Catalytic activity of γ-Al2O3(110) in the NO + H2 reaction: a DFT study.
In this work, the interaction of the surface of γ-Al2O3(110) with NO and H2 was studied using density functional theory calculations. Free γ-Al2O3(110) adsorbs NO and binds H atoms, but repels the H2 molecule. A triplet of low-coordinated OII-AlIII-OII atoms provides the catalytic activity of γ-Al2O3(110) along the path: (i) the adsorption of NO/AlIII is followed by the binding of H2 to form a hydroxylamine derivative NHOH through an intermediate NO/AlIII + 2 × H/OII complex; (ii) recombination of NHOH with the release of N2 through an intermediate NHOH/AlIII + NHOH/AlIV or adsorption of NO followed by the release of N2O through the intermediate NHOH/AlIII + NO/AlIV; the pathway ends with the regeneration of γ-Al2O3(110). The calculated adsorption heats ensure the diffusion of H atoms from the deposited Pt to the surface (110), initiating the formation of the NH2/AlIII + H/OII complex, which releases NH3 endothermically and is stable enough to inhibit stage (ii) of the above reaction pathway. An excess of O2 in the NO + H2 mixture excludes H/Pt and eliminates inhibition. The formation of oxynitrides is suppressed, but not excluded by more exothermic surface processes. The N-doped conductivity of bulk and surface oxynitrides Al32O47N and the dependence of the heat of adsorption of H atoms on the band gap width were revealed, which suggests a relationship between the band gap width and catalytic activity.


Semantic Textual Similarity in Japanese Clinical Domain Texts Using BERT.
Semantic textual similarity (STS) captures the degree of semantic similarity between texts. It plays an important role in many natural language processing applications such as text summarization, question answering, machine translation, information retrieval, dialog systems, plagiarism detection, and query ranking. STS has been widely studied in the general English domain. However, there exists few resources for STS tasks in the clinical domain and in languages other than English, such as Japanese. The objective of this study is to capture semantic similarity between Japanese clinical texts (Japanese clinical STS) by creating a Japanese dataset that is publicly available. We created two datasets for Japanese clinical STS: (1) Japanese case reports (CR dataset) and (2) Japanese electronic medical records (EMR dataset). The CR dataset was created from publicly available case reports extracted from the CiNii database. The EMR dataset was created from Japanese electronic medical records. We used an approach based on bidirectional encoder representations from transformers (BERT) to capture the semantic similarity between the clinical domain texts. BERT is a popular approach for transfer learning and has been proven to be effective in achieving high accuracy for small datasets. We implemented two Japanese pretrained BERT models: a general Japanese BERT and a clinical Japanese BERT. The general Japanese BERT is pretrained on Japanese Wikipedia texts while the clinical Japanese BERT is pretrained on Japanese clinical texts. The BERT models performed well in capturing semantic similarity in our datasets. The general Japanese BERT outperformed the clinical Japanese BERT and achieved a high correlation with human score (0.904 in the CR dataset and 0.875 in the EMR dataset). It was unexpected that the general Japanese BERT outperformed the clinical Japanese BERT on clinical domain dataset. This could be due to the fact that the general Japanese BERT is pretrained on a wide range of texts compared with the clinical Japanese BERT.


The zebrafish cornea: structure and development.
To evaluate the zebrafish as a model for the studies of corneal development and disease. Zebrafish embryos and larvae at various stages of development were used for documenting corneal morphogenesis and differentiation. Corneal samples were collected from embryos, larvae, and adult zebrafish for histologic and electron microscopy analysis. Expression patterns of corneal polypeptides were investigated by immunostaining of sections. The zebrafish cornea develops rapidly during embryogenesis, so that its three major layers, the epithelium, the stroma, and the endothelium, are well formed by day 3 postfertilization. The subsequent steps of corneal differentiation, such as the thickening of the corneal stroma, proceed relatively slowly. Several polypeptides are highly enriched in the epithelium or the stroma of the larval and adult zebrafish cornea and are excellent markers of corneal differentiation. Development and differentiation of the zebrafish cornea are easily accessible to analysis. Anatomic and ultrastructural characterization of the zebrafish cornea demonstrates many similarities to the human cornea and provides the basis for the use of the zebrafish model both to analyze the basic genetic mechanisms of corneal development and to study the causes of corneal disease.


Peroxisome proliferator-activated receptor-{gamma} as a regulator of lung inflammation and repair.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that regulate the expression of genes involved in a variety of biological processes, including lipid metabolism and insulin sensitivity. Members of the PPAR family-in particular, PPAR-gamma-have more recently been shown to broadly regulate inflammatory and reparative responses. PPAR-gamma is expressed in both alveolar macrophages and neutrophils, and the ligand-dependent activation of this receptor results in suppression of leukocyte effector responses, including cytokine production, the elaboration of reactive oxygen and nitrogen species, and migratory responses. In addition to antiinflammatory effects, PPAR-gamma regulates diverse processes in lung stromal/parenchymal cells, including cell growth, differentiation, and apoptosis. Studies examining in vivo effects of PPAR-gamma have produced complex and at times conflicting results. However, evidence to date generally suggests that PPAR-gamma functions to dampen inflammation and injury in various animal models of acute lung injury. PPAR-gamma may also play an important role in other inflammatory/immune lung diseases, including ischemia-reperfusion injury, allergic airway inflammation, and cancer. The role of PPAR-gamma in human lung diseases, including acute lung injury, requires further study.


Hair transplant for acne scars: an innovative approach.
Postacne scarring is a common entity that affects patients both physically and psychologically. Treatment of facial scarring is rarely a mono-dimensional process. Various modalities of treatments from cheaper subcision, punch techniques and excision to expensive laser resurfacing techniques are available. Treatment of postacne scars in a particular case has to be individualized, taking into consideration many factors like age, gender, types of scarring, Fitzpatrick skin type, and socioeconomic status of the patient. In this article, we describe an innovative method of simply doing hair transplantation in acne scars and hence making them less visible and cosmetically well acceptable to the patient.


Alterations of voltage-dependent calcium channel currents in basilar artery smooth muscle cells at early stage of subarachnoid hemorrhage in a rabbit model.
To investigate the changes in the currents of voltage-dependent calcium channels (VDCCs) in smooth muscle cells of basilar artery in a rabbit model of subarachnoid hemorrhage (SAH). New Zealand white rabbits were randomly divided into five groups: sham (C), normal (N), 24 hours (S1), 48 hours (S2) and 72 hours (S3) after SAH. Non-heparinized autologous arterial blood (1 ml/kg) was injected into the cisterna magna to create SAH after intravenous anesthesia, and 1 ml/kg of saline was injected into cisterna magna in the sham group. Rabbits in group N received no injections. Basilar artery in S1, S2, S3 group were isolated at 24, 48, 72 hours after SAH. Basilar artery in group C was isolated at 72 hours after physiological saline injection. Basilar artery smooth muscle cells were isolated for all groups. Whole-cell patch-clamp technique was utilized to record cell membrane capacitance and VDCCs currents. The VDCCs antagonist nifedipine was added to the bath solution to block the Ca(++) channels currents. There were no significant differences in the number of cells isolated, the cell size and membrane capacitance among all the five groups. VDCC currents in the S1-S3 groups had higher amplitudes than those in control and sham groups. The significant change of current amplitude was observed at 72 hours after SAH, which was higher than those of 24 and 48 hours. The VDCCs were shown to expression in human artery smooth muscle cells. The changes of activation characteristics and voltage-current relationship at 72 hours after SAH might be an important event which leads to a series of molecular events in the microenvironment of the basilar artery smooth muscle cells. This may be the key time point for potential therapeutic intervention against subarachnoid hemorrhage.


Wide dynamic range neutron flux monitor having fast time response for the Large Helical Device.
A fast time response, wide dynamic range neutron flux monitor has been developed toward the LHD deuterium operation by using leading-edge signal processing technologies providing maximum counting rate up to ∼5 × 10(9) counts/s. Because a maximum total neutron emission rate over 1 × 10(16) n/s is predicted in neutral beam-heated LHD plasmas, fast response and wide dynamic range capabilities of the system are essential. Preliminary tests have demonstrated successful performance as a wide dynamic range monitor along the design.


Degradation and intrahepatic compatibility of albumin-heparin conjugate microspheres.
The in vitro degradation properties of glutaraldehyde cross-linked albumin and albumin-heparin conjugate microspheres (AMS and AHCMS respectively) were evaluated using light microscopy, turbidity measurements and heparin release determinations, showing that the microspheres are degraded by proteolytic enzymes such as trypsin, proteinase K and lysosomal enzymes. The degradation rate was inversely related to the cross-link density of the microspheres. After intrahepatic administration of AHCMS, cross-linked with 0.5% glutaraldehyde, to male Wag/Rij rats by injection into a mesenteric vein (intravenoportal: i.v.p.), the microspheres were entrapped in the hepatic vascular system. The AHCMS were entrapped within terminal portal veins predominantly at the periphery of the liver. The AHCMS were degraded by cellular enzymatic processes within 2 wk after injection, with a half life of approximately 1 d. Biocompatibility of AHCMS and adriamycin-loaded AHCMS was evaluated by histological assessment of the mitotic activity of liver parenchyma and inflammatory response, and by determination of liver damage marker enzymes during 4 wk after administration. Liver damage marker enzymes were not increased compared with controls, nor were adverse effects observed upon histological examination. There was no difference in response between empty and adriamycin-loaded AHCMS.


Children's understanding of their emotionally disturbed peers. I. The concept of emotional disturbance.
Study of the interpersonal relations of emotionally disturbed children has focused largely on relationships within the family. Theories of childhood psychopathology focus almost exclusively on the parent-child triad as the etiological core of childhood emotional disturbance (Frank, 1965). Far less attention has been paid to the role of extra-familial attitudes and relationships in childhood psychopathology. In a general way, the increasing importance of the peer group during childhood has been recognized, but researchers have hardly begun to consider whether and how the manifold aspects of relationships between the emotionally disturbed and their normal peers might bear on the course of the disturbance or its refractoriness to treatment (e.g., Solomon and Wahler, 1973). Nor have they considered peer group influences on the development of the emotionally disturbed child's perception of the world and his place within it. Despite increasing recognition of the early importance of peer relations, virtually no systematic information exists on the ways in which normal children view their emotionally disturbed peers. Our purpose in this paper is to report the first of several analyses of data from an initial investigation of children's understanding of their emotionally disturbed peers. Specifically, we wish to examine whether there is evidence that normal children do, in fact, perceive as emotionally disturbed the symptomatic and distressing behavior of peers that mental health professionals would recognize as indicative of psychopathology. Further, we wish to study these issues with respect to grade and sex differences.


The use of sequential silver and quinacrine staining to determine the parental origin and breakpoints of a ring-22 human chromosome.
We delineated a G-ring syndrome in 1968 and suggested it was due to a ring-22 (Weleber et al. 1969). We confirmed in 1972 that the ring was derived from chromosome 22 (Magenis et al. 1973). The present report constitutes a new case of the ring-22 syndrome with clinical findings virtually identical to those we described earlier. By sequential staining techniques with silver and quinacrine, it was possible to determine the parental origin of the ring (maternal) and to estimate the breakpoints in the chromosome 22 (22p12 and 22q13) leading to the ring configuration. The clinical abnormalities are due to terminal deletion of 22q distal to the breakpoint in band 22q13. The silver technique, especially in sequence with other stains, provides new and useful data concerning the origin and precise cytology of this, one of the tiniest rings known in humans.


[Quantitative study of brain perfusion patterns of 99mTc-ECD SPECT in children with developmental disabilities].
The aim of this study was to investigate the relationship between developmental disabilities and brain perfusion patterns. We performed technetium-99 m-ethylcysteinate dimer (99m-Tc-ECD) single photon emission computed tomography (SPECT) in 30 children with neurological disorders using the Patlak plot method. In children without developmental disabilities, the distribution of regional cortical perfusion evolved in relation to brain maturation. At one month of age, there was a predominant uptake in the perirolandic cortex. Radionuclide uptake in both the parietal and occipital cortices became evident by three months. Uptake in the temporal and frontal cortex increased by 6 and 11 months, respectively. Brain perfusion showed a pattern similar to that of adults by two years of age at the latest. In children with developmental disabilities, developmental changes of brain perfusion were delayed compared to normally developing children. Brain SPECT is a useful tool to assess the brain maturation in children with developmental disabilities.


Does metabolic syndrome influence psoriasis?
The metabolic syndrome is a combination of diabetes mellitus type 2, hypertension, central obesity and combined hyperlipidemia. The metabolic syndrome and its components have been largely associated with psoriasis. We report the case of a 66-year-old man affected with metabolic syndrome and psoriasis in which a multidisciplinary approach with endocrinologists and nutritionists led to an improvement of both conditions. After only 4 months of diet and an appropriate therapeutic regimen we observed an improvement of the hyperglycaemia, dyslipidemia, significant lose of weight, BMI switching from obesity to overweight and improvement of plaque psoriasis in absence of other treatments. We report this case to emphasise the need of a major control of the metabolic syndrome and associated comorbidities in psoriatic patients. Moreover we suggest that diet counselling and regular nutritional visits should be recommended in some patients to obtain dual benefits.


Motivational systems and the neural circuitry of maternal behavior in the rat.
Jay Rosenblatt's approach-avoidance model of maternal behavior proposes that maternal behavior occurs when the tendency to approach infant stimuli is greater than the tendency to avoid such stimuli. Our research program has uncovered neural circuits which conform to such a model. We present evidence that the medial preoptic area (MPOA: located in the rostral hypothalamus) may regulate maternal responsiveness by depressing antagonistic neural systems which promote withdrawal responses while also activating appetitive neural systems which increase the attractiveness of infant-related stimuli. These MPOA circuits are activated by the hormonal events of late pregnancy. Preoptic efferents may suppress a central aversion system which includes an amygdala to anterior hypothalamic circuit. Preoptic efferents are also shown to interact with components of the mesolimbic dopamine (DA) system to regulate proactive voluntary maternal responses. We make a distinction between specific (MPOA neurons) and nonspecific motivational systems (mesolimbic DA system) in the regulation of maternal responsiveness.


Acupuncture for sensorineural hearing loss.
Forty children, aged 9 to 16 years, with severe and profound sensorineural hearing loss received acupuncture five times weekly for three out of four weeks for a period of six months. The children had weekly audiometric evaluations. There were no clinically important differences during and post acupuncture.


Effect of superoxide dismutase deficiency on the life span of the yeast Saccharomyces cerevisiae. An oxygen-independent role of Cu,Zn-superoxide dismutase.
Effects of the absence of Cu,Zn-superoxide dismutase (CuZnSOD) on the replicative life span of the yeast Saccharomyces cerevisiae were studied under different oxygen conditions. In both strains, replicative life span and the rate of cell divisions were found to be similar under the atmosphere of air and under hypoxic (3% oxygen) and anoxic conditions. These results indicate that deleterious consequences of the lack of CuZnSOD are not limited to elevation of superoxide concentration and involve function(s) other than superoxide scavenging.


Spatio-angular consistent construction of neonatal diffusion MRI atlases.
Atlases constructed using diffusion-weighted imaging are important tools for studying human brain development. Atlas construction is in general a two-step process involving spatial registration and fusion of individual images. The focus of most studies so far has been on improving the accuracy of registration while image fusion is commonly performed using simple averaging, often resulting in fuzzy atlases. In this article, we propose a patch-based method for diffusion-weighted (DW) atlas construction. Unlike other atlases that are based on the diffusion tensor model, our atlas is model-free and generated directly from the diffusion-weighted images. Instead of independently generating an atlas for each gradient direction and hence neglecting angular image correlation, we propose to construct the atlas by jointly considering DW images of neighboring gradient directions. We employ a group regularization framework where local patches of angularly neighboring images are constrained for consistent spatio-angular atlas reconstruction. Experimental results confirm that our atlas, constructed for neonatal data, reveals more structural details with higher fractional anisotropy than the atlas generated without angular consistency as well as the average atlas. Also the normalization of test subjects to the proposed atlas results in better alignment of brain structures. Hum Brain Mapp 38:3175-3189, 2017. © 2017 Wiley Periodicals, Inc.


Mechanism of electrochemical charge transport in individual transition metal complexes.
We used electrochemical scanning tunneling microscopy (STM) and spectroscopy (STS) to elucidate the mechanism of electron transport through individual pyridyl-based Os complexes. Our tunneling data obtained by two-dimensional electrochemical STS and STM imaging lead us to the conclusion that electron transport occurs by thermally activated hopping. The conductance enhancement around the redox potential of the complex, which is reminiscent of switching and transistor characterics in electronics, is reflected both in the STM imaging contrast and directly in the tunneling current. The latter shows a biphasic distance dependence, in line with a two-step electron hopping process. Under conditions where the substrate/molecule electron transfer (ET) step is dominant in determining the overall tunneling current, we determined the conductance of an individual Os complex to be 9 nS (Vbias = 0.1 V). We use theoretical approaches to connect the single-molecule conductance with electrochemical kinetics data obtained from monolayer experiments. While the latter leave some controversy regarding the degree of electronic coupling, our results suggest that electron transport occurs in the adiabatic limit of strong electronic coupling. Remarkably, and in contrast to established ET theory, the redox-mediated tunneling current remains strongly distance dependent due to the electronic coupling, even in the adiabatic limit. We exploit this feature and apply it to electrochemical single-molecule conductance data. In this way, we attempt to paint a unified picture of electrochemical charge transport at the single-molecule and monolayer levels.


Study on inter-ethnic human differences in bioactivation and detoxification of estragole using physiologically based kinetic modeling.
Considering the rapid developments in food safety in the past decade in China, it is of importance to obtain insight into what extent safety and risk assessments of chemicals performed for the Caucasian population apply to the Chinese population. The aim of the present study was to determine physiologically based kinetic (PBK) modeling-based predictions for differences between Chinese and Caucasians in terms of metabolic bioactivation and detoxification of the food-borne genotoxic carcinogen estragole. The PBK models were defined based on kinetic constants for hepatic metabolism derived from in vitro incubations using liver fractions of the two ethnic groups, and used to evaluate the inter-ethnic differences in metabolic activation and detoxification of estragole. The models predicted that at realistic dietary intake levels, only 0.02% of the dose was converted to the ultimate carcinogenic metabolite 1'-sulfooxyestragole in Chinese subjects, whereas this amounted to 0.09% of the dose in Caucasian subjects. Detoxification of 1'-hydroxyestragole, mainly via conversion to 1'-oxoestragole, was similar within the two ethnic groups. The 4.5-fold variation in formation of the ultimate carcinogenic metabolite of estragole accompanied by similar rates of detoxification may indicate a lower risk of estragole for the Chinese population at similar levels of exposure. The study provides a proof of principle for how PBK modeling can identify differences in ethnic sensitivity and provide a more refined risk assessment for a specific ethnic group for a compound of concern.


Body and blood clearance and marrow radiation dose of 131I-Lym-1 in patients with B-cell malignancies.
Fifty-eight per cent of patients with B-cell malignancies had durable responses to treatment with 131I-Lym-1. Myelosuppression manifested by peripheral blood cytopenia was the radiation dose-limiting toxicity. The mean biologic half-times were 3.3 and 31.2 h for the fast and slow phases, respectively, of the blood clearance and 33.5 h for the clearance from the total body. Nonpenetrating radiation from the blood contributed 0.18 rad and penetrating radiations from the total body contributed 0.18 rad per administered mCi to the bone marrow. The average total contribution from both of these sources was 0.36 +/- 0.14 rad mCi-1. Clearances and marrow radiation doses were remarkably constant among different patients and among different therapy doses for the same patient. These results are potentially useful as an initial approximation for other mouse monoclonal antibodies of the same isotype. While radiation to normal marrow from 'spill-over' incident to specific targeting of 131I-Lym-1 on malignant B-cells in the marrow is not addressed in this publication because it is unique for each patient, it should be considered in the case of individual patients.


Use of a multi-instrument access device in abdominoperineal resections.
Laparoscopic colorectal surgery results in less post-operative pain, faster recovery, shorter length of stay and reduced morbidity compared with open procedures. Less or minimally invasive techniques have been developed to further minimise surgical trauma and to decrease the size and number of incisions. This study describes the safety and feasibility of using an umbilical multi-instrument access (MIA) port (Olympus TriPort+) device with the placement of just one 12-mm suprapubic trocar in laparoscopic (double-port) abdominoperineal resections (APRs) in rectal cancer patients. The study included 20 patients undergoing double-port APRs for rectal cancer between June 2011 and August 2013. Preoperative data were gathered in a prospective database, and post-operative data were collected retrospectively. The 20 patients (30% female) had a median age of 67 years (range 46-80 years), and their median body mass index (BMI) was 26 kg/m2 (range 20-31 kg/m2). An additional third trocar was placed in 2 patients. No laparoscopic procedures were converted to an open procedure. Median operating time was 195 min (range 115-306 min). A radical resection (R0 resection) was achieved in all patients, with a median of 14 lymph nodes harvested. Median length of stay was 8 days (range 5-43 days). Laparoscopic APR using a MIA trocar is a feasible and safe procedure. A MIA port might be of benefit as an extra option in the toolbox of the laparoscopic surgeon to further minimise surgical trauma.


The role of clinical "experience" in diagnostic performance.
Twenty-one physicians examined records of 43 patients who had attended the hospital because of chest pain. Of these patients, 20 had had coronary heart disease (CHD), 15 had had nonspecific pain, and eight had had pulmonary embolism. The physicians indicated the probability of CHD in each case on the basis of 18 clinical findings, not including ECG, x-ray, or biochemical studies. The trial was repeated five years later, using the same records, by 16 of the same physicians. Diagnostic accuracy was evaluated by ROC curves, and the weight ascribed to each cue was inferred by multiple regression with estimated probability of CHD as the dependent variable. No significant change of areas under the ROC curves with increasing length of clinical experience was observed. Multiple regression was significant in 30 of 37 analyses. The distributions of most physicians' estimates of probabilities had similar shapes five years apart. It is concluded that "experience" does not have a clear role in diagnostic performance based on recorded data and that personal calibration and preferences in estimating probabilities often persist for years.


Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation.
The effect of modulators of protein phosphorylation on the transcriptional activity of the androgen receptor (AR) was studied under transient expression conditions. Activators of protein kinase-A [8-bromo-cAMP (8-Br-cAMP)] and protein kinase-C (phorbol 12-myristate 13-acetate) or an inhibitor of protein phosphatase-1 and -2A (okadaic acid) influenced minimally pMMTV-chloramphenicol acetyl-transferase (CAT) activity in CV-1 cells cotransfected with an AR expression plasmid in the absence of androgen. In the presence of testosterone, however, all compounds enhanced AR-mediated transactivation by 2- to 4-fold. A nonsteroidal antiandrogen, Casodex, behaved as a pure antagonist; it blunted the action of testosterone and was not rendered agonistic by activators of protein kinase-A. A reporter plasmid containing two androgen response elements (AREs) in front of the thymidine kinase promoter (pARE2tk-CAT) was also used to examine promoter specificity. It was activated by 8-Br-cAMP, forskolin, or okadaic acid even without AR or androgen. However, when forskolin or okadaic acid was used together with androgen and AR, the resulting AR-dependent transactivation of pARE2tk-CAT was more than additive. Intact DNA- and ligand-binding domains, but not the N-terminal amino acid residues 40-147, of the receptor were mandatory for the synergism between protein kinase-A activators and androgen. Immunoreactive AR content in transfected COS-1 cells was not influenced by exposure to 8-Br-cAMP. Similar results were obtained by ligand binding assays. Quantitative or qualitative differences were not observed in DNA-binding characteristics between receptors extracted from cells treated with testosterone with or without protein kinase-A activator. Collectively, the synergistic stimulation of AR-dependent transactivation by androgen and protein kinase activators is not due to changes in cellular AR content or affinity of the receptor for the cognate DNA element; rather, this phenomenon seems to result from altered interaction of ligand-activated AR with other proteins in the transcription machinery.


Endothelial function in the time of the giants.
Paul Vanhoutte is one of the fathers of vascular biology. Among his great contributions, he demonstrated that endothelium modulates vasomotor response to vasoactive products (including serotonin) that are released when platelets aggregate in an artery. He found in arteries ex vivo that when endothelium is dysfunctional, in atherosclerosis or hypertension, normal relaxation to aggregation of platelets is impaired and vessels may contract. He proposed that this mechanism may predispose to vasospasm. The results of our experiments in vivo indicate that atherosclerosis greatly potentiates vasoconstrictor responses to serotonin in the limb, brain, and eye of monkeys. We proposed that transient ischemic attacks may be mediated by platelet-induced vasospasm. We observed endothelial dysfunction in atherosclerotic monkeys, with improvement of endothelial function when hypercholesterolemia was corrected. Recently, we studied the aortic valve, which has unique endothelium, in hypercholesterolemic mice to examine the pathophysiology of aortic valvular stenosis. Oxidative stress is increased in stenotic valves, and severe aortic stenosis develops in about one third of old, hypercholesterolemic mice. In stenotic aortic valves from humans, there is increased oxidative stress near calcified regions of the valves. Oxidative stress may trigger expression of pro-calcific genes in the aortic valve. Finally, we have used gene transfer of extracellular superoxide dismutase (ecSOD) to study endothelial effects of oxidative stress. Gene transfer of normal ecSOD improves endothelial dysfunction in several disease states, but gene transfer of ecSOD(R213G), a gene variant of ecSOD that is common in humans, fails to improve endothelial function. Gene transfer approaches may be useful to study mechanisms by which gene variants predispose to endothelial dysfunction and vascular disease.


Absence of postmating barriers between a selfing vs. outcrossing Chilean Mimulus species pair.
Reproductive isolation between sympatric species pairs may be maintained by both pre- and postmating barriers. Here we evaluate potential barriers to mating between the outcrossing Mimulus luteus and its more highly selfing sympatric congener, M. cupreus, two members of the South American luteus complex of Mimulus. Seed set was compared following autonomous self-pollination, manual pollination, conspecific outcrossing, and sympatric and allopatric hybridization, for laboratory-maintained inbred lines and wild-collected accessions. Survival and reproductive fitness of hybrids relative to parental species were examined across environments that differed with respect to temperature and soil nutrients, two factors that vary across the ranges of M. luteus and M. cupreus. Mimulus luteus was minimally capable of autonomous self-fertilization, consistent with reliance on an animal pollinator, whereas M. cupreus was a successful selfer across all tested accessions. Postmating barriers to hybridization are negligible, in both low- and high-stress environments, across multiple sympatric and allopatric populations. As in the North American M. guttatus-M. nasutus species pair, postmating barriers contribute little to isolation between M. luteus and M. cupreus. This result reinforces the importance of premating barriers, specifically species differences in reliance on, and accessibility to, animal pollinators. A unique aspect of the M. luteus-M. cupreus pair is the recent gain of red floral anthocyanin pigmentation in M. cupreus. On the basis of species differences in vegetative anthocyanin production, a facultative stress-protective response, we propose a potential stress-protective role for the constitutive floral anthocyanins of M. cupreus.


Idiopathic venous thromboembolism as a first manifestation of cancer.
Since Trousseau's time it has been documented the strong two-way relationship between cancer and venous thromboembolism (VTE). Moreover it has been clearly demonstrated that patients with a first episode of idiopathic VTE exhibit a higher risk of newly discovered cancer during follow-up when compared to those suffering from secondary VTE. The performance of a selected diagnostic work-up for cancer detection at the time of referral for index VTE in these patients appears to be capable to identify most of these malignancies and the earlier detection is likely to be associated with improved treatment possibilities and thus prognosis.


Seeking a New Paradigm for Alzheimer's Disease: Considering the Roles of Inflammation, Blood-Brain Barrier Dysfunction, and Prion Disease.
There is no effective etiologic treatment for Alzheimer's disease, nor is there a prophylactic medication which delays or prevents its onset. The lack of an accurate paradigm is undoubtedly related to the lack of effective means of prophylaxis and treatment. The current paradigm of beta amyloid in Alzheimer's brains causing cognitive dysfunction must be modified. Despite failed clinical trials, research continues into amyloid-oriented treatments. The persistence of the amyloid hypothesis/paradigm is an example of anchoring and representativeness heuristics described by Kahneman and Tversky in their classic 1974 Science paper. Economic factors also contribute to the persistence of this paradigm. Paradigms impact the scientific process by the following: (1) what is studied; (2) the types of questions that are asked; (3) the structure and nature of the questions; (4) the interpretations of research findings. We review the contribution of inflammation, malfunction of the neurovascular unit, and prion disease to Alzheimer's disease manifestations. Any or all of these are candidates for inclusion into a more accurate, inclusive, and useful new paradigm. By incorporating emerging facts and understanding into a new paradigm, we will enhance our ability to move toward effective prophylaxis and therapy for this tragic disease.


Factors influencing special education teachers' self-efficacy to provide transitional services for students with disabilities.
This study examined factors that may influence the self-efficacy level of special education teachers in delivering transition services to students with disabilities. Five independent variables were examined: attitudes, preparation level, teaching experiences, academic degree level, and level of available resources. The current study sample comprised 231 intermediate and secondary special education teachers in the city of Riyadh, Saudi Arabia. The results showed that attitudes are the best predictor of teachers' self-efficacy to provide transitional services for students with disabilities. Teacher preparation for transition services was the second most important variable that was positively associated with teachers' self-efficacy.


[Psychosomatic motor disorders in the structure of depression in children and adolescents].
106 patients (40 boys and 66 girls) at the age from 3 to 15 years with depression of neurotic level with motor disorders (hyperkinetic, hypokinetic, pseudoepileptic) were examined. The motor disorders were estimated as pseudoneurological ones. The treatment of such patients must be performed with estimation of the typological variations of depression (asthenic type was observed in 31 cases, anxious type--in 37, melancholic type--in 6, combined type--in 32), of the degree of depressions manifestation, of their etiology as well as the pathological "basis" and personal peculiarities of the patients. 81 patients were treated by antidepressants (AD) in combination with tranquilizers and nootropes. AD weren't applied in 25 cases. Of all the patients in which AD were used complete correction of pseudoneurological and depressive disorders was observed in 46 cases (56.8%), considerable improvement--in 26 patients, the improvement--in 9 cases. Meanwhile improvement was observed only in 15 cases and slight improvement in 10 persons in patients who had not received any AD (group differences were significant).


Sparse Bayesian Classification of EEG for Brain-Computer Interface.
Regularization has been one of the most popular approaches to prevent overfitting in electroencephalogram (EEG) classification of brain-computer interfaces (BCIs). The effectiveness of regularization is often highly dependent on the selection of regularization parameters that are typically determined by cross-validation (CV). However, the CV imposes two main limitations on BCIs: 1) a large amount of training data is required from the user and 2) it takes a relatively long time to calibrate the classifier. These limitations substantially deteriorate the system's practicability and may cause a user to be reluctant to use BCIs. In this paper, we introduce a sparse Bayesian method by exploiting Laplace priors, namely, SBLaplace, for EEG classification. A sparse discriminant vector is learned with a Laplace prior in a hierarchical fashion under a Bayesian evidence framework. All required model parameters are automatically estimated from training data without the need of CV. Extensive comparisons are carried out between the SBLaplace algorithm and several other competing methods based on two EEG data sets. The experimental results demonstrate that the SBLaplace algorithm achieves better overall performance than the competing algorithms for EEG classification.


Comparison of glycosaminoglycan chemical exchange saturation transfer using Gaussian-shaped and off-resonant spin-lock radiofrequency pulses in intervertebral disks.
To investigate, if a train of spin-lock pulses (chemical exchange saturation transfer with spin-lock pulses = CESL) improves biochemical glycosaminoglycan imaging compared with conventional chemical exchange saturation transfer with Gaussian-shaped pulses (CEST) in lumbar intervertebral discs. T2 , CEST, and CESL imaging was performed in lumbar intervertebral discs of 15 healthy volunteers at 3 Tesla. Mean and standard deviation of the asymmetric magnetization transfer ratio (MTRasym ), the asymmetric spin-lock ratio (SLRasym ) and T2 values were calculated for nucleus pulposus (NP) and annulus fibrosus (AF). Wilcoxon test was used to analyze differences between MTRasym and SLRasym . Pearson correlation was used to determine the relationship between MTRasym , SLRasym and T2 . Data showed no significant difference between MTRasym and SLRasym (NP: P = 0.35; AF: P = 0.34). MTRasym and SLRasym values differed significantly between NP and AF (MTRasym : P = 0.014, SLRasym : P = 0.005). T2 values correlated significantly with MTRasym (NP: ρ = 0.76, P < 0.001; AF: ρ = 0.60, P < 0.001) and SLRasym (NP: ρ = 0.73, P < 0.001; AF: ρ = 0.47, P < 0.001). CESL does not improve the chemical exchange asymmetry effect compared with conventional CEST, but leads to comparable results. Magn Reson Med 78:280-284, 2017. © 2016 International Society for Magnetic Resonance in Medicine.


The elucidation of the microheterogeneity of highly purified p-hydroxybenzoate hydroxylase from Pseudomonas fluorescens by various biochemical techniques.
Highly purified p-hydroxybenzoate hydroxylase from Pseudomonas fluorescens can be separated into at least five fractions by anion-exchange chromatography. All fractions exhibit the same specific activity and the enzyme exists mainly in the dimeric form in solution. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis of a mixture of the different fractions reveals two apparent forms of enzyme molecules, while isoelectric focusing experiments, on the other hand, reveal six apparently different forms of enzyme molecules. It is shown that the different forms of enzyme molecules are due to the (partial) oxidation of Cys-116 in the sequence of the enzyme. This interpretation of the data is supported by kinetic measurements of the formation of hybrid dimeric molecules monitored by fast protein liquid chromatography, using purified enzyme containing Cys-116 either in the native and or the fully oxidized (sulfonic acid) state. By chemical modification studies using maleimide derivatives, 5,5'-dithiobis(2-nitrobenzoate) and H2O2, it is shown that sulfenic, sulfinic and sulfonic acid derivatives of Cys-116 are products of oxidation. The results are briefly discussed with respect to the possibility that this isolation artifact might also be partially responsible for the appearance of multiple forms of enzyme molecules in other biochemical preparations.


A DNA Inversion System in Eukaryotes Established via Laboratory Evolution.
DNA inversion is a type of site-specific recombination system that plays an important role in the generation of genetic diversity and phenotypic adaptation by programmed rearrangements in bacteria. However, no such inversion system exhibiting a strong directionality bias has been identified or developed in eukaryotes yet. Here, using directed evolution of Rci recombinase, a tyrosine recombinase from a bacterial DNA inversion system, we identified a mutant Rci8 with a ratio of inversion/deletion up to ∼4320 in yeast. Based on Rci8 recombinase and sfxa101 sites, we have established a DNA inversion system in yeast and mammalian cells, enabling specificity for DNA inversions between inverted sites over deletions between directly repeated sites. Our results validated that the reversible DNA inversion system can act as an on/off transcriptional switch. Moreover, we demonstrate that the inversion system can also work on linear chromosomes. The eukaryotic DNA inversion system would provide a new tool for fields of genetic circuits, cellular barcoding, and synthetic genomes.


Diagnostic approaches for inherited hemolytic anemia in the genetic era.
Inherited hemolytic anemias (IHAs) are genetic diseases that present with anemia due to the increased destruction of circulating abnormal RBCs. The RBC abnormalities are classified into the three major disorders of membranopathies, hemoglobinopathies, and enzymopathies. Traditional diagnosis of IHA has been performed via a step-wise process combining clinical and laboratory findings. Nowadays, the etiology of IHA accounts for germline mutations of the responsible genes coding for the structural components of RBCs. Recent advances in molecular technologies, including next-generation sequencing, inspire us to apply these technologies as a first-line approach for the identification of potential mutations and to determine the novel causative genes in patients with IHAs. We herein review the concept and strategy for the genetic diagnosis of IHAs and provide an overview of the preparations for clinical applications of the new molecular technologies.


Field evaluation of zero vector durable lining to assess its efficacy against malaria vectors and malaria transmission in tribal areas of the Balaghat district of central India.
Indoor residual spray (IRS) and long-lasting insecticidal nets are the two principal intervention methods of vector control. Zero vector durable lining (ZVDL), a relatively new vector control method, was evaluated to assess its efficacy against malaria vectors in hard to reach areas in the Balaghat district, where malaria transmission is perennial. ZVDL was installed in six experimental villages during November-December 2012. In control villages, IRS was carried out with Alphacypermethrin. Cone bioassays were performed to assess the efficacy and persistence of insecticide-treated ZVDL following WHO bioassays. The mean per man hour density of Anopheles caught during 2013 was 12.1 in experimental villages and 16.2 in control villages. No sporozoite-positive Anopheles culicifacies were found in experimental villages; however, in control villages, four sporozoite-positive A. culicifacies were found (two Plasmodium vivax and two P. falciparum). The knock-down rate of A. culicifacies was 95-100% with 100% mortality during the 24 h recovery period. Malaria declined sharply in experimental villages showing a slide positivity rate of 22.3% compared with control villages (36.4%) (p<0.05). A supplementary vector control intervention such as ZVDL has the potential to become a viable alternative to IRS in malaria endemic areas.


Air Pollution Predicts Harsh Moral Judgment.
The present research recruited participants from China, which is suffering from serious air pollution, and examined whether air pollution would be associated with moral judgment and immoral behavioral intention. Study 1 (n = 145) used the objective Air Quality Index to indicate the level of air pollution and found that it predicted harsh judgment on others' moral violations but did not predict judgment on others' non-moral negative behaviors or their own immoral behavioral intentions. Study 2 (n = 90) asked participants either to recall a past experience of being exposed to air pollution or to recall a neutral experience and consistently found that air pollution only influenced judgment on moral violations. The findings also ruled out the feeling of threat or the trust of government as possible mediators in the relationship between air pollution and harsh moral judgment.


Lobo's disease in a bottlenose dolphin (Tursiops truncatus) from Matagorda Bay, Texas.
Lobo's disease was diagnosed in a free-ranging male bottlenose dolphin Tursiops truncatus examined as part of a live-capture and release program conducted in Matagorda Bay, Texas, USA, during July 1992. Diagnosis was based on typical presentation of a raised skin lesion, with sub-epidermal granuloma and demonstration of typical features of the organism by light microscopy, using hematoxylin and eosin, and methenamine silver stains. This is the first instance of Lobo's disease found in a dolphin on the western coast of the Gulf of Mexico.


Adenovirus infection enhances killing of melanoma cells by a mitotoxin.
Toxins are effective in cell killing if internalized efficiently. Conjugation of the plant toxin saporin with basic fibroblast growth factor has increased tumor killing due to better internalization, but toxin uptake by cells has remained relatively inefficient. We show here that infection of melanoma cells with a replication-defective adenovirus enhances cell killing by the mitotoxin basic fibroblast growth factor-saporin more than 10-fold, thus allowing tumor cell killing in vivo at nontoxic concentrations. Adenovirus infection leads to increased apoptosis by the mitotoxin due to enhanced internalization of the ligand-receptor complex and release of the active toxin from the endosomes.


Soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) in scleroderma skin.
In order to investigate whether soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) were present in scleroderma skin, and to compare their levels to concentrations measured in plasma and clinical parameters, we examined suction blister fluid and plasma from 13 patients with systemic sclerosis and 11 healthy volunteers. Suction blisters and biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin. The levels of sICAM-1 and sIL-2R were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy volunteers. ICAM-1 was localized to vessels and perivascular mononuclear infiltrates by immunohistochemical methods. IL-2R was expressed by CD3-positive cells. The elevated levels of sICAM-1 and sIL-2R in suction blister fluid point towards activation of endothelial cells and T cells in both the transition zone and uninvolved skin of systemic sclerosis patients.


A comparison of an electronic version of the SF-36 General Health Questionnaire to the standard paper version.
Because of its sound psychometric properties the SF-36 General Health Questionnaire is used throughout the world, yet it is difficult to analyse and score. Using a newly developed software package, onto which any questionnaire can be loaded, we developed an electronic version of the SF-36 General Health Questionnaire. The purpose of this study is test the effect of the electronic mode of administration on the measurement properties of the SF-36. In a randomised cross-over design study 79 healthy individuals and 36 chronic pain patients completed both electronic and paper versions of the SF-36. Seventy-one percent preferred the electronic SF-36, 7% stated no preference, and 22% preferred the paper version. Completion time for the electronic SF-36 was slightly less, and there were no missing or problematical responses, whereas 44% of participants had at least one missing or problematical response in the paper version. Data entry and auditing time was 8 hours. There was less than 4% inter-version difference for any of the SF-36 sub-scales. The electronic SF-36 was well accepted and slightly quicker to complete than the paper version. We conclude that the electronic SF-36 is equivalent in performance and more effective than the paper version.


Expression and diagnostic value of lncRNA HCG18 in gestational diabetes mellitus.
Gestational diabetes mellitus (GDM) is the first type of diabetes induced by abnormal maternal glucose metabolism after pregnancy. Long non-coding RNA (lncRNA) has been found to be of great value in the study of its pathogenesis and treatment. This study aimed to explore the expression and diagnostic value of lncRNA HCG18 in GDM. The expression levels of HCG18 in serum of participating GDM patients and healthy controls were detected by polymerase chain reaction (RT-qPCR). The correlation between the expression of HCG18 and the blood glucose level was clarified by the detection of blood glucose levels in GDM patients. The receiver operating characteristic curve (ROC) was used to evaluate the clinical diagnostic value of HCG18 for GDM. Furthermore, multivariate logistic analysis was used to verify the diagnostic value of HCG18 in GDM. This study concluded that the expression level of HCG18 was upregulated in the serum of GDM patients compared with the control group. ROC curve showed that the AUC was 0.916, the sensitivity was 80.5%, the specificity was 90.2%, and multivariate logistic regression analysis verified that HCG18 (OR = 6.984, 95% CI = 3.751-13.005, p < 0.001) was significantly associated with GDM, which suggesting that HCG18 has diagnostic significance for GDM. In addition, the expression of HCG18 was positively correlated with fasting blood glucose, 1h blood glucose and 2 h blood glucose of patients. LncRNA HCG18 was elevated in patient serum and might serve as a diagnostic biomarker for GDM.


Quantifying Intraoperative Laparoscopic Visual Field Opacity.
Laparoscopic surgery can be complicated by condensation and debris on the lens obscuring the visual field, increasing the risk of surgical error and injury to the patient. Despite, development of possible solutions, little is known regarding the quantitative measure of time lost during surgery because of an obscured visual field. Without this knowledge, the cost of laparoscopic lens fogging cannot be quantified and compared to the cost of antifogging devices. In the present study, we investigated the amount of time a laparoscope is withdrawn for cleaning during surgery. This was a prospective, observational study of patients (n = 52) who underwent laparoscopic surgery at Florida Hospital Celebration Health. Patient's age, gender, and body mass index, operative time, wound class, estimated blood loss, type of procedure, and complication (if any) were collected. In addition, intraoperative information on the number of times and total amount of time the laparoscope was withdrawn because of obscured visual field were recorded. Eighty-two percent (43) of the procedures required laparoscope withdrawal because of fogging. Increased operative time, increased blood loss, and patient age correlated with the number of times (P < .05) and amount of time (P < .05) the laparoscope was withdrawn. There was a significant correlation between increased laparoscope withdrawal because of an obscured visual field with increased EBL, operative time, and patient age. Possible explanations include change in body composition with age, the increased viewing angles required for more complex procedures, and increasing intraoperative effect on the surgeon of the poor visual field caused by fogging and debris.


Effects of insecticide sublethal concentrations on the ringlegged earwig, Euborellia annulipes (Lucas).
Integrated pest control of the sugarcane stem borer (SSB), Chila infuscatellus, recommends the use of a voracious predator as the ring legged earwig (RE), Euborellia annulipes (Lucas) and insecticide application. This study was conducted to determine sublethal effects of two recommended pyrethroid insecticides, cypermethrin and deltamethrin, on predation, the number of eggs/batch, % egg hatch and the developmental period of the offspring of RE adults. Sublethal concentrations of cypermethrin (10% EC) and deltamethrin (3% EC) at LC1 and LC10 were topically applied with a micro-applicator on tested individuals with direct and indirect methods. They were applied directly once on adults of RE or on ten 3rd instar larvae of SSB which were then fed to RE adults. Surviving adults were further investigated. Insecticide-treated RE adults with LC1 and LC10 of cypermethrin showed significantly slower onset of predation averaged 14.20 and 18.35 h, lower number of preys killed, averaged 4.8 and 4.2 larvae/d, respectively, as compared to those of untreated ones. The corresponding figures of treated adults with deltamethrin were 30.5 and 42.2 h, 4.6 and 3.8 larvae/d respectively. Similar results were obtained on RE adults that fed on insecticide-treated 3rd instar SSB larvae with the same concentrations of insecticides. The only different result was recorded on the number of preys killed by indirectly treated adults with LC1 of cypermethrin and deltamethrin averaged 9.6 and 8.8 larvae/d, respectively, which was not significantly different as compared to those of untreated ones. Insecticide-treated RE adults with LC10 of cypermethrin and deltamethrin showed significantly lower number of eggs/batch averaged 31.4 and 27.4 eggs, lower % egg hatch averaged 29.8 and 31.7%, prolonged developmental period of the offspring averaged 91.8 and 113.0 d, respectively, as compared to those of untreated ones. The corresponding figures of those from RE adults that fed on insecticide-treated 3rd instar SSB larvae were 30.7 and 37.5 eggs, 36.1 and 32.8%, 95.6 and 113.7 d, respectively, as compared to those of untreated ones. This study concluded that sublethal concentrations of cypermethrin and deltamethrin at LC1 and LC10 which did not kill RE adults reduced their predation, lowered the number of eggs/batch and % egg hatch, and prolonged the developmental period of their offspring. It is suggested that RE may not be totally safe for combination use with cypermethrin and deltamethrin in controlling SSB.


Recent Developments on the Synthesis and Biological Activities of Fused Pyrimidinone Derivatives.
Heterocyclic compounds constitute a unique class of organic compounds endowed with a wide range of synthetic and pharmaceutical applications. Pyrimidinones and their fused analogues have received focused attention in this regard, partly due to their mimicry of nucleobases which consequently forges their interesting medicinal properties. Over the years, the medicinal chemistry research community has experienced an upsurge in articles describing the exploration of these scaffolds to develop effective therapeutic agents. Several biological activities, including antimicrobial, antiviral, anticancer, antidiabetic, anti-inflammatory, anticonvulsive, and antihistaminic, have been well documented. This minireview presents a compendium of recent developments (2017-2020) focused on the synthesis and biological activities of fused pyrimidinones. The goal is to update medicinal chemists on the therapeutic relevance of fused pyrimidinones and the molecular architecture of clinic-worthy drug candidates. A brief account of the structure-activity relationships (SAR) revealed from different biological assays is also discussed.


Collagenase Clostridium histolyticum Treatment Improves Degree of Curvature in Peyronie's Disease with Calcified Plaques.
Peyronie's disease (PD) is a fibrotic condition of the penis characterized by abnormal plaque formation. Intralesional collagenase Clostridium histolyticum (CCh) is effective in noncalcified PD; however, its effectiveness in calcified PD is not well characterized. To assess curvature improvement in calcified PD plaques treated with CCh. We prospectively evaluated men with calcified PD electing CCh treatment at our institution from October 2018 to November 2020. We assessed curvature with artificial erection and goniometer before and at least 3 mo after treatment. We classified the type of plaque calcification based on ultrasound. Intralesional CCh. Each treatment cycle consisted of two CCh injections (0.58 mg) into the plaque at the point of maximal penile curvature. The second injection was performed 72 h to 1 wk later, after which participants began modeling. All men were intended to receive a total of eight injections in four cycles, each 6 wk apart. Change in penile curvature after CCh was measured. We assessed for differences in outcomes based on the number of injections and type of calcification. Unless otherwise specified, data are presented as medians (interquartile range). Sixty men with calcified PD elected CCh; 47 had complete follow-up data. Thirty-nine men completed treatments with eight injections, while the remaining discontinued after a median of five (four to six) injections. There was no difference in response between type 2 and type 3 plaques. Curvature significantly improved by 17.5° (37.5-10.0°) in patients who completed treatment and by 15.0° (20.0-0.0°) in those who discontinued. Limitations include a small sample. Men with calcified PD plaques improve with CCh treatment and show similar improvements regardless of calcification type. In this study, we evaluated the efficacy of collagenase Clostridium histolyticum (CCh) treatment in calcified Peyronie's disease (PD) plaques. We found that treatment in calcified plaques demonstrated significant improvement in curvature and the grading of calcification did not impact the degree of curvature improvement. We conclude that participants with calcified PD plaques can benefit from nonsurgical CCh treatment.


[Evolution of patients with long-term methadone substitution].
The Drop-in in Neuchâtel (Switzerland) offers methadone substitution treatments since 1975. In the present research, we analyze the progress of 119 patients in treatment over a period of ten years. Our results confirm that substitution treatments do often last long (56% over ten years) and that they can be stopped successfully by some patients (29%). Among patients who maintain in the long-term the methadone, we do observe a global stabili zation of their medico-psycho-social situation. The results are convincing concerning the diminution of the heroin consumption and criminality. However, the professional reintegration rate is small and we observe for 30% of them a slow deterioration of their physical health, mainly bond with chronic illnesses (HIV, HCV) and life habits (not appropriate alcohol consumption, nicotine addiction...).


Comparison of conformational analysis techniques to generate pharmacophore hypotheses using catalyst.
Generation of reliable pharmacophore models is a key strategy in drug design. The quality of a pharmacophore model is known to depend on several factors, with the quality of the conformer sets used perhaps being one of the most important. The goal of this study was to compare different conformational analysis methods to determine if one was superior to the others for pharmacophore generation using Catalyst/HypoGen. The five methods selected were Catalyst/Fast, Catalyst/Best, Omega, Chem-X and MacroModel. Data sets for which Catalysts models had previously been published were selected using defined quality measures. Hypotheses were generated for each of the data sets and the performance of the different conformational analysis methods was compared using both quantitative (cost and correlation coefficients) and qualitative measures (by comparing the hypotheses in terms of the features present and their spatial relationships). Two main conclusions emerged from the study. First, it was not always possible to replicate the literature results. The reasons for these failures are explored in detail, and a template for use in publications that apply the Catalyst methodology is proposed. Second, the faster rule-based methods for conformational analysis give pharmacophore models that are just as good as, and in some cases better than, the models generated using the slower, more rigorous approaches.


Incorporating Neutrophil-to-lymphocyte Ratio and Platelet-to-lymphocyte Ratio in Place of Neutrophil Count and Platelet Count Improves Prognostic Accuracy of the International Metastatic Renal Cell Carcinoma Database Consortium Model.
The study investigated whether a replacement of neutrophil count and platelet count by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model would improve its prognostic accuracy. This retrospective analysis included consecutive patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors. The IMDC and modified-IMDC models were compared using: concordance index (CI), bias-corrected concordance index (BCCI), calibration plots, the Grønnesby and Borgan test, Bayesian Information Criterion (BIC), generalized R2, Integrated Discrimination Improvement (IDI), and continuous Net Reclassification Index (cNRI) for individual risk factors and the three risk groups. Three hundred and twenty-one patients were eligible for analyses. The modified-IMDC model with NLR value of 3.6 and PLR value of 157 was selected for comparison with the IMDC model. Both models were well calibrated. All other measures favoured the modified-IMDC model over the IMDC model (CI, 0.706 vs. 0.677; BCCI, 0.699 vs. 0.671; BIC, 2,176.2 vs. 2,190.7; generalized R2, 0.238 vs. 0.202; IDI, 0.044; cNRI, 0.279 for individual risk factors; and CI, 0.669 vs. 0.641; BCCI, 0.669 vs. 0.641; BIC, 2,183.2 vs. 2,198.1; generalized R2, 0.163 vs. 0.123; IDI, 0.045; cNRI, 0.165 for the three risk groups). Incorporation of NLR and PLR in place of neutrophil count and platelet count improved prognostic accuracy of the IMDC model. These findings require external validation before introducing into clinical practice.


Chemokine CXC receptor 4: an evolutionary approach.
Selected segments of the nucleotide sequences of the human 18S rRNA and the human formyl peptide receptor 1 mRNA exhibit structural similarities that are unlikely to be due simply to chance. Herein we analyze the structural similarities between the human 18S rRNA gene and the vertebrate chemokine CXC receptor 4 (CXCR4) gene that encodes a class A (rhodopsin-like) seven-transmembrane G-protein coupled receptor belonging to the same superfamily of formyl peptide receptors. The method of study was based on the recording of the positions of the 7-or-more-base oligonucleotide identities encountered in the 18S and CXCR4 genes and the construction of scatter-plots (abscissa-18S; ordinate-CXCR4) displaying the identity points positions. Analysis of the distribution of distances between identity points (abscissa-ordinate in the scatter-plot) demonstrated distinct peaks of frequency around 1200. Series of identities arranged near diagonal lines at 45 degrees in the scatter-plot (quasialignments) were evaluated for their probabilistic level of random occurrence. Results of this analysis demonstrated nonrandom quasialignments between (i) a 900-nt ca. section of the human CXCR4 intron that immediately precedes almost the whole of the coding sequence and the 18S gene from nt 125 to 1025 ca.; and (ii) a 425-nt ca. section of the CXCR4 vertebrate genes, corresponding to nt 137-560 of the coding sequence, and the 18S gene from nt 1300 to 1730 ca. In both instances significant quasialignments are evidenced when CXCR4 nt sequences are shifted to the right by about 1200 nt with respect to the 18S nt sequence, as confirmed by analysis of the abscissa - ordinate differences. Taken together, these results indicate that, at least in humans, a continuous nonrandom quasialignment extends for some 1600 nt, from the second part of the (single) intron to the first part of the coding sequence. We hypothesize that the relatively more recent CXCR4 vertebrate gene might be evolutionarily related to the more ancient and highly conserved 18S gene.


Review article: vitamin D and inflammatory bowel disease--established concepts and future directions.
Understanding of the role of vitamin D in health and disease has increased markedly in the past decade, with its involvement extending well beyond traditional roles in calcium and phosphate homeostasis and musculoskeletal health. This conceptual expansion has been underpinned by identification and exploration of components of this axis including vitamin D-binding protein, key enzymes and receptors in multiple cell types, and a greater recognition of nonclassical autocrine and paracrine effects. Its influence in IBD remains uncertain. To review the role of vitamin D in bone health, immune regulation and cancer prevention in IBD, and to outline practical issues and limitations of its use. An extensive online literature review including PubMed and Medline. In patients with IBD, the vitamin D axis provides an important and often underutilised pathway to preserving bone health. Furthermore, an exciting body of clinical and basic science research demonstrates that these pathways may have an integral part to play in regulation of the immune response in IBD, through effects on the intestinal barrier, antigen presenting cells and adaptive T cells. The possibility of chemoprevention requires further study. The optimal target level of 25-hydroxy vitamin D in patients with IBD is currently uncertain, as is the best therapeutic modality. Study of vitamin D pathways may result in the development of relatively inexpensive therapeutic options to optimise patient outcomes. Further prospective clinical research is required to address efficacy and long-term safety.


Neoantigen-based immunotherapy in pancreatic ductal adenocarcinoma (PDAC).
Neoantigens generated in neoplasms are a type of protein completely absent in healthy tissues. Therefore, anti-tumor immunity targeting neoantigens is highly specific, which provides an optional approach to boost tumor immunotherapy. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies in humans, with few efficient treatments to improve its prognosis. Therefore, immunotherapies reinforced by neoantigen-based strategies should be considered. In PDAC, the mutational burden is intermediate compared with other common malignancies, while the naturally formed tumor immunity is significantly inferior. Moreover, the high mutation load in PDAC correlates with a poor clinical prognosis, although the combination of a large mutation repertoire and competent T cell population is indispensable for long-term survival. In clinical practice, three strategies have been mainly used: peptide or tumor cell vaccines, neo-epitope-coding nucleotide vaccines, and dendritic cell vaccines. However, three major problems remain to be addressed, including (1) highly personalized protocols after sampling, (2) insufficient neoantigen quantity, and (3) ineffective immunotherapy of PDAC. In summary, neoantigen-based therapy of PDAC is increasing and the treatment methods are accompanied by great challenges. Currently, extensive development is needed for effective neoantigen-based therapy.


Implementing the WISEWOMAN program in local health departments: staff attitudes, beliefs, and perceived barriers.
Although most health departments recognize the need for programs to reduce the risk of cardiovascular disease (CVD) among older, low-income women, they face numerous barriers to successfully implementing such programs. This paper explores counselors' attitudes and beliefs about patients and perceived barriers to implementing the North Carolina Well-Integrated Screening and Evaluation for Women Across the Nation (WISEWOMAN) program. Health departments were assigned to provide patients with either an enhanced intervention (EI) or a minimum intervention (MI). Cross-sectional baseline and 12-month follow-up surveys were completed by health department counselors designated to deliver the MI or EI. Both surveys addressed counselors' beliefs about patients' motivation and attitudes, their counseling practices, and their personal diet and physical activity behaviors and attitudes. The follow-up survey also addressed opinions about the feasibility of long-term WISEWOMAN implementation. Counselors were skeptical about patients' motivation to improve their lifestyle, citing high perceived cost and burden. At follow-up, EI counselors reported having higher self-efficacy for counseling, incorporating more behavioral change strategies, and spending more time counseling than did counselors at MI sites. They were also more likely to report making healthful personal lifestyle choices. All counselors identified lack of time as a major barrier to counseling, and most cited obtaining low-cost medications for patients, ensuring that patients made follow-up visits, and implementing the program with existing staff as key challenges to the long-term sustainability of WISEWOMAN. Our findings provide insight into the organizational challenges of implementing a CVD risk-reduction program for low-income women. We discuss ways in which intervention and training programs can be improved.


An outreach program improved osteoporosis management after a fracture.
This longitudinal retrospective cohort study evaluated implementation of an intervention to improve management of osteoporosis after a fracture in a nonprofit group-model health maintenance organization (HMO) in the U.S. Pacific Northwest with 480,000 members and electronic medical record data. Participants were female HMO members aged 67 and older who sustained a qualifying clinical fracture(s) and who had not received a bone mineral density (BMD) measurement or osteoporosis treatment in the 12 months before the fracture (N=3,588). Phase 1 included outreach to clinicians and patients; Phase 2 added clinician and staff incentives. Primary outcome was "osteoporosis management"--receipt of a BMD measurement or osteoporosis medication in the 6 months after an index fracture. Before the intervention, 13.4% (95% confidence interval (CI)=12.0-14.8%) of patients had received osteoporosis management, and the time trend was not significant. Post-intervention, the probability of osteoporosis management increased on average 3.1% (95% CI=2.6-3.5%) every 2 months throughout both study phases without a significant added improvement in Phase 2. Improvement varied according to clinic and was less likely for patients with dementia. Overall, the probability of osteoporosis management increased from the baseline level of 13.4% to 44.0% (95% CI=40.0-48.0%) by the end of the study period (20 months post-intervention). The study found that an outreach program to primary care providers and patients improved the management of osteoporosis after a fracture. If widely implemented, this intervention could substantially improve the secondary prevention of osteoporosis. More-individualized interventions may be necessary for high-risk subgroups.


The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells.
Extracellular superoxide (O2-.) was detected in cultures of monkey arterial smooth muscle cells as measured by the superoxide dismutase-inhibitable reduction of cytochrome c and acetylated cytochrome c. Reduction of cytochrome c by these cells required L-cystine in the incubation medium. A variety of other sulfur-containing amino acids, including D-cystine, L-cystathionine, L-methionine, and djenkolic acid did not support O2-. generation when present at concentrations equimolar to L-cystine. At millimolar concentrations, the chelators EDTA and diethylene triamine penta-acetic acid inhibited O2-. production by smooth muscle cells. This effect was maximal when the chelator was present at the same concentration as the sum of the Ca2+ and Mg2+ in the medium, suggesting a role for these cations in O2-. generation by cells. Modification of low density lipoprotein (LDL) by arterial smooth muscle cells, as assessed by changes in lipid peroxide content, mobility on agarose gel electrophoresis, and apoprotein B fragmentation, was also L-cystine-dependent. LDL modification also required micromolar concentrations of the transition metal ion Cu(II) or Fe(III) and was inhibited by superoxide dismutase. LDL modified by smooth muscle cells in the presence of L-cystine and Cu(II) was taken up and degraded less well than native LDL by human skin fibroblasts, suggesting that recognition by the LDL receptor was lost. In contrast, LDL modified by smooth muscle cells was taken up and degraded to a greater degree than native LDL by mouse peritoneal macrophages, consistent with recognition by the scavenger receptor. These results indicate that monkey arterial smooth muscle cells produce O2-. and modify LDL by an L-cystine-dependent process. This may involve reduction of cystine to a thiol, possibly cysteine or a cysteine-containing peptide such as glutathione. Sulfur-containing amino acids may play a role in atherogenesis by supporting cell-mediated generation of reactive oxygen species and modification of lipoprotein to a form recognized by the scavenger receptor.


Anti-steroidogenic activity of methanolic extract of Cuscuta reflexa roxb. stem and Corchorus olitorius Linn. seed in mouse ovary.
Methanolic extract (ME) of both C. reflexa stem and C. olitorius seed arrested the normal oestrus cycle of adult female mouse and significantly decreased the weight of ovaries and uterus. The cholesterol and ascorbic acid contents in ovaries were significantly increased in the treated mice. Two key enzymes, delta5-3beta-hydroxysteroid dehydrogenase and glucose-6-phosphate dehydrogenase, were decreased significantly in ME of both C. reflexa stem and C. olitorius seed after 17 days of treatment. High level of substrates and low level of enzymes indicate the inhibition of steroidogenesis in treated mice and may be due to the presence of flavonoids.


Surgical resection for liver recurrence after curative resection of pancreatic ductal adenocarcinoma.
This study aimed to evaluate the clinical significance of surgical resection for liver recurrence in patients with curatively resected pancreatic ductal adenocarcinoma. The medical records of patients with a liver recurrence after undergoing curative pancreatectomy for pancreatic ductal adenocarcinoma were retrospectively reviewed. Clinicopathological and prognostic factors were analyzed, as was the clinical impact of surgical resection for liver recurrence. Overall, 502 patients underwent curative pancreatic ductal adenocarcinoma resection. Of the 311 patients with recurrence after curative pancreatectomy, 71 (23%) had an initial recurrence in the liver, with 35 having solitary recurrence (11%). Patients with solitary, two or three, or more than four recurrences had median overall survival times of 28.5, 18.0, and 12.2 months, respectively (p < 0.001). Surgical indications for liver recurrence in our institution included solitary tumor, good disease control under chemotherapy after recurrence for > 6 months, and sufficient remnant liver function. Ten patients who met our institutional policy inclusion criteria underwent liver resection. Among 35 patients with initially solitary liver recurrence, those who underwent liver resection outlived those who did not (57.6 months vs. 20.1 months, p < 0.001). In multivariate analysis of overall survival, solitary liver recurrence and liver resection were independent favorable prognostic factors in patients with initial liver recurrence. In selected patients with solitary liver recurrence after curatively resected pancreatic ductal adenocarcinoma, liver resection may be a treatment option.


Thirty-year trends of physical activity in relation to age, calendar time and birth cohort in Finnish adults.
The aim of this article was to investigate time trends 1972-2002 in leisure time, occupational and commuting physical activity across birth cohorts in Finnish adults. The study population comprised 59 028 men and women aged 25-64 years who participated in the FINRISK Study. The first birth cohort was born in 1913 and the last in 1977. Prevalence of physical activity was reported across birth cohorts and study years and change in the prevalence was tested using log-linear regression analysis. The prevalence of leisure-time physical activity increased between 1972 and 2002 from 66% to 77% in men and from 49% to 76% in women. In each study year, the younger people were more active than the older ones. However, within the birth cohorts, physical activity tended to increase with age. The prevalence of physically demanding work decreased from 60% to 38% in men and from 47% to 25% in women and the prevalence of daily commuting activity decreased from 30% to 10% in men and from 34% to 22% in women, in the same time period. In the 1970s and the 80s, the older people had more physically demanding work than the younger ones, but within the birth cohorts, occupational activity decreased with age. During the past 30 years, the prevalence of leisure-time physical activity has increased, while the prevalence of occupational and commuting physical activity has decreased. The cross-sectional association of age with different types of physical activity was different from that assessed within the birth cohorts.


Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis.
The effect of moderate alcohol consumption on liver fibrosis is not well understood, but evidence suggests that adenosine may play a role in mediating the effects of moderate ethanol on tissue injury. Ethanol increases the concentration of adenosine in the liver. Adenosine 2A receptor (A2AR) activation is known to enhance hepatic stellate cell (HSC) activation and A2AR deficient mice are protected from fibrosis in mice. Making use of a novel mouse model of moderate ethanol consumption in which female C57BL/6J mice were allowed continued access to 2% (vol/vol) ethanol (11% calories) or pair-fed control diets for 2 days, 2 weeks or 5 weeks and superimposed with exposure to CCl4, we tested the hypothesis that moderate ethanol consumption increases fibrosis in response to carbon tetrachloride (CCl4) and that treatment of mice with an A2AR antagonist prevents and/or reverses this ethanol-induced increase in liver fibrosis. Neither the expression or activity of CYP2E1, required for bio-activation of CCl4, nor AST and ALT activity in the plasma were affected by ethanol, indicating that moderate ethanol did not increase the direct hepatotoxicity of CCl4. However, ethanol feeding enhanced HSC activation and exacerbated liver fibrosis upon exposure to CCl4. This was associated with an increased sinusoidal angiogenic response in the liver. Treatment with A2AR antagonist both prevented and reversed the ability of ethanol to exacerbate liver fibrosis. Moderate ethanol consumption exacerbates hepatic fibrosis upon exposure to CCl4. A2AR antagonism may be a potential pharmaceutical intervention to decrease hepatic fibrosis in response to ethanol.


Effects of short- and long-duration hypothyroidism on hypothalamic-pituitary-adrenal axis function in rats: in vitro and in situ studies.
The purpose of this study is to assess the effects of hypothyroidism on the hypothalamic-pituitary-adrenal (HPA) axis; the functional integrity of each component of the HPA axis was examined in short-term and long-term hypothyroidism. Neuropeptide synthesis, release, and content were evaluated in vitro both in the hypothalamus and anterior pituitary, and corticosterone release was assessed in primary adrenal cell cultures at 7 (short-term) and 60 days (long-term hypothyroidism) after thyroidectomy in male rats. Hypothyroid rats showed adrenal insufficiency in several parameters, which were associated with the duration of hypothyroidism. Cerebrospinal (CSF) ACTH was decreased in all hypothyroid animals, while CSF corticosterone levels were significantly decreased only in long-term hypothyroidism. Long-term hypothyroid animals showed decreased corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus under both basal and stress conditions, decreased CRH release from hypothalamic organ cultures after KCL and arginine vasopressin stimulation, as well as an increased number of anterior pituitary CRH receptors. In contrast, short-term hypothyroid rats showed changes in anterior pituitary function with an increased responsiveness to CRH that was associated with an increase in CRH receptors. Although both short- and long-term hypothyroidism was associated with significant decreases in adrenal weights, only long-term hypothyroid rats showed changes in adrenal function with a significant decrease of ACTH-induced corticosterone release from cultured adrenal cells. The data suggest that long-term hypothyroidism is associated with adrenal insufficiency with abnormalities in all three components of the HPA axis. Short-term hypothyroidism, on the other hand, is associated with increased pituitary corticotroph responsiveness to CRH.


Characterization of the cellulosomal scaffolding protein CbpC from Clostridium cellulovorans 743B.
Clostridium cellulovorans 743B, an anaerobic and mesophilic bacterium, produces an extracellular enzyme complex called the cellulosome on the cell surface. Recently, we have reported the whole genome sequence of C. cellulovorans, which revealed that a total of 4 cellulosomal scaffolding proteins: CbpA, HbpA, CbpB, and CbpC were encoded in the C. cellulovorans genome. In particular, cbpC encoded a 429-residue polypeptide that includes a carbohydrate-binding module (CBM), an S-layer homology module, and a cohesin. CbpC was also detected in the culture supernatant of C. cellulovorans. Genomic DNA coding for CbpC was subcloned into a pET-22b+ vector in order to express and produce the recombinant protein in Escherichia coli BL21(DE3). Measurement of CbpC adsorption to crystalline cellulose indicated a dissociation constant of 0.60 μM, which is a similar to that of CBM from CbpA. We also subcloned the region encoding xylanase B (XynB) with the dockerin from C. cellulovorans and analyzed the interaction between XynB and CbpC by GST pull-down assay. It was observed that GST-CbpC assembles with XynB to form a minimal cellulosome. The activity of XynB against rice straw tended to be increased in the presence of CbpC. These results showed a synergistic effect on rice straw as a representative cellulosic biomass through the formation of a minimal cellulosome containing XynB bound to CbpC. Thus, our findings provide a foundation for the development of cellulosic biomass saccharification using a minimal cellulosome.


Thermosensitive Triterpenoid-Appended Polymers with Broad Temperature Tunability Regulated by Host-Guest Chemistry.
Thermoresponsive water-soluble polymers are of great importance since they typically show a lower critical solution temperature (LCST) in aqueous media. In this research, the LCST change in broad temperature ranges of copolymers composed of natural glycyrrhetinic acid (GA)-based methacrylate and N,N'-dimethylacrylamides (DMAs) was investigated as a function of the concentration and the content of GA pendants. By complexation of GA pendants with β-cyclodextrin (β-CD), a side-chain polypseudorotaxane was obtained, which exhibited a significant increase in the LCST of copolymers. Moreover, the precisely reversible control of the LCST behavior was realized through adding a competing guest molecule, sodium 1-admantylcarboxylate. This work illustrates a simple and effective approach to endow water-soluble polymers with broad temperature tunability and helps us further understand the effect of a biocompatible host-guest complementary β-CD/GA pair on the thermoresponsive process.


Sleep duration, temperament, and Conners' ratings of three-year-old children.
Parental reports of sleep patterns, ratings on the Behavioral Style Questionnaire, and Conners' Abbreviated Parents' Questionnaire were obtained for 60 three-year-old children. Children who were more adaptable, mild, and positive in mood, or children with an easy temperament, had longer total sleep durations and lower Conners' ratings than children with opposite traits. Adaptability was the temperament characteristic most highly correlated with total sleep duration and the only characteristic which correlated with the number of night wakings. In addition, children with low activity ratings had long total sleep durations, low Conners' ratings, and were described as having a quiet sleep pattern. Long sleep durations and low Conners' ratings appear to be features of children with an easy temperament or low motor activity when awake and asleep.


A Simple and Fast Extraction Method for the Determination of Multiclass Antibiotics in Eggs Using LC-MS/MS.
The purpose of this study was to develop and validate a simple, fast, and specific extraction method for the analysis of 64 antibiotics from nine classes (including sulfonamides, quinolones, tetracyclines, macrolides, lincosamide, nitrofurans, β-lactams, nitromidazoles, and cloramphenicols) in chicken eggs. Briefly, egg samples were simply extracted with a mixture of acetonitrile-water (90:10, v/v) and 0.1 mol·L-1 Na2EDTA solution assisted with ultrasonic. The extract was centrifuged, condensed, and directly analyzed on a liquid chromatography coupled to tandem mass spectrometry. Compared with conventional cleanup methods (passing through solid phase extract cartridges), the established method demonstrated comparable efficiencies in eliminating matrix effects and higher or equivalent recoveries for most of the target compounds. Typical validation parameters including specificity, linearity, matrix effect, limits of detection (LODs) and quantification (LOQs), the decision limit, detection capability, trueness, and precision were evaluated. The recoveries of target compounds ranged from 70.8% to 116.1% at three spiking levels (5, 20, and 50 μg·kg-1), with relative standard deviations less than 14%. LODs and LOQs were in the ranges of 0.005-2.00 μg·kg-1 and 0.015-6.00 μg·kg-1 for all of the antibiotics, respectively. A total of five antibiotics were successfully detected in 22 commercial eggs from local markets. This work suggests that the method is suitable for the analysis of multiclass antibiotics in eggs.


Tetranuclear ruthenium(II) complex with a dinucleating ligand forming multi-mixed-valence states.
A square-shaped tetranuclear ruthenium(II) complex, [Ru(II)4Cl5(bpmpm)2](3+) [1; bpmpm = 4,6-bis[[N,N-bis(2'-pyridylmethyl)amino]methyl]pyrimidine], exhibited four reversible and stepwise one-electron-oxidation processes: chemical oxidation of 1 formed three different mixed-valence states, in one of which the charge is partially delocalized on the two Ru centers, to be evidenced by observation of an intervalence charge-transfer absorption band, categorized into the Robin-Day class II.


Comparison of magnetic tracking and optical tracking by simultaneous use of two independent frameless stereotactic systems.
The goal of this study was to compare the calculated accuracy and the true surgical accuracy of a magnetic and an optical tracking system at surgical registration and during surgery. Two Food and Drug Administration-approved, commercially available frameless stereotactic systems were used simultaneously in 70 surgical cases. The Compass Cygnus-PFS system (Compass International, Rochester MN) uses magnetic field referencing and tracking. The StealthStation (Medtronic SNT, Louisville, CO) uses optical referencing and tracking. Registration was performed for each of the systems using adhesive fiducial markers, cranial-implanted markers, anatomic landmarks, or a combination thereof. Preoperative imaging consisted of volumetric computed tomography, magnetic resonance imaging, or both. Calculated accuracy was given by each of the systems as the root mean square after registration. Surgical accuracy was assessed by comparing the anatomic accuracy of each system with a number of recognizable intraoperative anatomic landmarks. Calculated accuracy (root mean square) was 1.4 +/- 0.6 mm using the magnetic system and 1.4 +/- 0.8 mm using the optical tracking system. In the 42 patients with implanted cranial fiducials, the calculated accuracies were 1.0 +/- 0.5 mm (magnetic) and 0.9 +/- 0.4 mm (optical). True surgical accuracy was considered good (3 mm or less) in both systems in 60 of 70 patients. In two patients, neither system was accurate. In eight patients, one of the two systems was considered inaccurate. Of these, the magnetic system was considered inaccurate three times and the optical system five times. Magnetic referencing and tracking was found to be comparable with optical tracking both with regard to calculated and true surgical accuracy. Interference from metal objects in the magnetic field was seen rarely.


Targeting cysteine proteases in trypanosomatid disease drug discovery.
Chagas disease and human African trypanosomiasis are endemic conditions in Latin America and Africa, respectively, for which no effective and safe therapy is available. Efforts in drug discovery have focused on several enzymes from these protozoans, among which cysteine proteases have been validated as molecular targets for pharmacological intervention. These enzymes are expressed during the entire life cycle of trypanosomatid parasites and are essential to many biological processes, including infectivity to the human host. As a result of advances in the knowledge of the structural aspects of cysteine proteases and their role in disease physiopathology, inhibition of these enzymes by small molecules has been demonstrated to be a worthwhile approach to trypanosomatid drug research. This review provides an update on drug discovery strategies targeting the cysteine peptidases cruzain from Trypanosoma cruzi and rhodesain and cathepsin B from Trypanosoma brucei. Given that current chemotherapy for Chagas disease and human African trypanosomiasis has several drawbacks, cysteine proteases will continue to be actively pursued as valuable molecular targets in trypanosomatid disease drug discovery efforts.


Treatment of Cannabinoid Hyperemesis With Olanzapine: A Case Series.
The use and availability of cannabis for recreational and medical purposes has become more widespread with increased legalization. Adverse health outcomes of this increased use include cannabinoid hyperemesis syndrome (CHS), which is underrecognized in medical settings. Cessation of substance use is the recommendation of choice for the complete resolution of CHS. However, interventions that provide rapid relief may be necessary in treatment-refractory cases. Little evidence is available to guide care in these cases. Here we report 4 cases of treatment-refractory CHS, all of which remitted after treatment with olanzapine. Olanzapine is known to block multiple neurotransmitter receptors involved in nausea and vomiting in chemotherapy-induced nausea and vomiting. Outcomes of the cases reported here suggest that off-label use of olanzapine may be effective in the symptomatic treatment of refractory CHS and may be the preferred treatment in cases in which comorbid psychotic symptoms or agitation are present.


Analysis of the Risk Factors and a Prediction Model for Postherpetic Trigeminal Neuralgia Recurrence After Extracranial Nonsemilunar Ganglion Radiofrequency Thermocoagulation.
Extracranial nonsemilunar ganglion radiofrequency thermocoagulation in the treatment of postherpetic trigeminal neuralgia has significant clinical effects. However, the related risk factors for its recurrence have not been studied. This study aimed to investigate the risk factors for the recurrence of postherpetic trigeminal neuralgia after extracranial nonsemilunar ganglion radiofrequency thermocoagulation, and to construct a recurrence prediction model. This is a single-center, retrospective observational study. The study was conducted in the Department of Pain, Affiliated Hospital of Jiaxing College, Jiaxing, People's Republic of China. A total of 76 patients with postherpetic trigeminal neuralgia admitted to the First Hospital of Jiaxing from July 2013 through October 2021 were retrospectively analyzed. All patients were treated with computed tomography-guided extracranial nonsemilunar segment radiofrequency therapy. The Kaplan-Meier method was used for survival analysis, the log-rank test was used, and the Cox proportional hazards regression model was used to analyze the clinical factors affecting postherpetic trigeminal neuralgia recurrence after extracranial nosemilunar ganglia radiofrequency thermocoagulation; in addition, a recurrence prediction model was established. Patients were followed-up for 12 months. A univariate analysis showed that age and disease duration are the factors affecting postherpetic trigeminal neuralgia recurrence after extracranial nonsemilunar ganglion radiofrequency thermocoagulation (P < 0.05). A multivariate Cox proportional hazards regression analysis showed that age and disease duration were independent influencing factors. The recurrence risk function model is expressed as follows. H (t) = h0exp (1.116 X1 + 1.340 X2), where X1 and X2 represent age and disease duration, respectively. The likelihood ratio of the model was tested, and the likelihood ratio was 195.776, showing statistical significance. We look forward to increasing the sample size in subsequent studies and exploring relevant conclusions in randomized controlled trials. A short disease duration and young age can reduce the risk of recurrence after extracranial nonsemilunar ganglia radiofrequency thermocoagulation in patients with postherpetic trigeminal neuralgia. Our established recurrence prediction model can provide a reference for clinical diagnosis and treatment.


MMPI-2 restructured form over-reporting scales in first-episode psychosis.
MMPI-2-RF over-reporting scales for physical, cognitive, or psychological symptoms were examined in 130 consecutive referrals to a first-episode psychosis (FEP) clinic. Although acutely ill upon presentation, consistent and responsive profiles were obtained in 79% of the sample. There was no indication of under-reporting on defensive scales, and anticipated elevations were observed on clinical scales sensitive to thought disorder, ideas of persecution, and aberrant experiences. The Infrequent Somatic (Fs), Symptom Validity Scale (FBS-r), and Response Bias (RBS) scales did not indicate somatic or cognitive over-reporting, but the Infrequent Psychopathology Scale (Fp-r) showed a moderate elevation that may suggest a propensity for over-reporting or an effect of clinical symptoms on the over-reporting scale. Clinician ratings of positive symptoms of psychosis were related to the Fp-r. Although the over-reporting classifications with the RBS were relatively low, RBS scores were directly related to positive and general symptoms of psychosis. The MMPI-2-RF appears to have clinical value in an acutely ill FEP sample. The sample was not prone to over-reporting pathology, but associations between both the Fp-r and the RBS with clinical symptoms will warrant further investigation.


Dissociation of human neutrophil activation events by prolonged treatment with amiloride.
Human polymorphonuclear leukocytes (PMNs) can be stimulated to release granule contents and to produce superoxide anion. These functional responses are associated with cellular alkalinization and influx of Na+ in exchange for H+. Amiloride is a potassium-sparing diuretic that will inhibit stimulus-induced Na+-H+ exchange and prevent an increase in cell pH. Amiloride has been shown to inhibit a number of protein kinases including the calcium phospholipid-dependent protein kinase. Because PMA, which binds and activates C-kinase, is a potent stimulus of the PMN, this study was undertaken to investigate the effect of prolonged incubation of PMNs with amiloride on PMN stimulation by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), the calcium ionophore A23187, opsonized zymosan particles, and the tumor promoter phorbol myristate acetate (PMA). Our results demonstrate that amiloride inhibits superoxide anion production by FMLP, A23187, and opsonized zymosan by causing a slower rate of release and lower maximal release without altering lag time. In contrast, amiloride, despite an inhibition of 22Na+ influx, did not affect superoxide anion production stimulated by PMA. PMN degranulation, phagocytosis, arachidonic acid release, and early influx of calcium were unaffected by preincubation with amiloride. These data suggest that PMN superoxide release induced by FMLP, A23187, and opsonized zymosan is likely modulated by amiloride-sensitive Na+-H+ exchange; and phorbol ester-induced superoxide anion release and degranulation by any stimulant do not appear to be modulated by inhibition of an amiloride-sensitive Na+-H+ exchange.