the PJI incidence rate, patient clinical and microbiological characteristics of PJI, outcome of the DAIR treatment and adherence to the regional protocol. Results: A total of 310 primary THA or TKA with a suspected PJI were registered in the regional PJI database, 236 met the definition of acute PJI, representing overall incidence of 1.12%. Following the regional treatment protocol replacement of exchangeable parts took place in 45% in 2014 to 70% in 2016. After 12 months follow-up, prosthesis retention was achieved in 87% and 3% of the patients died within one year after the primary surgery. Conclusion: Results of the regional cohort are in line with the available literature. Regional collaboration and regular feedback on registered data resulted in better adherence to the combined treatment protocol. Despite our attempts to improve PJI care, PJI remains a serious complication of THA and TKA with a significant mortality rate and burden for the patient.