Curcumin inhibits proliferation and induces apoptosis of human colorectal cancer cells by activating the mitochondria apoptotic pathway.
Curcumin, a natural plant extract from Curcuma longa, is known for its anti-carcinogenic and chemopreventive effects on a variety of experimental cancer models. In this study, we evaluated the effects of curcumin and elucidated its mechanism in human colorectal carcinoma cells. Cell viability assay showed that curcumin significantly inhibited the growth of LoVo cells. Curcumin treatment induced the apoptosis accompanied by ultra-structural changes and release of lactate dehydrogenase in a dose-dependent manner. Moreover, treatment with 0-30 µg/mL curcumin decreased the mitochondrial membrane potential and activated the caspase-3 and caspase-9 in a dose- and time-dependent manner. Nuclear and annexin V/PI staining showed that curcumin induced the apoptosis of LoVo cells. FACS analysis revealed that curcumin could induce the cell cycle arrest of LoVo cells at the S phase. Furthermore, western blotting analysis indicated that curcumin induced the release of cytochrome c, a significant increase of Bax and p53 and a marked reduction of Bcl-2 and survivin in LoVo cells. Taken together, our results suggested that curcumin inhibited the growth of LoVo cells by inducing apoptosis through a mitochondria-mediated pathway.


Molecular pathways underlying tissue injuries in the bladder with ketamine cystitis.
Ketamine cystitis (KC) is a chronic bladder inflammation leading to urinary urgency, frequency, and pain. The pathogenesis of KC is complicated and involves multiple tissue injuries in the bladder. Recent studies indicated that urothelium disruption, lamina propria fibrosis and inflammation, microvascular injury, neuropathological alterations, and bladder smooth muscle (BSM) abnormalities all contribute to the pathogenesis of KC. Ketamine has been shown to induce these tissue injuries by regulating different signaling pathways. Ketamine can stimulate antiproliferative factor, adenosine triphosphate, and oxidative stress to disrupt urothelium. Lamina propria fibrosis and inflammation are associated with the activation of cyclooxygenase-2, nitric oxide synthase, immunoglobulin E, and transforming growth factor β1. Ketamine contributes to microvascular injury via the N-methyl-D aspartic receptor (NMDAR), and multiple inflammatory and angiogenic factors such as tumor necrosis factor α and vascular endothelial growth factor. For BSM abnormalities, ketamine can depress the protein kinase B, extracellular signal-regulated kinase, Cav1.2, and muscarinic receptor signaling. Elevated purinergic signaling also plays a role in BSM abnormalities. In addition, ketamine affects neuropathological alterations in the bladder by regulating NMDAR- and brain-derived neurotrophic factor-dependent signaling. Inflammatory cells also contribute to neuropathological changes via the secretion of chemical mediators. Clarifying the role and function of these signaling underlying tissue injuries in the bladder with KC can contribute to a better understanding of the pathophysiology of this disease and to the design of effective treatments for KC.


Prognosis in solitary intraventricular haemorrhage. Clinical and computed tomographic observations.
Isolated intraventricular haemorrhage (IVH) in the absence of parenchymal haematoma is unusual. Fifteen patients with solitary IVH among 170 with intracranial haemorrhage were studied. Clinical details and computed tomographic features were analysed to evaluate the prognostic significance of various clinical and CT parameters. Outcome is affected by hypertension, level of consciousness, clinical progression, pupillary changes and restriction of eye movements. Factors found on CT to have prognostic significance included degree of ventricular bleed, presence of cisternal bleed, hydrocephalus and cerebral atrophy.


Nicotine replacement: ten-week effects on tobacco withdrawal symptoms.
This study examined the long-term effects of nicotine replacement on tobacco withdrawal symptoms. Smokers (N = 40 community volunteers) maintained biologically validated smoking abstinence under closely monitored conditions while chewing 2 mg nicotine gum (Nicorette; average of 6.9 pieces per day) or placebo gum during the first 10 weeks following smoking cessation. During the first postcessation week symptoms of irritability, anxiety, impatience, restlessness, excessive hunger, difficulty concentrating, drowsiness, sleep disturbance and tobacco craving intensity were significantly lower in active as compared with placebo nicotine gum subjects. Symptoms of psychological distress including irritability, anxiety and impatience declined over time in placebo subjects and were suppressed by replacement therapy below placebo treatment levels only during the first 4-5 weeks after smoking cessation. On other items, most notably increased appetite and excessive eating, stable between-group differences persisted over the entire 10-week trial. The data suggest that use of active gum beyond the first 5 weeks post-cessation may be inconsequential as far as suppression of certain key symptoms of psychological disturbance is concerned, but more prolonged use of active gum would be advisable if the long-term nicotine replacement effects observed (e.g. decreased hunger) are relevant to smoking relapse prevention.


Daily prostate volume and position monitoring using implanted gold markers and on-board imaging during radiotherapy.
This study aimed to evaluate prostate volume changes and prostate motions during radiotherapy. In 2010, twenty-five patients were treated for prostate cancer by external beam radiotherapy with implanted fiducial markers. Coordinates of three gold markers on kilovoltage images were calculated daily. Volume changes in target structure were observed through changes in intermarker distances. Differences in patient position between laser-tattoo alignment and gold marker localization were evaluated. Intrafraction motion was assessed by measuring marker displacement on kilovoltage images acquired before and after fraction delivery. Prostate shrinkage was observed in 60% of patients. The average shrinkage was 7% of the prostate's initial volume. Corrections after laser-tattoo alignment remained mostly below 1 cm. The difference between marker centroid position on the actual images and the planning images was 2 +/- 1 mm on average. The extension of intrafraction movements was 7.6 +/- 0.2 mm on average. In our retrospective study, the possibility for prostate volume changes during radiotherapy was revealed. Intrafraction movements turned out to be the limiting factor in safety margin reduction.


Splashing of a water drop.
Measurements have been made of the number of spray droplets produced by the impact of a water drop on water, and of the charge to mass ratio for these droplets. For a drop 3 millimeters in diameter, the number of spray droplets increases linearly with the fall-distance of the drop over the range 10 to 200 centimeters. When the drop falls 100 centimeters, about 25 spray droplets are produced. The majority of the droplets carry a negative charge, and the ratio of the charge to the mass varies from 4 to 28 electrostatic units per gram.


Activity-based costing technology adoption in Australian universities.
Strategic cost management is vital to the Australian university sector's performance, and activity-based costing (ABC) is a widely accepted and used accounting technology assisting with this. We examine the status of ABC technology adoption in two categories-adopters and non-adopters of the technology-informed by Technology Diffusion Framework, Social Cognitive Theory and Dynamic Theory of Strategy. The study collected data by sending a pilot-tested survey questionnaire to senior executives for electronic completion. From the 39 universities that elected to participate, 24 usable responses were received, representing a 61% response rate. The data were analyzed using cognitive characteristics supported by Social Cognitive Theory, and organizational characteristics supported by the Dynamic Theory of Strategy of universities ABC technology adopter and non-adopter status. Cognitive characteristics provide a qualitative explanation, but selected determinants show no statistical significance. Organizational characteristics also provide a qualitative explanation and show organizational revenue is the most significant determinant; followed by universities located outside the cities, and in the southern part of Australia, have more propensity for ABC technology adoption.


Food groups and risk of colorectal cancer in Italy.
The proportion of colorectal cancer attributed to dietary habits is high, but several inconsistencies remain, especially with respect to the influence of some food groups. To further elucidate the role of dietary habits, 1,225 subjects with cancer of the colon, 728 with cancer of the rectum and 4,154 controls, hospitalized with acute non-neoplastic diseases, were interviewed between 1992 and 1996 in 6 different Italian areas. The validated food-frequency questionnaire included 79 questions on food items and recipes, categorised into 16 food groups. After allowance for non-dietary confounding factors and total energy intake, significant trends of increasing risk of colorectal cancer with increasing intake emerged for bread and cereal dishes (odds ratio [OR] in highest vs. lowest quintile = 1.7), potatoes (OR = 1.2), cakes and desserts (OR = 1.1), and refined sugar (OR = 1.4). Intakes of fish (OR = 0.7), raw and cooked vegetables (OR = 0.6 for both) and fruit other than citrus fruit (OR = 0.7) showed a negative association with risk. Consumption of eggs and meat (white, red or processed meats) seemed uninfluential. Most findings were similar for colon and rectum, but some negative associations (i.e., coffee and tea, and fish) appeared stronger for colon cancer. Our findings lead us to reconsider the role of starchy foods and refined sugar in light of recent knowledge on the digestive physiology of carbohydrates and the insulin/colon cancer hypothesis. The beneficial role of most vegetables is confirmed, with more than 20% reduction in risk of colorectal cancer from the addition of one daily serving.


Scopolamine sublingual spray: an alternative route of delivery for the treatment of motion sickness.
The purpose of this study was to develop a sublingual drug delivery spray formulation of scopolamine hydrobromide (L-(-)-hyoscine hydrobromide) and to determine the absolute bioavailability of scopolamine hydrobromide following sublingual delivery and to investigate the effect of a bioadhesive on the pharmacokinetic parameters of this drug in a rabbit model. Rabbits received a single scopolamine free base equivalent sublingual dose of 100 microg/kg and this was compared to intravenous administration of the drug. Blood samples were collected at different time points, and plasma scopolamine concentrations were determined using a new sensitive and specific LC/MS analytical method which utilized electrospray ionization detection. The bioavailability of sublingual scopolamine was determined by comparing plasma concentrations after sublingual spray delivery with equivalent intravenous doses. Following delivery of the sublingual spray dose, the average Cmax was 1024.4+/-177 ng/mL, and the AUC value was found to be 61067.6+/-9605 ng.min/mL. Relative to the intravenous dose (100% bioavailability), the bioavailability was 79.8% after sublingual spray administration. The addition of 2% chitosan, a bio-adhesive material and an absorption enhancer, showed a significant improvement in scopolamine sublingual absorption (p<0.05) was observed. Considering the limitations of delivering scopolamine orally or transdermally to patients who experience motion sickness, the sublingual route of administration using a spray delivery dosage form, is a potential alternative modality for the prevention of nausea and vomiting associated with motion sickness.


Analysis of errors in finished DNA sequences: the surfactin operon of Bacillus subtilis as an example.
Increased productivity in DNA sequencing would not be valid without a straightforward detection and estimation of errors in finished sequences. The sequence of the surfactin operon from Bacillus subtilis was obtained by two different groups and by chance we were also working on the same chromosome region. Taking advantage of this situation we report in this paper, the number and nature of errors found in the overlapping part of the DNA sequences obtained by the three laboratories. The coincidence of some of the errors with compression in sequence ladders and with secondary DNA structures as well as the detection of frameshift errors using computer programs, are demonstrated. Finally we discuss the definition of a new sequencing strategy that might minimize both the error rate and the cost of sequencing.


Cortical and Subcortical Brain Changes in Children and Adolescents With Narcolepsy Type 1.
Neuroimaging studies on structural alterations in patients with type 1 narcolepsy (NT1) have shown controversial and heterogeneous results. The purpose of this study was to investigate microstructural brain changes in patients with NT1 close to disease onset. We examined cortical and subcortical grey matter volumes in 20 drug-naïve children and adolescents with NT1 compared with 19 healthy controls; whole-brain voxel-based morphometry, shape and volumetric analyses, and cortical thickness analysis were used. When compared with controls, NT1 patients revealed reduced grey matter volume in cerebellum and medial prefrontal cortex and increased volume in right hippocampus. Cortical thickness in frontal lobe was also reduced in patients compared with controls. Increased volume and shape expansion in right hippocampus in patients compared with controls were also confirmed by both vertex and volumetric analyses. Our results indicate that subtle structural brain changes involving attentional and limbic circuits are detectable in children and adolescents with NT1. Cerebellum involvement might be related to the childhood NT1 clinical phenotype.


CD8⁺ Foxp3⁺ tumor infiltrating lymphocytes accumulate in the context of an effective anti-tumor response.
The composition of tumor infiltrating lymphocytes (TIL) is heterogeneous. In addition, the ratio of various subpopulations in the tumor microenvironment is highly dependent on the nature of the host's immune response. Here, we characterize Foxp3-expressing CD8(+) T cells in the tumor that demonstrate effector function and accumulate in the context of an effective anti-tumor response. CD8(+) Foxp3(+) T cells are induced in TIL in regressing tumors of FVB/N mice treated with a GM-CSF secreting HER-2/neu targeted whole cell vaccine. Foxp3 expression in tumor antigen-specific CD8 T cells is restricted to the tumor microenvironment and influenced by cues in the tumor. Interestingly, Foxp3(+) and Foxp3(-) CD8(+) T cells have similar IFN-γ production and antigen-specific degranulation after stimulation with RNEU(420-429) , the immunodominant HER-2/neu (neu) epitope in this model. Adoptive transfer studies, using RNEU((420-429)) -specific effector T cells into neu-N mice (a model that results in immune tolerance to neu), confirm that CD8(+) Foxp3(+) T cells are present in tumors only if there is an existing pool of tumor-rejecting effector T cells. CD8(+) Foxp3(+) TILs mark the presence of tumor-rejecting antigen-specific T cells and their accumulation serves as a marker for an effective T cell response.


The monomeric and dimeric mannose-binding proteins from the Orchidaceae species Listera ovata and Epipactis helleborine: sequence homologies and differences in biological activities.
The Orchidaceae species Listera ovata and Epipactis helleborine contain two types of mannose-binding proteins. Using a combination of affinity chromatography on mannose-Sepharose-4B and ion exchange chromatography on a Mono-S column eight different mannose-binding proteins were isolated from the leaves of Listera ovata. Whereas seven of these mannose-binding proteins have agglutination activity and occur as dimers composed of lectin subunits of 11-13 kDa, the eighth mannose-binding protein is a monomer of 14 kDa devoid of agglutination activity. Moreover, the monomeric mannose-binding protein does not react with an antiserum raised against the dimeric lectin and, in contrast to the lectins, is completely inactive when tested for antiretroviral activity against human immunodeficiency virus type 1 and type 2. Mannose-binding proteins with similar properties were also found in the leaves of Epipactis helleborine. However, in contrast to Listera only one lectin was found in Epipactis. Despite the obvious differences in molecular structure and biological activities molecular cloning of different mannose-binding proteins from Listera and Epipactis has shown that these proteins are related and some parts of the sequences show a high degree of sequence homology indicating that they have been conserved through evolution.


Serious Drug-Drug Interactions in the Prescriptions of Diabetic Patients.
A large number of drugs are introduced every year, and newer interactions between medications are increasingly reported. Clinically significant drug interactions can occur when two or more drugs are taken in combination. With the continuing increase in the list of drugs capable of interactions, detection of these interactions from prescriptions becomes more important to ensure effective patient care. The aim of this study is to identify the possible drug interactions in the prescriptions of diabetic inpatients and to make physicians aware of these interactions to prevent the occurrence of clinically adverse effects. In a specially designed and validated data entry format, data for the following criteria were collected: drugs prescribed, major drug class prescribed, pharmacological classification of the observed drug interaction, and frequently occurring drug interactions. All the possible drug interactions were identified and evaluated using standard drug interaction reference books and databases. During the study period, 50 prescriptions of diabetic inpatients were screened randomly. Out of these prescriptions, 35 (70%) prescriptions had at least one possible drug-drug interaction. The major classes of drugs causing interactions included cardiac drugs (92%), analgesic drugs (66%), antibiotic drugs (52%), antidiabetic drugs (26%), diuretic drugs (26%), and antipsychotic drugs (24%). This study showed that 34 (68%) of the above prescriptions had minor interactions, 33(66%) had moderate interactions, and 10 (20%) had severe interactions. Of these, the drugs prescribed specifically for diabetes caused only nine moderate interactions. Thus, screening of prescriptions by the clinical pharmacist will help to minimize clinical occurrence of major/severe drug interactions in diabetic patients.


Quantum deep reinforcement learning for clinical decision support in oncology: application to adaptive radiotherapy.
Subtle differences in a patient's genetics and physiology may alter radiotherapy (RT) treatment responses, motivating the need for a more personalized treatment plan. Accordingly, we have developed a novel quantum deep reinforcement learning (qDRL) framework for clinical decision support that can estimate an individual patient's dose response mid-treatment and recommend an optimal dose adjustment. Our framework considers patients' specific information including biological, physical, genetic, clinical, and dosimetric factors. Recognizing that physicians must make decisions amidst uncertainty in RT treatment outcomes, we employed indeterministic quantum states to represent human decision making in a real-life scenario. We paired quantum decision states with a model-based deep q-learning algorithm to optimize the clinical decision-making process in RT. We trained our proposed qDRL framework on an institutional dataset of 67 stage III non-small cell lung cancer (NSCLC) patients treated on prospective adaptive protocols and independently validated our framework in an external multi-institutional dataset of 174 NSCLC patients. For a comprehensive evaluation, we compared three frameworks: DRL, qDRL trained in a Qiskit quantum computing simulator, and qDRL trained in an IBM quantum computer. Two metrics were considered to evaluate our framework: (1) similarity score, defined as the root mean square error between retrospective clinical decisions and the AI recommendations, and (2) self-evaluation scheme that compares retrospective clinical decisions and AI recommendations based on the improvement in the observed clinical outcomes. Our analysis shows that our framework, which takes into consideration individual patient dose response in its decision-making, can potentially improve clinical RT decision-making by at least about 10% compared to unaided clinical practice. Further validation of our novel quantitative approach in a prospective study will provide a necessary framework for improving the standard of care in personalized RT.


Bile acid interactions with cholangiocytes.
Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter (ASBT) (also referred to as Ibat; gene name Slc10a2) is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified (t-ASBT, multidrug resistance (MDR)3, an unidentified anion exchanger system and organic solute transporter (Ost) heteromeric transporter, Ostalpha-Ostbeta. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3', 5'-monophosphate (cAMP)-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and extracellular signal-regulated protein kinase (ERK) intracellular signals. Bile acids significantly alter cholangiocyte secretion, proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals, and in some instances trigger opposing effects on cholangiocyte secretion, proliferation and survival. Based upon these concepts and observations, the cholangiocyte has been proposed to be the principle target cell for bile acids in the liver.


DNA fragmentation in permeabilized cells and nuclei. The role of (Ca2+ + Mg2+)-dependent endodeoxyribonuclease.
Permeabilized mammalian cells and isolated nuclei were used to study various aspects of DNA replication and repair. The present paper describes a progressive fragmentation of parental DNA in human lymphoblastoid cells that were permeabilized with L-alpha-lysophosphatidylcholine or with saponin and incubated at 37 degrees C in a DNA-synthesis mixture. The formation of DNA single-strand breaks (measured by alkaline elution) was linear with the time of incubation and was temperature-dependent. It was prevented by deleting Mg2+ or both Mg2+ and Ca2+ from the incubation mixture, or by the addition of EDTA. It was increased by deleting the components necessary for DNA synthesis, and by substituting Mn2+ for Mg2+ and Ca2+. DNA strand breaks also accumulated in isolated nuclei incubated in a DNA synthesis mixture, but not when Mg2+ was omitted. These results suggest that DNA fragmentation in permeabilized cells and nuclei was due to an activation of (Ca2+ + Mg2+)-dependent endodeoxyribonucleases. The integrity of template DNA needs to be ascertained when the conditions for measuring DNA synthesis in permeabilized cells or in nuclei are formulated.


Optimization of HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques.
HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb). We compared three different animal models: guinea pigs, rabbits and cynomolgus macaques. Envelope genes from the prototype isolate HIV-1 Bx08 and two elite neutralizers were included. Codon-optimized genes, encoded secreted gp140 or membrane bound gp150, were modified for expression of stabilized soluble trimer gene products, and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity. Evaluations of rabbits and guinea pigs displayed similar results. The superior DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envelope genes. Despite NAb responses with some potency and breadth in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity. It was concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates was, in this study, the best option to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into similar responses in cynomolgus macaques.


Safety evaluation of long-chain glycolipids from Dacryopinax spathularia.
The EFSA Panel on Food Additives and Flavourings (FAF) provides a scientific opinion on the safety of long-chain glycolipids from Dacryopinax spathularia (also called AM-1) as a food additive. AM-1 is a purified mixture of long-chain glycolipid congeners obtained by fermentation of the edible non-genetically modified fungus Dacryopinax spathularia. AM-1 glycolipids have very low oral bioavailability and overall available toxicology data do not demonstrate any adverse effects of the proposed food additive. Considering the available data set the Panel established an ADI of 10 mg/kg bw per day based on a range of NOAELs between 1,000 and 1,423 mg/kg bw per day (the highest doses tested), from the reproductive and a prenatal developmental toxicity studies in rats and 90-day studies in rat and dog. At the proposed maximum use levels, the exposure estimates ranged at the mean from 0.01 to 1.07 mg/kg bw per day and at the p95 from 0 to 3.1 mg/kg mg/kg bw per day. At the proposed typical use levels, the exposure estimates ranged at the mean from < 0.01 mg/kg bw per day to 0.23 mg/kg bw per day and at the p95 from 0 to 0.64 mg/kg bw per day. The Panel noted that the highest estimate of exposure of 3.1 mg/kg bw per day (in toddlers) is within the established ADI of 10 mg/kg bw per day and concluded that the exposure to long-chain glycolipids from Dacryopinax spathularia does not raise a safety concern at the uses and use levels proposed by the applicant.


The relationship between hypomethylation and CpG island methylation in colorectal neoplasia.
Tumors are often characterized by an imbalance in cytosine methylation as manifested both by hypermethylation of CpG islands and by genome hypomethylation. These epigenetic changes were assessed in colorectal neoplasia to determine whether they arose through a common mechanism or indeed were distinct and unrelated phenomena. Fresh representative samples of adenomas, hyperplastic polyps, colorectal cancers, and normal mucosa were used in this study. Global methylation levels were measured by analyzing the methyl-accepting capacity of DNA. Methylation of p16, hMLH1, and MINT 1, 2, 12, and 31 were assessed by bisulfite polymerase chain reaction. Microsatellite status was determined by polymerase chain reaction using six markers and hMLH1 and proliferating cell nuclear antigen expression was assessed by immunohistochemistry. Normal colonic mucosa had a higher endogenous 5-methyl cytosine content than all proliferative lesions of the colon (P < 0.001). The extent of demethylation in hyperplastic polyps and adenomas was significantly related to its proliferative rate. Right-sided hyperplastic polyps were more likely to be methylated than adenomas (odds ratio, 2.3; confidence interval, 1.1 to 4.6). There was no relationship between the level of global hypomethylation and hypermethylation. Some hyperplastic colorectal polyps have a propensity to develop dense CpG island methylation. Hypermethylation and hypomethylation contribute separately to the process of carcinogenesis.


Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8.
In the course of a clinical trial consisting of intratumoral injections of dendritic cells (DCs) transfected to produce interleukin-12, the use of (111)In-labeled tracing doses of DCs showed that most DCs remained inside tumor tissue, instead of migrating out. In search for factors that could explain this retention, it was found that tumors from patients suffering hepatocellular carcinoma, colorectal or pancreatic cancer were producing IL-8 and that this chemokine attracted monocyte-derived dendritic cells that uniformly express both IL-8 receptors CXCR1 and CXCR2. Accordingly, neutralizing antihuman IL-8 monoclonal antibodies blocked the chemotactic attraction of DCs by recombinant IL-8, as well as by the serum of the patients or culture supernatants of human colorectal carcinomas. In addition, tissue culture supernatants of colon carcinoma cells inhibited DC migration induced by MIP-3beta in an IL-8-dependent fashion. IL-8 production in malignant tissue and the responsiveness of DCs to IL-8 are a likely explanation of the clinical images, which suggest retention of DCs inside human malignant lesions. Impairment of DC migration toward lymphoid tissue could be involved in cancer immune evasion.


Management of women who are Rhesus D negative in Northern Ireland.
In 1998, all 15 maternity hospitals in Northern Ireland participated in a retrospective survey of the management of pregnant women who were Rhesus D (RhD) negative. This area of clinical practice was chosen for study in the knowledge that a policy of routine antenatal prophylaxis had been proposed at the RCP/RCOG Consensus Conference, and that a change in current clinical practice was likely to follow. It was therefore felt prudent to survey critically current practice in order to collect baseline data before the introduction of new guidelines. Data were analysed on 3274 RhD negative women. The findings from this study show that current management of women who are RhD negative is suboptimal. In particular, there is poor adherence to the guidelines relating to the management of potentially sensitising events in pregnancy. Testing to assess the size of a feto-maternal bleed was often omitted, and it was therefore impossible to ascertain whether an appropriate dose of anti-D immunoglobulin had been administered. Recent publications have also identified this as an area of concern. Trauma during pregnancy was often not managed appropriately, as a potentially sensitising event. Better compliance with the current guidelines was noted when management after delivery was considered. The reasons for this apparent inconsistency should be addressed. New guidelines, recommending the use of routine antenatal prophylaxis to all women who are RhD negative, have recently been published. Providers of antenatal care will need to address this issue within the context of their own practice environment. In doing so they should be mindful of current deficits in guideline compliance which may need to be remedied, to avoid building new practices upon fragile foundations.


A novel system applying the 2-deoxyglucose method to fish for characterization of environmental neurotoxins.
Methods of identifying and preventing ecotoxicity related to environmental stressors on wildlife species are underdeveloped. To detect sublethal effects, we have devised a neurochemical method of evaluating environmental neurotoxins by a measuring changes in regional neural activity in the central nervous system of fish. Our system is a unique adaptation of the 2-deoxyglucose (2-DG) method originally developed by L. Sokoloff in 1977, which is based on the direct relationship between glucose metabolism and neural functioning at the regional level. We applied these concepts to test the assumption that changes in neural activity as a result of chemical exposure would produce measurable effects on the amount of [(14)C]2-DG accumulated regionally in the brain of Tilapia nilatica. For purposes of this study, we utilized the excitotoxin N-methyl-D-aspartate (NMDA) to characterize the response of the central nervous system. Regional accumulation of [(14)C]2-DG was visualized by autoradiography and digital image processing. Observable increases in regional [(14) C] 2-DG uptake were evident in all NMDA-treated groups as compared to controls. Specific areas of increased [(14)C] 2-DG uptake included the telencephalon, optic tectum, and regions of the cerebellum, all areas in which high concentrations of NMDA-subtype glutamate receptors have been found in Tilapia monsanbica. These results are consistent with the known neural excitatory action of NMDA.


Insulin Independence in Newly Diagnosed Type 1 Diabetes Patient following Fenofibrate Treatment.
A 19-year-old girl was diagnosed with type 1 diabetes and showing polydipsia and polyuria. She was double autoantibody-positive and had a diabetes-prone tissue type. She was immediately started on insulin. Fenofibrate treatment (160 mg daily) was initiated seven days after diagnosis. The need for insulin quickly declined, and she took her last dose of insulin 19 days after the first dose of fenofibrate, having regained endogenous control of blood glucose concentrations. She has now been insulin independent for one year and 9 months. Unstimulated C-peptide has increased by 51% (317 to 479 pmol/l), and IA-2 autoantibody level has decreased by 65% (49 to 17 × 103 arbitrary units). Fenofibrate is a widely used drug for reducing triglyceride and cholesterol levels. Fenofibrate reverses and prevents autoimmune diabetes in nonobese diabetic (NOD) mice by increasing the amount of the sphingolipid sulfatide in islets. Sphingolipid metabolism is otherwise abnormal in the islets at diagnosis of type 1 diabetes. In conclusion, we describe a 19-year-old patient with classical newly diagnosed type 1 diabetes, which following fenofibrate treatment has been without insulin for 21 months.


Graduate nurse perceptions of caring for people with posttraumatic amnesia.
: This article reports a qualitative study of the phenomenon of posttraumatic amnesia, a common behavioral sequelae to traumatic brain injury frequently encountered by nurses on trauma wards. Specifically, it focuses on the experiences of newly registered Australian graduate nurses (N = 6) providing care for this patient cohort. An atheoretical qualitative descriptive design (Sandelowski, 2000) has been used to explore graduate nurses' experiences with posttraumatic amnesia. Themes that emerged from the transcripts were perceptions of behavior, difficulties in clinical management, safety, risk of wandering, external support, containment, and advocating for patient safety.


Increased precipitation and nitrogen addition accelerate the temporal increase in soil respiration during 8-year old-field grassland succession.
Ecological succession after disturbance plays a vital role in influencing ecosystem structure and functioning. However, how global change factors regulate ecosystem carbon (C) cycling in successional plant communities remains largely elusive. As part of an 8-year (2012-2019) manipulative experiment, this study was designed to examine the responses of soil respiration and its heterotrophic component to simulated increases in precipitation and atmospheric nitrogen (N) deposition in an old-field grassland undergoing secondary succession. Over the 8-year experimental period, increased precipitation stimulated soil respiration by 11.6%, but did not affect soil heterotrophic respiration. Nitrogen addition increased both soil respiration (5.1%) and heterotrophic respiration (6.2%). Soil respiration and heterotrophic respiration linearly increased with time in the control plots, resulting from changes in soil moisture and shifts of plant community composition from grass-forb codominance to grass dominance in this old-field grassland. Compared to the control, increased precipitation significantly strengthened the temporal increase in soil respiration through stimulating belowground net primary productivity. By contrast, N addition accelerated temporal increases in both soil respiration and its heterotrophic component by driving plant community shifts and thus stimulating soil organic C. Our findings indicate that increases in water and N availabilities may accelerate soil C release during old-field grassland succession and reduce their potential positive impacts on soil C accumulation under future climate change scenarios.


Defining the Concept and Clinical Features of Epistemic Trust: A Delphi study.
Early identification of "patients at risk" for not completing regular treatment or not benefitting (sufficiently) from treatment might be among the most cost-effective strategies in mental health care. The recently introduced concept of epistemic trust (ET) may have the potential value to predict patients at risk and therefore act as a marker of treatment outcome. We argue that ET may be the final common pathway through which aversive relational experiences in the past result in interpersonal dysfunctioning, which in turn result in dysfunctional therapeutic relationships, rendering it difficult for patients to trust whatever is offered to learn in therapy. Hence, the concept of ET can play an essential role in personalized medicine, allowing for a more tailored treatment assignment to specific patients' characteristics, which may improve treatment outcomes. In this brief report, we define the clinical features of ET by describing its core domains based on consensus of expert opinion on the concept. The response rate was high, and there was a high level of agreement across experts, demonstrating a strong consensus between experts on the definition and clinical features of ET and mistrust and its significance to the understanding of personality disorders.By means of having a clear definition of the clinical features of ET, we hope to make it accessible for assessment.


Amphotericin B protects cis-parinaric acid against peroxyl radical-induced oxidation: amphotericin B as an antioxidant.
The antifungal effects of amphotericin B are believed to be due to two possibly interrelated mechanisms: an increase in permeation by binding to sterols in cellular membranes and a prooxidant effect causing oxidative damage in target cells. However, the seven conjugated double bonds in amphotericin B raise the possibility that it could be highly susceptible to autoxidation, causing an antioxidant effect. In the present study, we investigated the prooxidant and antioxidant properties of amphotericin B in a model system in which oxidation of a reporter molecule, cis-parinaric acid, was induced by azo initiators of peroxyl radicals. Since interactions of amphotericin B with sterols are essential for its pharmacological and toxic actions, we also studied the effects of cholesterol on the prooxidant and antioxidant properties of amphotericin B. Amphotericin B caused a noncollisional quenching of a characteristic fluorescence of cholesteryl cis-parinarate integrated in liposomes, suggesting the formation of amphotericin B-cholesteryl cis-parinarate complex. This effect of amphotericin B was ablated by increasing concentrations of cholesterol. We found that amphotericin B inhibited oxidation of cis-parinaric acid complexed with human serum albumin [using a water-soluble azo initiator, 2,2'-azobis(2aminopropane)dihydrochloride] and in liposomes [using a lipid-soluble azo initiator, 2,2'-azobis(2,4-dimethylvaleronitrile)]. The inhibitory effect of amphotericin B on 2,2'-azobis(2,4-dimethylvaleronitrile)-induced peroxidation of cis-parinaric acid in liposomes was also diminished by cholesterol. The antioxidant effect of amphotericin B in this model system suggests that amphotericin B does not exert its pharmacological and toxicological responses through a prooxidant effect to cause damage in target cells.


Preclinical evaluation of riluzole: assessments of ethanol self-administration and ethanol withdrawal symptoms.
Many of the neurobehavioral effects of ethanol are mediated by inhibition of excitatory N-methyl-D-aspartate (NMDA) and enhancement of inhibitory gamma-amino-butyric-acid (GABA) receptor systems. There is growing interest in drugs that alter these systems as potential medications for problems associated with alcoholism. The drug riluzole, approved for treatment of amyotrophic lateral sclerosis (ALS), inhibits NMDA and enhances GABA(A) receptor system activity. This study was designed to determine the preclinical efficacy of riluzole to modulate ethanol self-administration and withdrawal. Male C57BL/6J mice were trained to lever press on a concurrent fixed-ratio 1 schedule of ethanol (10% v/v) versus water reinforcement during daily 16-hour sessions. Riluzole (1 to 40 mg/kg, IP) was evaluated on ethanol self-administration after acute and chronic (2 week) treatment. To determine if riluzole influences ethanol withdrawal-associated seizures, mice were fed an ethanol-containing or control liquid diet for 18 days. The effects of a single injection of riluzole (30 mg/kg) were examined on handling-induced convulsions after ethanol withdrawal. Acute riluzole (30 and 40 mg/kg) reduced ethanol self-administration during the first 4 hours of the session, which corresponds to the known pharmacokinetics of this drug. Ethanol self-administration was also reduced by riluzole after chronic treatment. Riluzole (30 mg/kg) significantly decreased the severity of ethanol-induced convulsions 2 hours after ethanol withdrawal. These results demonstrate that riluzole decreases ethanol self-administration and may reduce ethanol withdrawal severity in mice. Thus, riluzole may have utility in the treatment of problems associated with alcoholism.


Antibodies to opacity proteins (Opa) correlate with a reduced risk of gonococcal salpingitis.
Acute salpingitis complicating cervical gonococcal infection is a significant cause of infertility. Relatively little data are available concerning the pathophysiologic mechanisms of this disease. A cohort of 243 prostitutes residing in Nairobi were followed between March 1985 and April 1988. Gonococcal cultures were performed at each visit, and acute salpingitis was diagnosed clinically. Serum at enrollment was tested by immunoblot for antibody to gonococcal outer membrane proteins. 8.6% (146/1689) of gonococcal infections were complicated by salpingitis. Increased risk of salpingitis was associated with younger age, shorter duration of prostitution, HIV infection, number of gonococcal infections, and episodes of nongonococcal salpingitis. Rmp antibody increased the risk of salpingitis. Antibody to Opa decreased the risk of salpingitis. By logistic regression analysis, antibody to Opa was independently associated with decreased risk of gonococcal salpingitis (adjusted odds ratio [OR], 0.35; 95% confidence interval [95%CI], 0.17-0.76); HIV infection (adjusted OR, 3.5; 95% CI, 0.96-12.8) and episodes of nongonococcal salpingitis (adjusted OR, 3.4; 95% CI, 1.8-6.4) were independently associated with an increased risk of salpingitis. Antibody to Opa appears to protect against ascending gonococcal infection, perhaps by interfering with Opa mediated adherence and endocytosis. The demonstration of natural immunity that protects against upper genital tract infection in women suggests that a vaccine to prevent gonococcal salpingitis is possible.


[Dog bites in children. Epidemiologic and clinical study of 144 cases].
We have done a prospective study of 144 cases of dog bites in children between 1 and 13 years of age that were attended at the Emergency Department of the "Miguel Servet" Children's Hospital of Zaragoza over a period of 30 months. The average child is an 8 year old boy who is bitten at 4 p.m. in the lower limbs by a dog belonging to either the family, a neighbor, or to some friends. The dog of unknown breed and the German shepherd are those most frequently involved (39.5% and 22.2%, respectively). There is a low incidence of infection (4.8%). The attacks were provoked by petting in 52.7%; therefore, we recommend not to get close to the animals even if they are known. In our area, 83.3% of the children are correctly vaccinated. Finally, we compare our results with other studies and we suggest that it is of great interest to establish measures in order to reduce the incidence of dog bites.


Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia (B-CLL) at sites typical for Borrelia burgdorferi infection.
Cutaneous manifestations of B-cell chronic lymphocytic leukemia (B-CLL) comprise a wide spectrum of clinicopathologic presentations. In some cases, onset of skin lesions is triggered by antigenic stimulation, and specific skin infiltrates at sites of previous herpes simplex or herpes zoster infection have been well documented. Specific skin manifestations of B-CLL can also be observed at sites typical for lymphadenosis benigna cutis (nipple, scrotum, earlobe), a Borrelia burgdorferi-associated cutaneous B-cell pseudolymphoma. We studied specific skin manifestations of B-CLL arising at sites typical for B. burgdorferi-induced lymphadenosis benigna cutis, analyzing tissues for presence of B. burgdorferi DNA using the polymerase chain reaction (PCR) technique. Six patients with B-CLL (M : F = 4 : 2; mean age: 67.8) presented with specific skin lesions located on the nipple (four cases) and scrotum (two cases). Clinically there were solitary erythematous plaques or nodules. Histology revealed in all cases a dense, monomorphous infiltrate of small lymphocytes showing an aberrant CD20+/CD43+ phenotype. In all cases monoclonality was demonstrated by PCR analysis of the JH gene rearrangement. PCR analysis showed in four of the six cases the presence of DNA sequences specific for B.burgdorferi. Our study demonstrates that infection with B. burgdorferi can trigger the development of specific cutaneous infiltrates in patients with B-CLL.


Endoscopically assisted enucleation of a large mandibular periapical cyst.
Enucleation of large cysts in the jaws is an invasive method that might be associated with complications. Marsupialization is a less invasive alternative method but it involves a prolonged and uncomfortable healing period. This study addresses a contemporaneous and less invasive surgical technique for treating larger mandibular cysts. MATERIALS AND METHODS. A 48-year-old woman presented with a large mandibular apical cyst involving the left parasymphysis, body, ramus and condylar neck, with involvement of the alveolar inferior nerve. The cystic lesion was enucleated using a 30° 4.0 mm endoscopic scope and endoscopic instruments through two small accesses: the ostectomy site of previously performed marsupialization and the alveolus of the involved third molar extracted of the time of the enucleation of the cyst. RESULTS. The endoscopic scope provided good visualization of the whole cystic cavity allowing the removal of any residual pathologic tissue and preservation of the integrity of the involved inferior alveolar nerve. The morbidity of the surgical procedure was extremely reduced. At a 6-month follow-up the patient did not present any symptom of inflammation and a panoramic X-ray showed good bone repair and remodelation. CONCLUSIONS. Endoscopically assisted enucleation proved to be effective method of treating a large mandibular cyst, providing total enucleation with a minimal invasive technique.


Humans rapidly estimate expected gain in movement planning.
We studied human movement planning in tasks in which subjects selected one of two goals that differed in expected gain. Each goal configuration consisted of a target circle and a partially overlapping penalty circle. Rapid hits into the target region led to a monetary bonus; accidental hits into the penalty region incurred a penalty. The outcomes assigned to target and penalty regions and the spatial arrangement of those regions were varied. Subjects preferred configurations with higher expected gain whether selection involved a rapid pointing movement or a choice by key press. Movements executed to select one of two goal configurations exhibited the same movement dynamics as pointing movements directed at a single configuration, and were executed with the same high efficiency. Our results suggest that humans choose near-optimal strategies when planning their movement, and can base their selection of strategy on a rapid judgment about the expected gain associated with possible movement goals.


Formation of peripheral anterior synechiae following argon laser trabeculoplasty. A prospective study to determine relationship to position of laser burns.
One hundred eighteen eyes with primary open-angle glaucoma underwent argon laser trabeculoplasty . Laser burns were placed in the anterior trabecular meshwork (ATM) in 58 eyes and directly over Schlemm's canal in the posterior trabecular meshwork (PTM) in 60 eyes. Twenty-nine eyes received 100 burns and 89 eyes received 50 burns distributed equally over 360 degrees. Peripheral anterior synechiae (PAS) developed in seven (12%) of the eyes having anterior trabeculoplasty and in 26 (43%) of those having posterior trabeculoplasty . There was no correlation between the development of PAS and sex, width of the anterior chamber angle, or the number of laser burns. Eyes having anterior trabeculoplasty had a final decrease in intraocular pressure equal to those having posterior trabeculoplasties . Our results strongly suggest that trabeculoplasty is a safer but no less effective procedure when the laser burns are placed on the ATM rather than the PTM.


Methyl Jasmonate Increases Isoflavone Production in Soybean Cell Cultures by Activating Structural Genes Involved in Isoflavonoid Biosynthesis.
Isoflavonoids are a class of biologically active natural products that accumulate in soybean ( Glycine max L.) seeds during development, play vital roles in plant defense, and act as phytoestrogens with important human health benefits. Plant cell suspension cultures represent an excellent source of biologically important secondary metabolites. We found that methyl jasmonate (MJ) treatment increased isoflavone production in soybean suspension cell cultures. To investigate the underlying mechanism, we examined the expression of structural genes ( CHS6, CHS7, CHI1, IFS1, IFS2, IFMaT, and HID) in the isoflavonoid biosynthesis pathways in soybean suspension cells under various abiotic stress conditions. MJ treatment had the most significant effect on gene expression and increased the production of three glycosidic isoflavones (daidzin, malonyldaidzin, and malonylgenistin), with the maximum total isoflavone production (∼10-fold increase) obtained on day 9 after MJ application. MJ treatment significantly increased total phenolic contents and upregulated isoflavonoid biosynthesis genes, shedding light on the underlying mechanism.


Uses and mechanisms of apnoeic oxygenation: a narrative review.
Apnoeic oxygenation refers to oxygenation in the absence of spontaneous respiration or mechanical ventilation. It has been described in humans for over half a century and has seen a resurgence in interest given its potential to delay oxygen desaturation during airway management, especially with the advent of high-flow nasal cannulae. This narrative review summarises our current understanding of the mechanisms of gas exchange during apnoeic oxygenation and its diverse range of clinical applications, including its use at induction of anaesthesia and for the facilitation of 'tubeless anaesthesia'. Additional discussion covers use in critical care, obese, obstetric and paediatric sub-populations. The article also highlights current research efforts aiming to enhance the evidence base for the use of this technique.


Thoracic splanchnic nerves: implications for splanchnic denervation.
Splanchnic neurectomy is of value in the management of chronic abdominal pain. It is postulated that the inconsistent results of splanchnicectomies may be due to anatomical variations in the pattern of splanchnic nerves. The advent of minimally invasive and video-assisted surgery has rekindled interest in the frequency of variations of the splanchnic nerves. The aims of this study were to investigate the incidence, origin and pattern of the splanchnic nerves in order to establish a predictable pattern of splanchnic neural anatomy that may be of surgical relevance. Six adult and 14 fetal cadavers were dissected (n = 38). The origin of the splanchnic nerve was bilaterally asymmetrical in all cases. The greater splanchnic nerve (GSN) was always present, whereas the lesser splanchnic nerve (LSN) and least splanchnic nerve (ISN) were inconsistent (LSN, 35 of 38 sides (92%); LSN, 21 of 38 sides (55%). The splanchnic nerves were observed most frequently over the following ranges: GSN, T6-9: 28 of 38 sides (73%); LSN, when present, T10-11: (10 of 35 sides (29%); and ISN, T11-12: 3 of 21 sides (14%). The number of ganglionic roots of the GSN varied between 3 and 10 (widest T4-11; narrowest, T5-7). Intermediate splanchnic ganglia, when present, were observed only on the GSN main trunk with an incidence of 6 of 10 sides (60%) in the adult and 11 of 28 sides (39%) in the fetus. The higher incidence of the origin of GSN above T5 has clinical implications, given the widely discussed technique of undertaking splanchnicectomy from the T5 ganglion distally. This approach overlooks important nerve contributions and thereby may compromise clinical outcome. In the light of these variations, a reappraisal of current surgical techniques used in thoracoscopic splanchnicectomy is warranted.


Adolescent pre-exposure prophylaxis for HIV prevention: current perspectives.
Adolescents are a critical population that is disproportionately impacted by the HIV epidemic. More than 2 million adolescents between the age group of 10 and 19 years are living with HIV, and millions are at risk of infection. HIV risks are considerably higher among girls, especially in high-prevalence settings such as eastern and southern Africa. In addition to girls, there are other vulnerable adolescent subgroups, such as teenagers, who use intravenous (IV) drugs, gay and bisexual boys, transgender youth, male sex workers, and people who fall into more than one of these categories. Pre-exposure prophylaxis (PrEP) is a new intervention for people at high risk for acquiring HIV, with an estimated HIV incidence of >3%. Recent data from trials show evidence of the efficacy of PrEP as a powerful HIV prevention tool in high-risk populations, including men who have sex with men, HIV-1-serodiscordant heterosexual couples, and IV drug users. The reported efficacy in those trials of the daily use of oral tenofovir, alone or in combination with emtricitabine, to prevent HIV infection ranged from 44% to 75% and was heavily dependent on adherence. Despite the proven efficacy of PrEP in adult trials, concerns remain about its feasibility in real-life scenarios due to stigma, cost, and limited clinician experience with PrEP delivery. Recent studies are attempting to expand the inquiry into the efficacy of such HIV prophylaxis approaches in adolescent populations, but there are still many gaps in knowledge, and no country has yet approved it for use with adolescents. The aim of this review was to identify and summarize the evidence from studies on PrEP for adolescents. We have compiled and reviewed published studies focusing on safety, feasibility, adherence to therapeutics, self-perception, and legal issues related to PrEP in people aged between 10 and 24 years.


Spatial heterogeneity in sediment-associated bacterial and eukaryotic communities in a landfill leachate-contaminated aquifer.
Heterogeneity in eukaryotic and bacteria community structure in surface and subsurface sediment samples downgradient of the Banisveld landfill (The Netherlands) was studied using a culturing-independent molecular approach. Along a transect covering the part of the aquifer most polluted by landfill leachate, sediment was sampled at 1-m depth intervals, until a depth of 5.5 m, at four distances from the landfill. Two drillings were placed in a nearby clean area as a reference. Denaturing gradient gel electrophoresis banding patterns revealed high bacterial and eukaryotic diversity and complex community structures. Bacteria and eukaryotic community profiles in polluted samples grouped different from those in clean samples. Bacteria community profiles in surface samples clustered together and separately from subsurface community profiles. Subsurface bacteria profiles clustered in a location-specific manner. Eukaryotic community structure did not significantly relate to distance from the landfill or depth. No significant spatial autocorrelation of bacteria or eukaryotic communities was observed over 1-m depth intervals per sampling location. Spatial heterogeneity in sediment-associated bacterial communities appears to be much larger than in groundwater. We discuss how on the one hand, spatial heterogeneity may complicate the assessment of microbial community structure and functioning, while on the other it may provide better opportunities for natural attenuation.


Standardized patients in audiology: a proposal for a new method of evaluating clinical competence.
While accrediting organizations require AuD programs to provide evidence that their students are able to demonstrate knowledge and competencies in specific content areas, there are no generally accepted mechanisms for the assessment and the measurement of these proficiencies. We propose that AuD programs consider developing standardized patient (SP) cases in order to develop consistent summative assessment programs within and across universities. The purpose of this article is to provide a framework for establishing SP programs to evaluate competencies in AuD students by detailing the history of SP cases and their use, developing a rationale for this method of assessment, and outlining the steps for writing and implementing SP cases. Literature review. SPs have been used to assess clinical competence in medical students for over 50 yr. The prevalence of SP assessment in allied health professions (e.g., dentistry, psychology, pharmacy) has increased over the last two decades but has only gained a limited following in audiology. SP assessment has been implemented in medical education using the Objective Structured Clinical Examination, a multistation, timed exam that uses fictional cases to assess students' clinical abilities. To date, only one published report has been completed that evaluates the use of SPs to assess clinical abilities in audiology students. This article expands upon the work of English et al (2007) and their efforts to use SPs to evaluate counseling abilities. To this end, we describe the steps necessary to write a case, procedures to determine performance requirements, and the need to develop remediation plans. As an example, we include a case that we have developed in order to evaluate vestibular assessment and patient communication skills. Utilizing SP assessment in audiology education would provide useful means to evaluate competence in a uniform way. Future research is necessary to develop reliable and valid cases that may be implemented across programs. This article aims to serve as a call to audiology programs to begin developing and reporting these cases. Once these are established we can begin to use SP cases for summative assessment.


Crystal structure and biochemical characterization of O-acetylhomoserine acetyltransferase from Mycobacterium smegmatis ATCC 19420.
Mycobacterium smegmatis is a good model for studying the physiology and pathogenesis of Mycobacterium tuberculosis due to its genetic similarity. As methionine biosynthesis exists only in microorganisms, the enzymes involved in methionine biosynthesis can be a potential target for novel antibiotics. Homoserine O-acetyltransferase from M. smegmatis (MsHAT) catalyzes the transfer of acetyl-group from acetyl-CoA to homoserine. To investigate the molecular mechanism of MsHAT, we determined its crystal structure in apo-form and in complex with either CoA or homoserine and revealed the substrate binding mode of MsHAT. A structural comparison of MsHAT with other HATs suggests that the conformation of the α5 to α6 region might influence the shape of the dimer. In addition, the active site entrance shows an open or closed conformation and might determine the substrate binding affinity of HATs.


TGF-beta, eosinophils and IL-13 in allergic airway remodeling: a critical appraisal with therapeutic considerations.
Airway remodeling is a characteristic feature of allergic asthma that is now thought to contribute to airway dysfunction and, ultimately, to clinical symptoms. A prevalent hypothesis holds that eosinophil-derived transforming growth factor-beta (TGF-beta) is a predominant underlying mechanism driving the development of remodeling and thus, represent promising targets for therapeutic intervention. This notion is supported by in vivo evidence from loss of function experiments conducted in animal models employing the surrogate allergen ovalbumin (OVA), and by indirect evidence from studies in human asthmatics. However, it is important to note that various studies in OVA systems have reported disconnects between eosinophils, TGF-beta and allergic remodeling. Moreover, recent investigations in a mouse model induced by respiratory exposure to a house dust mite extract have shown that remodeling can develop independently of TGF-beta. These findings challenge the above hypothesis and suggest that the mechanisms governing remodeling may be context specific. In addition to TGF-beta and eosinophils, several other factors have been implicated in the development of airway remodeling. Among these, interleukin (IL)-13 may be of particular importance given its role in type-2 immunity and in the tissue repair/fibrotic response. This review will appraise the evidence pertaining to the roles of TGF-beta, eosinophils and IL-13 in allergic remodeling, and will suggest that identifying robust targets for therapeutic intervention might benefit from a reconsideration of our approach to understanding remodeling.


Steered molecular dynamics simulations of a type IV pilus probe initial stages of a force-induced conformational transition.
Type IV pili are long, protein filaments built from a repeating subunit that protrudes from the surface of a wide variety of infectious bacteria. They are implicated in a vast array of functions, ranging from bacterial motility to microcolony formation to infection. One of the most well-studied type IV filaments is the gonococcal type IV pilus (GC-T4P) from Neisseria gonorrhoeae, the causative agent of gonorrhea. Cryo-electron microscopy has been used to construct a model of this filament, offering insights into the structure of type IV pili. In addition, experiments have demonstrated that GC-T4P can withstand very large tension forces, and transition to a force-induced conformation. However, the details of force-generation, and the atomic-level characteristics of the force-induced conformation, are unknown. Here, steered molecular dynamics (SMD) simulation was used to exert a force in silico on an 18 subunit segment of GC-T4P to address questions regarding the nature of the interactions that lead to the extraordinary strength of bacterial pili. SMD simulations revealed that the buried pilin α1 domains maintain hydrophobic contacts with one another within the core of the filament, leading to GC-T4P's structural stability. At the filament surface, gaps between pilin globular head domains in both the native and pulled states provide water accessible routes between the external environment and the interior of the filament, allowing water to access the pilin α1 domains as reported for VC-T4P in deuterium exchange experiments. Results were also compared to the experimentally observed force-induced conformation. In particular, an exposed amino acid sequence in the experimentally stretched filament was also found to become exposed during the SMD simulations, suggesting that initial stages of the force induced transition are well captured. Furthermore, a second sequence was shown to be initially hidden in the native filament and became exposed upon stretching.


Hemodynamic and thrombogenic analysis of a trileaflet polymeric valve using a fluid-structure interaction approach.
Surgical valve replacement in patients with severe calcific aortic valve disease using either bioprosthetic or mechanical heart valves is still limited by structural valve deterioration for the former and thrombosis risk mandating anticoagulant therapy for the latter. Prosthetic polymeric heart valves have the potential to overcome the inherent material and design limitations of these valves, but their development is still ongoing. The aim of this study was to characterize the hemodynamics and thrombogenic potential of the Polynova polymeric trileaflet valve prototype using a fluid-structure interaction (FSI) approach. The FSI model replicated experimental conditions of the valve as tested in a left heart simulator. Hemodynamic parameters (transvalvular pressure gradient, flow rate, maximum velocity, and effective orifice area) were compared to assess the validity of the FSI model. The thrombogenic footprint of the polymeric valve was evaluated using a Lagrangian approach to calculate the stress accumulation (SA) values along multiple platelet trajectories and their statistical distribution. In the commissural regions, platelets were exposed to the highest SA values because of highest stress levels combined with local reverse flow patterns and vortices. Stress-loading waveforms from representative trajectories in regions of interest were emulated in our hemodynamic shearing device (HSD). Platelet activity was measured using our platelet activation state (PAS) assay and the results confirmed the higher thrombogenic potential of the commissural hotspots. In conclusion, the proposed method provides an in depth analysis of the hemodynamic and thrombogenic performance of the polymer valve prototype and identifies locations for further design optimization.


Process of care in general hospital psychiatric units: national survey in Italy.
To investigate the process of care in Italian public acute inpatient facilities. Each facility's head psychiatrist (in all Italian regions except Sicily) completed a structured interview concerning provision of treatment and facility rules. Twenty-three university psychiatric clinics with 399 beds (mean=17.3 beds), 16 24 h community mental health centers with 98 beds (mean=6.1 beds), and 262 general hospital psychiatric units with 3431 beds (mean=13.1 beds) were surveyed. Mean length of stay was 18.5+/-7.1 days, 37.0+/-55.3 days and 12.0+/-3.4 days, respectively. Pharmacotherapy was ubiquitous. Approximately 80% of facilities held regular clinical evaluations, supportive talks, and counselling. Dynamic focused psychotherapy was available in 29% of the facilities; 24% provided cognitive behavioural therapy; 32% family therapy; and 39% structured rehabilitative intervention. Vocational training and activities targeted at helping patient integration into their local communities were uncommon. Most facilities did not allow the possession of cutting utensils (96%), personally possessed medication (96%), or lighters (72%), and most had locked doors (75%). Fewer facilities (37%) prohibited the use of mobile phones (32%) and metal knives during meal times (37%). Frequency of physical restraint was associated with number of internal rules. Delivery of psychotherapy was associated with nurse provision. The process of psychiatric inpatient care in Italy shows considerable variability. Future clinical practice guidelines should address the currently limited provision of evidence-based psychosocial intervention in these facilities. Efforts should also be devoted to improving the effectiveness of the hospital-community mental health service interface.


Language Beyond Labeling: Toward a Language Ideologies Analysis of Anti-Violence Interventions.
As scholars explore anti-carceral approaches to gender violence, they question how to structure interactive practices to transform, rather than reproduce, dynamics of inequality and harm. Drawing on ethnographic fieldwork conducted with frontline workers in north India, this article argues that the concept of language ideologies can help analyze how interactive practices address gender violence. Language ideologies are shared representations of how interaction connects speaker, audience, and context. By tracking the language ideologies that inform anti-violence interventions, researchers can better analyze the extraordinarily complex semiotic labor required to address gender violence.


Consumer preferences regarding physiotherapy practitioners and nurse practitioners in emergency departments - a qualitative investigation.
Workforce reform has led to Nurse Practitioners (NP) and Physiotherapy Practitioners (PP) employed in Emergency Departments (ED) to see patients alongside doctors. This qualitative study gathered consumer opinions and preferences regarding NPs, PPs, and doctors, and the attributes desired of them. Twenty-two members of the organization's Consumer Representative Program participated in one of three focus groups which were audio-recorded and transcribed verbatim. Data were subsequently collected using an emergent-systematic design that enabled ideas to be explored and refined in sequential focus groups. Data analysis, utilizing the principles of thematic analysis, identified four themes. First, consumers understand and accept that reform is necessary to improve care, better utilize available resources and create sustainable services. Second, although consumers accept the rationale for employing NPs and PPs, preferences vary regarding who they want as their primary clinician. Some consumers do not mind who provides care as long as they receive the care they need; others believe doctors provide superior care and preferred a doctor; a third group indicated that not everyone who presents to an ED needs to see a doctor and specialized care would be provided by NPs and PPs for certain conditions. Some consumers expressed incomplete or inaccurate understanding of ED staff roles, responsibilities, and skillsets, which influenced their care preferences. Third, consumers identified a core set of desirable staff attributes that apply to everyone irrespective of professional demarcation; all staff should embody these attributes, though the expression of the attributes will vary according to circumstances and the staff member's scope of practice. Fourth, consumers expect effective governance over ED services so that all staff, irrespective of their profession provides safe and effective care. In conclusion, these results can be used by health-care administrators and clinicians to inform workforce reform in EDs, helping to ensure that consumers' opinions and preferences are acknowledged and appropriately addressed.


Modulation of Conflict Processing by Theta-Range tACS over the Dorsolateral Prefrontal Cortex.
Behavioral response conflict arises in the color-word Stroop task and triggers the cognitive control network. Midfrontal theta-band oscillations correlate with adaptive control mechanisms during and after conflict resolution. In order to prove causality, in two experiments, we applied transcranial alternating current stimulation (tACS) at 6 Hz to the dorsolateral prefrontal cortex (DLPFC) during Stroop task performance. Sham stimulation served as a control in both experiments; 9.7 Hz tACS served as a nonharmonic alpha band control in the second experiment. We employed generalized linear mixed models for analysis of behavioral data. Accuracy remained unchanged by any type of active stimulation. Over both experiments, the Stroop effect (response time difference between congruent and incongruent trials) was reduced by 6 Hz stimulation as compared to sham, mainly in trials without prior conflict adaptation. Alpha tACS did not modify the Stroop effect. Theta tACS can both reduce the Stroop effect and modulate adaptive mechanisms of the cognitive control network, suggesting midfrontal theta oscillations as causally involved in cognitive control.


Pattern Storage, Bifurcations, and Groupwise Correlation Structure of an Exactly Solvable Asymmetric Neural Network Model.
Despite their biological plausibility, neural network models with asymmetric weights are rarely solved analytically, and closed-form solutions are available only in some limiting cases or in some mean-field approximations. We found exact analytical solutions of an asymmetric spin model of neural networks with arbitrary size without resorting to any approximation, and we comprehensively studied its dynamical and statistical properties. The network had discrete time evolution equations and binary firing rates, and it could be driven by noise with any distribution. We found analytical expressions of the conditional and stationary joint probability distributions of the membrane potentials and the firing rates. By manipulating the conditional probability distribution of the firing rates, we extend to stochastic networks the associating learning rule previously introduced by Personnaz and coworkers. The new learning rule allowed the safe storage, under the presence of noise, of point and cyclic attractors, with useful implications for content-addressable memories. Furthermore, we studied the bifurcation structure of the network dynamics in the zero-noise limit. We analytically derived examples of the codimension 1 and codimension 2 bifurcation diagrams of the network, which describe how the neuronal dynamics changes with the external stimuli. This showed that the network may undergo transitions among multistable regimes, oscillatory behavior elicited by asymmetric synaptic connections, and various forms of spontaneous symmetry breaking. We also calculated analytically groupwise correlations of neural activity in the network in the stationary regime. This revealed neuronal regimes where, statistically, the membrane potentials and the firing rates are either synchronous or asynchronous. Our results are valid for networks with any number of neurons, although our equations can be realistically solved only for small networks. For completeness, we also derived the network equations in the thermodynamic limit of infinite network size and we analytically studied their local bifurcations. All the analytical results were extensively validated by numerical simulations.


Diversity of LTR-retrotransposons and Enhancer/Suppressor Mutator-like transposons in cassava (Manihot esculenta Crantz).
Cassava (Manihot esculenta Crantz), though a major world crop with enormous potential, is very under studied. Little is known about its genome structure and organisation. Transposable elements have a key role in the evolution of genome structure, and can be used as important tools in applied genetics. This paper sets out to survey the diversity of members of three major classes of transposable element within the cassava genome and in relation to similar elements in other plants. Members of two classes of LTR-retrotransposons, Ty1/copia-like and Ty3/gypsy-like, and of Enhancer/Suppressor Mutator (En/Spm)-like transposons were isolated and characterised. Analyses revealed 59 families of Ty1/copia, 26 families of Ty3/gypsy retrotransposons, and 40 families of En/Spm in the cassava genome. In the comparative analyses, the predicted amino acid sequences for these transposon classes were compared with those of related elements from other plant species. These revealed that there were multiple lineages of Ty1/copia-like retrotransposons in the genome of cassava and suggested that vertical and horizontal transmission as the source of cassava Mecops may not be mutually exclusive. For the Ty3/gypsy elements network, two groups of cassava Megyps were evident including the Arabidopsis Athila lineage. However, cassava En/Spm-like elements (Meens) constituted a single group within a network of plant En/Spm-like elements. Hybridisation analysis supported the presence of transposons in the genome of cassava in medium (Ty3/gypsy and En/Spm) to high (Ty1/copia) copy numbers. Thus the cassava genome was shown to contain diverse members of three major classes of transposable element; however, the different classes exhibited contrasting evolutionary histories.


[Anxiety-depressive disorders and paroxysmal atrial fibrillation: the psychosomatic aspects].
One hundred and forty-five patients with paroxysmal atrial fibrillation were examined to evaluate the effectiveness of the correction of physical state in the course of complex (somatotropic and psychotropic) therapy. Personality characteristics of patients with arrhythmias, the structure and severity of stress and anxiety-depressive disorders preceding the manifestation of paroxysmal atrial fibrillation were studied. Patients were examined at baseline and at the 21st day of therapy using clinical and instrumental methods (Holter ECG monitoring) and psychometric scales (the Beck Depression Inventory, the Zung Self-Rating Anxiety Scale, the Hamilton Depression Rating scale, the Hamilton Anxiety Rating scale). The complex treatment of patients with paroxysmal atrial fibrillation with SSRI antidepressants (paroxetine, fluvoxamine, sertraline) allowed to rapidly reduce neurotic anxiety depressive disorders. There was a significant positive trend in the course and frequency of paroxysms of atrial fibrillation on 21st day of treatment. These remedies help to reduce the duration of arrhythmia's attack which has already begun facilitating its relief. After 3-5 months of such regular complex pharmacotherapy, paroxysms of atrial fibrillation were completely stopped in 10.3% of patients. The follow-up investigation 18 months later showed that patients with certain personality traits and the positive dynamics of paroxysmal atrial fibrillation under a complex (somatotropic and psychotropic) treatment can develop cardiophobia' attacks in recurrent significant stress situations. Side-effects of the drugs were not significant and did not require discontinuation of the treatment.


Prevalence of generalized osteoarthritis in a population with knee osteoarthritis.
To determine the prevalence of generalized osteoarthritis in patients with knee osteoarthritis. Patients with knee osteoarthritis were recruited for a therapeutic trial via press announcement and selected based on American College of Rheumatology radioclinical criteria for femorotibial arthritis. Patients were asked to bring all their radiographs to the study visits, which included a physical examination. Each patient had an inclusion visit and a second visit 1 month later. The study physicians used a standardized chart to indicate clinical and radiographic evidence of osteoarthritis in each patient. At the hands and feet, the presence of clinical criteria was sufficient for the diagnosis of osteoarthritis. The shoulders and elbows were not assessed. Three criteria sets for generalized osteoarthritis were evaluated: Kellgren and Moore criteria (Heberden's nodes or interphalangeal osteoarthritis), ACR criteria (osteoarthritis of the spine and at least two other joints), and Dougados criteria (bilateral finger osteoarthritis or osteoarthritis of the spine and both knees). We included 302 patients for whom the side affected with knee osteoarthritis was known. Mean symptom duration was 5.9±5.7 years, mean number of painful flares was 10.1±9.4, mean number of joints with osteoarthritis was 2.6±1.8, and mean body mass index was 29.5±5.3 kg/m(2). A family history of osteoarthritis was noted in 154 (51%) patients and spinal osteoarthritis in 148 (49%) patients. Kellgren-Moore criteria for interphalangeal osteoarthritis were met in 42 (13.9%) patients, ACR criteria by 124 (41%) patients, and Dougados criteria by 127 (42%) patients. In all, 156 (52%) patients met at least one of the three definitions of generalized osteoarthritis. More than half the patients included in a therapeutic trial in knee osteoarthritis had generalized osteoarthritis with maximum symptoms at the knee at baseline. Some patients with osteoarthritis in multiple joints met none of the three criteria sets for generalized osteoarthritis. Further studies are needed to assess the sensitivity and specificity of current criteria sets and, if needed, to identify new criteria.


Classical and non-classical psychedelic drugs induce common network changes in human cortex.
The neurobiology of the psychedelic experience is not fully understood. Identifying common brain network changes induced by both classical (i.e., acting at the 5-HT2 receptor) and non-classical psychedelics would provide mechanistic insight into state-specific characteristics. We analyzed whole-brain functional connectivity based on resting-state fMRI data in humans, acquired before and during the administration of nitrous oxide, ketamine, and lysergic acid diethylamide. We report that, despite distinct molecular mechanisms and modes of delivery, all three psychedelics reduced within-network functional connectivity and enhanced between-network functional connectivity. More specifically, all three drugs increased connectivity between right temporoparietal junction and bilateral intraparietal sulcus as well as between precuneus and left intraparietal sulcus. These regions fall within the posterior cortical "hot zone," posited to mediate the qualitative aspects of experience. Thus, both classical and non-classical psychedelics modulate networks within an area of known relevance for consciousness, identifying a biologically plausible candidate for their subjective effects.


Evaluation of psoriasis patients with long-term topical corticosteroids for their risk of developing adrenal insufficiency, Cushing's syndrome and osteoporosis.
In this study, we will investigate the possible side effects of psoriasis patients using long-term topical corticosteroids (TCS) such as adrenal insufficiency, Cushing's Syndrome (CS) and osteoporosis and determine how these side effects develop. Forty-nine patients were included in the study. The patients were divided into two groups based on the potency of the topical steroid they took and the patients' ACTH, cortisol and bone densitometer values were evaluated. There was no significant difference between the two groups regarding the development of surrenal insufficiency, CS and osteoporosis. One patient in group 1 and 4 patients in group 2 were evaluated as iatrogenic CS. ACTH stimulation tests of these patients in group 2 showed consistent results with adrenal insufficiency, while no adrenal insufficiency was detected in the patient in Group 1. Patients who used more than 50g of superpotent topical steroids per week compared to patients who used 50g of superpotent topical steroids per week. It was identified that patients who used more than 50g of superpotent topical steroids had significantly lower cortisol levels, with a negatively significant correlation between cortisol level and the amount of topical steroid use (p < .01).Osteoporosis was detected in 3 patients in group 1 and 8 patients in Group 2. Because of the low number of patients between two groups, statistical analysis could not be performed to determine the risk factors. Our study is the first study that we know of that investigated these three side effects. We have shown that the development of CS, adrenal insufficiency and osteoporosis in patients who use topical steroids for a long time depends on the weekly TCS dosage and the risk increases when it exceeds the threshold of 50 grams per week. therefore, our recommendation would be to avoid long-term use of superpotent steroids and to choose from the medium-potent group if it is to be used.


Risk assessment of venous thromboembolism in hospitalized medical patients.
The aim is to provide a concise review of risk assessment models that stratify hospitalized acutely ill medical patients at risk of venous thromboembolism (VTE). Risk-assessment models (RAMs) for hospitalized medical patients at risk for VTE prior to 2005 attempted to identify at-risk patients using a point system or binary yes/no approach as to the existence of exposing (acute medical illness) or predisposing (genetic or clinical characteristic) risk factors for VTE. These RAMs were derived from data predominately from patient subgroups within randomized controlled trials and were cumbersome, not subject to rigorous validation, and were based on limited evidence of how these risk factors interacted in a quantitative manner. Recently, simplified RAMs have been proposed that have included this patient group. The RAMs are composed of various point systems and a threshold, which then would identify at-risk patient groups that would benefit from thromboprophylaxis. Although some of the point systems have been derived intuitively, they have been validated in large patient cohorts either prospectively or retrospectively and have shown good sensitivity. The presence of malignancy, prior VTE, hypercoagulability, advanced age and immobility all conferred increased risk of VTE during hospitalization or in the posthospital discharge period in the various models. Simple RAMs based on point systems to predict risk of VTE for the hospitalized medical patient have been validated that include either exposing or predisposing risk factors for VTE. It is hoped that these RAMs may identify acutely ill medical patients with additional characteristics that do not easily fit into group-specific thromboembolic risk assessment categories as currently proposed by international clinical guidelines.


[Analysis of loss of heterozygosity (LOH) at the p53 and Rb suppressor genes in urinary bladder carcinoma].
Loss of heterozygosity (LOH) at the p53 and Rb genes, and its clinical correlations were examined in 58 urinary bladder carcinomas. DNA was extracted from formalin-fixed, paraffin-embedded tissues, and amplified by polymerase chain reaction (PCR). The LOH at p53 was examined by restriction fragment length polymorphism (RFLP), and the LOH at Rb by single-strand conformation polymorphism (SSCP). Among patients with urinary bladder carcinoma, 60.3% (35/58 patients) showed heterozygosity at p53 and LOH was detected in carcinoma in 60.0% (21/35), i.e., LOH in 61.9% (13/21) of superficial (< or = pT1) and in 57.1% (8/14) of muscular invasive carcinomas. Therefore, LOH at p53 was considered to occur before the beginning of muscular invasion. Except for the patients who died of other causes or were missed during the follow-up, 67.4% (29/43) showed 43.8% (7/16) died of carcinomatosis, but, only 15.4% (2/13) of the patients without p53-LOH died. The 5-year survival rate calculated by the Kaplan-Meier method was 76.9% in patients with heterozygosity at p53, and 25.1% in those with LOH at p53, being significantly lower at p < 0.05 in the former than in the latter. From an analysis of multiple bladder carcinomas, LOH at p53 occurred on the same allele in different tumors of the same bladder, suggesting the monoclonal origin of each tumor of multiple bladder carcinomas. On the other hand, 51.7% (30/58) of patients showed heterozygosity at Rb, and LOH was detected in 16.7% (5/30) of them, i.e., 6.3% (1/16) in superficial carcinoma and 28.6% (4/14) in muscular invasive carcinoma.


Cuspal Flexure and Stress in Restored Teeth Caused by Amalgam Expansion.
Cracks in amalgam-filled teeth may be related to amalgam expansion. This study measured cuspal flexure and used finite element analysis to assess associated stress levels in amalgam-filled teeth. External surfaces of 18 extracted molars were scanned in three dimensions. Nine molars were restored with mesio-occluso-distal amalgam fillings; the other teeth were left intact as controls. All teeth were stored in saline and scanned after two, four, and eight weeks. Cuspal flexure and restoration expansion were determined by calculating the difference between scanned surfaces. Stresses in a flexed tooth were calculated using finite element analysis. Cusps of amalgam-filled teeth flexed outward approximately 3 μm, and restoration surfaces expanded 4 to 8 μm during storage. Cuspal flexure was significantly higher in the amalgam group (multivariate tests, p<0.05), but storage time had no significant effect (repeated measures, p>0.05). Expansion caused stress concentrations at the cavity line angles. These stress concentrations increased stresses due to mastication 44% to 178%. Amalgam expansion pushed cavity walls outward, which created stress concentrations at the cavity line angles. Expansion stresses can raise stresses in amalgam-filled teeth and contribute to incidentally observed cracks.


Pupillary Response of the Screech Owl, Otus asio.
The latent period of constriction in the owl is only half that in the human, and the latent period of dilatation is about equal to that in the human. Similarly, the rise time of constriction in the owl is much faster than that in the human. The owl system has the characteristics of a low-band-pass filter. The owl's frequency response is over an octave lower than that of the human, but its phase lags are shorter.


Four-dimensional cone beam CT with adaptive gantry rotation and adaptive data sampling.
We have developed a new four-dimensional cone beam CT (4D-CBCT) on a Varian image-guided radiation therapy system, which has radiation therapy treatment and cone beam CT imaging capabilities. We adapted the speed of gantry rotation time of the CBCT to the average breath cycle of the patient to maintain the same level of image quality and adjusted the data sampling frequency to keep a similar level of radiation exposure to the patient. Our design utilized the real-time positioning and monitoring system to record the respiratory signal of the patient during the acquisition of the CBCT data. We used the full-fan bowtie filter during data acquisition, acquired the projection data over 200 deg of gantry rotation, and reconstructed the images with a half-scan cone beam reconstruction. The scan time for a 200-deg gantry rotation per patient ranged from 3.3 to 6.6 min for the average breath cycle of 3-6 s. The radiation dose of the 4D-CBCT was about 1-2 times the radiation dose of the 4D-CT on a multislice CT scanner. We evaluated the 4D-CBCT in scanning, data processing and image quality with phantom studies. We demonstrated the clinical applicability of the 4D-CBCT and compared the 4D-CBCT and the 4D-CT scans in four patient studies. The contrast-to-noise ratio of the 4D-CT was 2.8-3.5 times of the contrast-to-noise ratio of the 4D-CBCT in the four patient studies.


Corticosteroid elimination: the Cincinnati experience.
Elimination of corticosteroid-related morbidity has been a goal of transplant clinicians from the earliest days of renal transplantation more than 50 years ago. Over the past decade, this goal has begun to be realized. Herein, we describe our efforts to eliminate corticosteroid therapy from maintenance immunosuppression-efforts that have spanned 15 years and have included design and conduct of five multicenter trials and over ten single center trials with over 650 patients at the University of Cincinnati. These efforts have led to a near complete elimination of corticosteroid-related morbidity, and, importantly, a more precise definition of the risk/benefit assessments of corticosteroid withdrawal in individual patient populations, which has allowed individualization and tailoring of corticosteroid-free immunosuppression.


LGL leukemia and HTLV.
Samples were obtained from 53 large granular lymphocytic leukemia (LGLL) patients and 10,000 volunteer blood donors (VBD). Sera were screened in an HTLV-1 enzyme immunoassay (EIA) and further analyzed in peptide-specific Western blots (WB). DNAs were analyzed by HTLV-1, -2, -3, and -4-specific PCR. Forty four percent of LGLL patients vs. 0.12 % of VBD had anti-HTLV antibodies via EIA (p < 0.001). WB and PCR revealed that four LGLL patients (7.5%) vs. one VBD patient (0.01%) were infected with HTLV-2 (p < 0.001), suggesting an HTLV-2 etiology in a minority of cases. No LGLL patient was positive for HTLV-1, -3, or -4, whereas only one EIA-positive VBD was positive for HTLV-1 and none for HTLV-3 or -4. The HTLV EIA-positive, PCR-negative LGLL patients' sera reacted to epitopes within HTLV p24 gag and gp21 env. Other then the PTLV/BLV viruses, human endogenous retroviral element HERV K10 was the only sequence homologous to these two HTLV peptides, raising the possibility of cross-reactivity. Although three LGLL patients (5.7%) vs. none of 110 VBD patients tested positive for antibodies to the homologous HERV K10 peptide (p = 0.03), the significance of the anti-HTLV seroreactivity observed in many LGLL patients remains unclear. Interestingly, out of 36 HTLV-1-positive control subjects, 3 (8%) (p = 0.014) were positive for antibodies to HERV K10; all three had myelopathy. Out of 64 HTLV-2-positive control subjects 16 (25%) (p = <0.001) were positive for HERV K10 antibodies, and 4 (6%) of these had myelopathy. Out of 22 subjects with either HTLV-1 or -2 myelopathy, 7 (31.8%) were positive for HERV K10 antibodies, and out of 72 HTLV-infected subjects without myelopathy, 12 (16.7%) were positive for anti-HERV K10 antibodies (p = 0.11). The prevalence of anti-HERV K10 antibodies in these populations and the clinical implications thereof need to be pursued further.


Night to night variability of pulse oximetry features in children at home and at the hospital.
Objective. Investigation of the night-to-night (NtN) variability of pulse oximetry features in children with suspicion of Sleep Apnea.Approach. Following ethics approval and informed consent, 75 children referred to British Columbia Children's Hospital for overnight PSG were recorded on three consecutive nights, including one at the hospital simultaneously with polysomnography and 2 nights at home. During all three nights, a smartphone-based pulse oximeter sensor was used to record overnight pulse oximetry (SpO2 and photoplethysmogram). Features characterizing SpO2 dynamics and heart rate were derived. The NtN variability of these features over the three different nights was investigated using linear mixed models.Main results. Overall most pulse oximetry features (e.g. the oxygen desaturation index) showed no NtN variability. One of the exceptions is for the signal quality, which was significantly lower during at home measurements compared to measurements in the hospital.Significance. At home pulse oximetry screening shows an increasing predictive value to investigate obstructive sleep apnea (OSA) severity. Hospital recordings affect subjects normal sleep and OSA severity and recordings may vary between nights at home. Before establishing the role of home monitoring as a diagnostic test for OSA, we must first determine their NtN variability. Most pulse oximetry features showed no significant NtN variability and could therefore be used in future at-home testing to create a reliable and consistent OSA screening tool. A single night recording at home should be able to characterize pulse oximetry features in children.


Sensory ganglioneuropathy in infantile spinal muscular atrophy. Light and electronmicroscopic findings in two cases.
Light and electronmicroscopic findings in two cases. Neuropediatrics 12: 215-31 (1981). Two cases of infantile spinal muscular atrophy (Werdnig-Hoffmann disease) are described in unrelated children deceased at 11 months (acute clinical onset at 6 months) and 2 years (onset at birth). Severe respiratory difficulties, hypotonia, muscular weakness and depressed tendon reflexes were the main clinical features. Bulbar palsy, bilateral ptosis, pale optic discs and atactic movements of the hands were observed in the child deceased at 11 months. Besides severe loss of anterior horn cells and neurogenic muscle atrophy there was evidence of an extensive sensory involvement in both cases. Shrinkage, vacuolation as well as chromatolytic changes of dorsal root ganglion cells, together with the evidence of a primary axonal damage in sural nerve biopsies were interpreted in terms of ganglioneuropathy of the primary sensory neurons. An invasion of fibrous astrocytes into dorsal roots constituted another striking anomaly in one case as well as a pronounced degeneration of cranial nerves V and VIII in the other case, a finding not hitherto reported in Werdnig-Hoffmann disease.


Assessment of ventricular function in dilated cardiomyopathies.
Regardless of its cause, systolic dysfunction in dilated cardiomyopathy triggers a wide variety of compensatory responses resulting in cardiac dilatation, fluid retention, and systemic vasoconstriction. Standard therapy with vasodilators, digoxin, and diuretics can provide symptomatic relief in many patients. However, many others do not respond adequately, and mortality from heart failure remains high. This has driven the search for novel therapies. To evaluate the efficacy and decipher mechanisms of action of these treatments, accurate assessments of left ventricular function are valuable. In particular, one seeks indexes that are cardiac-specific, in that they are minimally influenced by vascular loading conditions. An increasingly used "gold standard" that can achieve this goal is the invasively measured pressure-volume relation. Newer noninvasive methods have yielded several surrogates that have the key advantage of being applicable to chronic disease assessment. In this report, we review the current state-of-the-art in left ventricular function assessment, and describe recent advances in its noninvasive evaluation.