Systems Level Analyses Reveal Multiple Regulatory Activities of CodY Controlling Metabolism, Motility and Virulence in Listeria monocytogenes.
Bacteria sense and respond to many environmental cues, rewiring their regulatory network to facilitate adaptation to new conditions/niches. Global transcription factors that co-regulate multiple pathways simultaneously are essential to this regulatory rewiring. CodY is one such global regulator, controlling expression of both metabolic and virulence genes in Gram-positive bacteria. Branch chained amino acids (BCAAs) serve as a ligand for CodY and modulate its activity. Classically, CodY was considered to function primarily as a repressor under rich growth conditions. However, our previous studies of the bacterial pathogen Listeria monocytogenes revealed that CodY is active also when the bacteria are starved for BCAAs. Under these conditions, CodY loses the ability to repress genes (e.g., metabolic genes) and functions as a direct activator of the master virulence regulator gene, prfA. This observation raised the possibility that CodY possesses multiple functions that allow it to coordinate gene expression across a wide spectrum of metabolic growth conditions, and thus better adapt bacteria to the mammalian niche. To gain a deeper understanding of CodY's regulatory repertoire and identify direct target genes, we performed a genome wide analysis of the CodY regulon and DNA binding under both rich and minimal growth conditions, using RNA-Seq and ChIP-Seq techniques. We demonstrate here that CodY is indeed active (i.e., binds DNA) under both conditions, serving as a repressor and activator of different genes. Further, we identified new genes and pathways that are directly regulated by CodY (e.g., sigB, arg, his, actA, glpF, gadG, gdhA, poxB, glnR and fla genes), integrating metabolism, stress responses, motility and virulence in L. monocytogenes. This study establishes CodY as a multifaceted factor regulating L. monocytogenes physiology in a highly versatile manner.


Compliance Patterns and Utilization of e-Health for Glucose Monitoring: Standalone Internet Gateway and Tablet Device.
Knowledge regarding compliance patterns and service utilization in e-health is important for the development of effective services. To develop proper e-health, the characteristics of compliance patterns and utilization of e-health should be studied. We studied these for glucose monitoring of diabetic patients from primary clinics. Data were collected from 160 outpatients who participated in e-health for glucose monitoring funded by the Korean government. Specifically, this study focused on two device types: a standalone Internet gateway and a tablet device. The SPSS 18.0 software was used for statistical analyses of demographic characteristics, survival data, and Cox proportional hazards regression model. Standalone Internet gateway users demonstrated a more stable compliance pattern than did tablet device users. The compliance rate differed according to the device type. Typically, compliance decreases considerably around 8 months. In these results, standalone Internet gateway users utilized the service for longer periods than tablet device users. Gateway type and location also influenced utilization (p < 0.05). The service should be designed according to the device type to develop appropriate service models. Thus, service designers should understand the different characteristics of service devices. This study provides insight into compliance patterns and utilization to develop appropriate service models and service interventions depending on the device.


A case for steroids in acute lung injury associated with the retinoic acid syndrome.
A 62-year-old woman with acute promyelocytic leukaemia was treated with all-trans retinoic acid. On day 2 she suffered with dyspnoea and general fatigue. Marked hypoxia suggested the occurrence of retinoic acid syndrome. She underwent endotracheal intubation and mechanical ventilation with the administration of dexamethasone. Her symptoms promptly abated. She was subsequently treated with conventional chemotherapy and achieved complete remission.


Sea Buckthorn Fruit Oil Extract Alleviates Insulin Resistance through the PI3K/Akt Signaling Pathway in Type 2 Diabetes Mellitus Cells and Rats.
Sea buckthorn fruit oil is rich in palmitoleic acid (POA), which has been reported to play roles in many metabolic processes. In this study, a sea buckthorn fruit oil (SBFO) extract was evaluated through in vitro experiments (the doses were 50, 100, 200, and 400 μM) and in vivo experiments (the doses were 100, 200, and 300 mg/kg·day) to explore its mechanism of action in the treatment of type 2 diabetes mellitus (T2DM). The results revealed that the SBFO extract effectively increased the glucose uptake from 12.23 ± 1.09 to 14.90 ± 1.48 mmol/L in insulin resistance (IR) HepG2 cells, lowered blood glucose (the reductions rates of blood glucose in groups treated with SBFO extract at 200 and 300 mg/kg·day were 10.47% and 13.79%, respectively) and improved insulin indices from -6.11 ± 0.10 to -5.45 ± 0.31 after 4 weeks treatment with SBFO extract at 300 mg/kg·day in T2DM SD rats. RT-PCR and Western blotting analyses suggested that the SBFO extract could promote the expression of phosphatidylinositol-3-kinase (PI3K) and glycogen synthesis (GS) while inhibiting the expression of glycogen synthesis kinase-3β (GSK-3β). Thus, the SBFO extract played a positive role in alleviating T2DM through the PI3K/Akt signaling pathway in HepG2 cells, and diabetic rats and could be used for the future development of functional food and dietary supplements.


The band 12 issue in the electron momentum spectra of norbornane: a comparison with additional Green's Function calculations and ultraviolet photoemission measurements.
In continuation of a recent study of the electronic structure of norbornane [J. Chem. Phys., 2004, 121, 10525] by means of electron momentum spectroscopy (EMS), we present Green's Function calculations of the ionization spectrum of this compound at the ADC(3) level using basis sets of varying quality, along with accurate evaluations at the CCSD(T) level of the vertical (26.5 eV) and adiabatic (22.1 eV) double ionization thresholds under C(2v) symmetry. The obtained results are compared with newly recorded ultraviolet photoemission spectra (UPS), up to binding energies of 40 eV. The theoretical predictions are entirely consistent with experiment and indicate that, in a vertical depiction of ionization, shake-up states at binding energies larger than approximately 26.5 eV tend to decay via emission of a second electron in the continuum. A band of s-type symmetry that has been previously seen at approximately 25 eV in the electron impact ionization spectra of norbornane is entirely missing in the UPS measurements and theoretical ADC(3) spectra. With regard to these results and to the time scales characterizing electron-electron interactions in EMS (10(-17) s) as compared with that (10(-13) s) of photon-electron interactions in UPS, and considering the p-type symmetry of the electron momentum distributions for the nearest 1b(1) and 1b(2) orbitals, this additional band can certainly not be due to adiabatic double ionization processes starting from the ground electronic state of norbornane, or to exceptionally strong vibronic coupling interactions between cationic states derived from ionization of the latter orbitals. It is therefore tentatively ascribed to autoionization processes via electronically excited and possibly dissociating states.


Hsp90 as a gatekeeper of tumor angiogenesis: clinical promise and potential pitfalls.
Tumor vascularization is an essential modulator of early tumor growth, progression, and therapeutic outcome. Although antiangiogenic treatments appear promising, intrinsic and acquired tumor resistance contributes to treatment failure. Clinical inhibition of the molecular chaperone heat shock protein 90 (Hsp90) provides an opportunity to target multiple aspects of this signaling resiliency, which may elicit more robust and enduring tumor repression relative to effects elicited by specifically targeted agents. This review highlights several primary effectors of angiogenesis modulated by Hsp90 and describes the clinical challenges posed by the redundant circuitry of these pathways. The four main topics addressed include (1) Hsp90-mediated regulation of HIF/VEGF signaling, (2) chaperone-dependent regulation of HIF-independent VEGF-mediated angiogenesis, (3) Hsp90-dependent targeting of key proangiogenic receptor tyrosine kinases and modulation of drug resistance, and (4) consideration of factors such as tumor microenvironment that pose several challenges for the clinical efficacy of anti-angiogenic therapy and Hsp90-targeted strategies.


The human brain at stages 21-23, with particular reference to the cerebral cortical plate and to the development of the cerebellum.
The development of the human brain during the eighth embryonic week was studied in serial sections of 22 embryos, and graphic reconstructions were prepared. The cortical plate appears in stage 21 in the area of the future insula and is an excellent feature for staging. The internal capsule contains neocortical fibres. Its three main outlets begin to be present in stage 22 and lead to epithalamus, to dorsal thalamus, and to mesencephalon. At this time a well developed lateral olfactory tract can be seen. The anterior commissure appears in stage 23. A clear developmental relationship between claustrum and olfactory area is described for the first time in human embryos. The optic tract reaches the ventral area of the lateral geniculate body. Scattered fibres of the lateral lemniscus reach at least as far as the caudal mesencephalon, in which superior and inferior colliculi can be distinguished at stage 23; two caudal Blindsäcke containing ventricular recesses form in stage 23. The cerebellum is still present as a plate, but its internal bulge is considerably enlarged. It possesses radially- and tangentially-arranged cells; the latter form the external germinal layer. The dentate nucleus, as well as the inferior and superior cerebellar peduncles and some of the cerebellar commissures, are present. Compared with the highly developed and probably already functional remainder of the hindbrain, the cerebellar plate shows far less differentiation. Two caudal migratory streams (marginal and submarginal) are present and represent the corpus pontobulbare. The decussation of the pyramids appears in stage 23. This article concludes the study of the developing human brain during the embryonic period, from stage 8 to stage 23. The series was based on 340 serially-sectioned embryos and graphic reconstructions from 89 brains. No comparable investigation of the fetal brain is available.


[The effect of cycloheximide on DNA replication. II. Antibiotic resistance following L cell treatment with hydroxyurea].
DNA replication in eukaryotic cells is closely associated with protein synthesis. When protein synthesis is specifically inhibited, DNA synthesis stops quickly too. No precise knowledge has been so far available concerning the reasons of this coupling. The data presented confirm an earlier established for Chlorella fact that the inhibition of DNA synthesis in L-cells, due to a several hours treatment with hidroxyurea, results in a consequent stability of DNA synthesis in these cells to a protein synthesis inhibitor--cyclohexamide.


[Influence of oxygen content on photoluminescence from a-SiOxNy thin films].
Amorphous SiOxNy thin films were deposited by PECVD technique. Strong photoluminescence bands centered at about 340 and 600 nm and peaks centered at 365, 375, 380, 735 and 745 nm from as prepared samples were observed at room temperature. Influence of partial pressure of H2 during deposition was investigated. The results show that strength of PL and oxygen content increase with H2 partial pressure decrease, the position of PL peaks does not change, and the central position of PL bands shifts. The possible origin of PL and mechanism of the variations are discussed according to experimental results.


Taryn's story.
Hospitalization of a young child with a chronic illness is a nightmare for the child and family. And the nightmare can get worse for children with multiple health care problems managed by several sub-specialty teams. The child feels anxious; parents don't know who to turn to for information and support. Collaborative nursing and family interventions can help relieve some of these problems.


Genetic manipulation of palmitoylethanolamide production and inactivation in Saccharomyces cerevisiae.
Lipids can act as signaling molecules, activating intracellular and membrane-associated receptors to regulate physiological functions. To understand how a newly discovered signaling lipid functions, it is necessary to identify and characterize the enzymes involved in their production and inactivation. The signaling lipid N-palmitoylethanolamine (PEA) is known to activate intracellular and membrane-associated receptors and regulate physiological functions, but little is known about the enzymes involved in its production and inactivation. Here we show that Saccharomyces cerevisiae produce and inactivate PEA, suggesting that genetic manipulations of this lower eukaryote may be used to identify the enzymes involved in PEA metabolism. Accordingly, using single gene deletion mutants, we identified yeast genes that control PEA metabolism, including SPO14 (a yeast homologue of the mammalian phospholipase D) that controls PEA production and YJU3 (a yeast homologue of the mammalian monoacylglycerol lipase) that controls PEA inactivation. We also found that PEA metabolism is affected by heterologous expression of two mammalian proteins involved in neurodegenerative diseases, namely huntingtin and alpha-synuclein. Together these findings show that forward and reverse genetics in S. cerevisiae can be used to identify proteins involved in PEA production and inactivation, and suggest that mutated proteins causing neurodegenerative diseases might affect the metabolism of this important signaling lipid.


[Familial chromosome translocation (1;5;15) as a cause of partial trisomy 1p].
An unbalanced structural chromosome aberration was found in a 6-year-old girl. Mother and maternal grandmother were shown to be carriers of a complex balanced translocation involving chromosomes 1, 5 and 15 and are of normal phenotype. The unbalanced status in the proband was defined as a partial trisomy 1p21-1p31. Partial trisomies of this chromosomal segment have rarely been reported. Unexpectedly, the consequences on the child's phenotype are only minor. Main features are: facial dysmorphy, small stature and syndactyly of 4th and 5th toes; mental and statomotoric development are not grossly affected.


"Hit the Robot on the Head With This Mallet" - Making a Case for Including More Open Questions in HRI Research.
Researchers continue to devise creative ways to explore the extent to which people perceive robots as social agents, as opposed to objects. One such approach involves asking participants to inflict 'harm' on a robot. Researchers are interested in the length of time between the experimenter issuing the instruction and the participant complying, and propose that relatively long periods of hesitation might reflect empathy for the robot, and perhaps even attribution of human-like qualities, such as agency and sentience. In a recent experiment, we adapted the so-called 'hesitance to hit' paradigm, in which participants were instructed to hit a humanoid robot on the head with a mallet. After standing up to do so (signaling intent to hit the robot), participants were stopped, and then took part in a semi-structured interview to probe their thoughts and feelings during the period of hesitation. Thematic analysis of the responses indicate that hesitation not only reflects perceived socialness, but also other factors including (but not limited to) concerns about cost, mallet disbelief, processing of the task instruction, and the influence of authority. The open-ended, free responses participants provided also offer rich insights into individual differences with regards to anthropomorphism, perceived power imbalances, and feelings of connection toward the robot. In addition to aiding understanding of this measurement technique and related topics regarding socialness attribution to robots, we argue that greater use of open questions can lead to exciting new research questions and interdisciplinary collaborations in the domain of social robotics.


Migraine chronification is associated with beta-band connectivity within the pain-related cortical regions: a magnetoencephalographic study.
Pain disorders are associated with aberrant oscillations in the pain-related cortical regions; however, few studies have investigated the relationship between the functional cortical network and migraine chronification through direct neural signals. Magnetoencephalography was used to record the resting-state brain activity of healthy controls as well as patients with episodic migraine (EM) and chronic migraine (CM). The source-based oscillatory dynamics of the pain-related cortical regions, which comprises 10 node regions (the bilateral primary [SI] and secondary somatosensory cortices, insula, medial frontal cortex, and anterior cingulate cortex [ACC]), were calculated to determine the intrinsic connectivity and node strength at 1 to 40 Hz. The total node strength within the pain-related cortical regions was smaller in the beta band in patients with migraine (70 EM and 80 CM) than in controls (n = 65). In the beta band, the node strength and functional connectivity values of patients with CM and patients with EM differed from those of controls in specific cortical areas, notably the left SI (EM < control) and bilateral ACC (CM < control); moreover, the node strength was lower in patients with CM than in those with EM. In all patients with migraine, negative correlations were observed between headache frequency and node strength in the bilateral ACC. In conclusion, migraine is characterized by reduced beta oscillatory connectivity within the pain-related cortical regions. Reduced beta connectivity in the ACC is linked to migraine chronification. Longitudinal studies should verify whether this oscillation change is a brain signature and a potential neuromodulation target for migraine.


First auditory brainstem implant in the Czech Republic.
In the Czech Republic, the first implantation of a stimulation electrode into the brainstem was performed on 11 January 1999 in the Department of ORL, Head and Neck Surgery, The First Medical Faculty, Charles University in Prague, University Hospital Motol. The selected patient was a 40-year-old woman with neurofibromatosis type 2 (NF2) who had previously undergone bilateral vestibular schwannoma surgery. Both tumours had been radically removed, the left-sided tumour in 1987, the right-sided one in 1988. She had been completely deaf since the last operation, i.e., for 11 years. The surgery was realized by the international cooperation of three teams. Placement of the electrode pad of the Nucleus CI21 + 1M system on the ventral and dorsal cochlear nuclei was performed. Electrically evoked auditory brainstem responses (EABRs) proved the correct position of the electrode array. The post-operative course was uneventful. Six weeks after the surgery the patient received her speech processor. Since that time, the patient already absolved several sessions of a speech processor tune-up. She uses the device as an aid in lip-reading. No adverse or pathological side effects have been observed. The patient was the 45th person in Europe to receive an ABI and the first in the Czech Republic.


Risk factors for developing mild nutritional blindness in urban Bangladesh.
Mild vitamin A deficiency may be associated with increased morbidity and mortality among children in developing countries. A community-based case-control study was performed to determine risk factors for mild ophthalmologic manifestations of vitamin A deficiency in urban Bangladeshi children. Cases were identified in children less than 14 years of age with night blindness with or without other signs of mild xerophthalmia detected in a house-to-house survey. Controls were randomly selected neighbors who lacked subjective and objective ophthalmologic evidence of vitamin A deficiency. Demographic characteristics that were independently associated with vitamin A deficiency in a logistic model included male gender, greater age (mean, 6.1 years in children with cases and 2.8 years in controls), and a greater number of children living with the family. After controlling for these demographic characteristics, poor intake of locally available vitamin A-rich foods, cessation of breast-feeding, and a recent history of protracted diarrhea remained associated with vitamin A deficiency. Maternal ignorance of prevention and control of vitamin A deficiency was also associated with increased risk. The results support programs that educate mothers to breast-feed and to provide appropriate food supplements and suggest that clinicians caring for children with chronic diarrhea should initiate vitamin A supplementation.


Cross-validation of an algorithm detecting acute gastroenteritis episodes from prescribed drug dispensing data in France: comparison with clinical data reported in a primary care surveillance system, winter seasons 2014/15 to 2016/17.
This study compares an algorithm to detect acute gastroenteritis (AG) episodes from drug dispensing data to the validated data reported in a primary care surveillance system in France. We used drug dispensing data collected in a drugstore database and data collected by primary care physicians involved in a French surveillance network, from season 2014/15 to 2016/17. We used an adapted version of an AG discrimination algorithm to identify AG episodes from the drugstore database. We used Pearson's correlation coefficient to evaluate the agreement between weekly AG signals obtained from the two data sources during winter months, in the overall population, by specific age-groups and by regions. Correlations between AG signals for all ages were 0.84 [95%CI 0.69; 0.92] for season 2014/15, 0.87 [95%CI 0.75; 0.93] for season 2015/16 and 0.94 [95%CI 0.88; 0.97] for season 2016/17. The association between AG signals estimated from two data sources varied significantly across age groups in season 2016/17 (p-value < 0.01), and across regions in all three seasons studied (p-value < 0.01). There is a strong agreement between the dynamic of AG activity estimated from drug dispensing data and from validated primary care surveillance data collected during winter months in the overall population but the agreement is poorer in several age groups and in several regions. Once automated, the reuse of drug dispensing data, already collected for reimbursement purposes, could be a cost-efficient method to monitor AG activity at the national level.


Fetal heart rate decelerations during a nonstress test.
In a review of 2000 nonstress tests (NSTs) on 972 pregnant women at high risk at the authors' institution, 94 exhibited fetal heart rate (FHR) decelerations in response to fetal activity in 110 (46.6%) of the 236 NSTs. The NST results were interpreted as either reactive (178) or nonreactive (58). Of those cases with an FHR deceleration pattern, an abnormal cord position was observed in 55.3% (X2 = 68; P less than .001). Of the 74 patients who went into labor, 59.5% demonstrated variable FHR decelerations. Moreover, 8.5% required cesarean section for fetal distress. Of greater importance, 3 intrauterine fetal deaths occurred that appeared to be related to the abnormal cord position. FHR decelerations may occur during reactive as well as nonreactive NSTs. When FHR decelerations are present, they may signify some form of abnormal cord position and require further evaluation by ultrasonography and a contraction stress test.


Dopamine transporter gene moderates response to behavioral parent training in children with ADHD: a pilot study.
There is great variability in the degree to which children with attention deficit/hyperactivity disorder (ADHD) improve through behavioral treatments. This study investigates the influence of the dopamine transporter gene (SCL6A3/DAT1) on outcome of behavioral parent training (BPT). Study subjects were a subsample (n = 50, for whom DAT1 genotypes were available) of a randomized controlled BPT effectiveness study (N = 94) comparing BPT plus ongoing routine clinical care (RCC) versus RCC alone in referred children (4-12 years old) with ADHD. Treatment outcome was based on parent-reported ADHD symptoms and behavioral problems. Presence of 2 versus no or 1 DAT1 10-repeat allele served as moderator variable. Time × Treatment × Genotype effect was analyzed with repeated-measures analysis of variance, controlling for baseline medication status. Results indicate that DAT1 moderated treatment response (p = .009). In children with no or 1 DAT1 10-repeat allele, superior treatment effects of BPT + RCC compared with RCC alone were present (p = .005), which was not the case in children with 2 DAT1 10-repeat alleles (p = .57). Our findings suggest that genetic differences in DAT1 in children with ADHD influence their susceptibility to a behavioral intervention directed at shaping their environment through their parents. The role of the dopamine system in motivation and learning and in the aberrant sensitivity to reinforcement in children with ADHD may explain this moderating effect, given that the management of contingencies is typically addressed in BPT.


Asian American Surgery: A Short History of Immigration, Naturalization, and Refugee Laws and Policies that Brought Asians to America.
Chinese immigration in America in the mid-nineteenth century incited violence and governmental sanctions to restrict Asian immigration and reject citizenship rights. In 1870, Chinese strikebreakers in Massachusetts ignited nationwide demonstrations against Chinese immigration, which ended altogether with the Chinese Exclusion Act (1882). Japanese schoolchildren in San Francisco public schools sparked rioting in 1907, leading Japan to unilaterally limit emigration to the United States (Gentlemen's Agreement, 1908). Congress responded to anti-Punjabi riots (Bellingham, WA, 1907) by refusing naturalization rights to Asians (Barred Zone Act, 1917), policies supported by the Supreme Court (Ozawa, 1922; Thind, 1923). All immigration from Asia was soon prohibited (Johnson-Reed Act, 1924). Anti-Asian measures peaked in 1942 with imprisonment of Japanese in concentration camps, including those with birthright citizenship. Anti-Asian policies unwound in the last half of the 20th century, culminating in sweeping changes in US immunization policy. Naturalization rights were granted to wartime allies against Japan (China, 1943; the Philippines and India, 1946) and the Japanese themselves (1952). Asian women marrying American servicemen were allowed entry into the country (1945, 1950). Prohibitions against Asian immigration were lifted in 1965 (Hart-Celler Act), with preference for those trained in science, technology, and medicine. The refugee crisis that followed the fall of Saigon (1975) drove humanitarian policies that brought evacuees from Southeast Asia and others from throughout the world seeking freedom from persecution (Refugee Act, 1980). Hundreds of thousands from China, South Asia, the Philippines, and Southeast Asia thus settled in the United States, changing American society and medicine.


Complications in patients on therapeutic drugs.
Increasing numbers of patients take more drugs of ever-increasing potency. Dentists today see many of these patients. They should therefore be aware of the connection between drug administration and emergency situations. In certain instances drug-related complications, side-effects and emergencies of both a local and a general nature can arise. Some local complications are destruction of teeth due to the intake of medicines with high sugar content; erosive lesions of the oral mucosa; paraformaldehyde necrosis; and those arising from the use of chlorhexidine. Systemic complications are anaemia due to aspirin misuse; oral ulceration due to antirheumatic drugs; adrenal insufficiency after glucocorticosteroid medication; catecholamine reactions; anticoagulation therapy and bleeding problems; epilepsy; asthma; aplastic anaemia; opportunistic infections; and allergic reactions. The dentists should be prepared to diagnose and manage these complications whether they arise during dental treatment or following it.


High-throughput analysis of in vivo protein stability.
Determining the half-life of proteins is critical for an understanding of virtually all cellular processes. Current methods for measuring in vivo protein stability, including large-scale approaches, are limited in their throughput or in their ability to discriminate among small differences in stability. We developed a new method, Stable-seq, which uses a simple genetic selection combined with high-throughput DNA sequencing to assess the in vivo stability of a large number of variants of a protein. The variants are fused to a metabolic enzyme, which here is the yeast Leu2 protein. Plasmids encoding these Leu2 fusion proteins are transformed into yeast, with the resultant fusion proteins accumulating to different levels based on their stability and leading to different doubling times when the yeast are grown in the absence of leucine. Sequencing of an input population of variants of a protein and the population of variants after leucine selection allows the stability of tens of thousands of variants to be scored in parallel. By applying the Stable-seq method to variants of the protein degradation signal Deg1 from the yeast Matα2 protein, we generated a high-resolution map that reveals the effect of ∼30,000 mutations on protein stability. We identified mutations that likely affect stability by changing the activity of the degron, by leading to translation from new start codons, or by affecting N-terminal processing. Stable-seq should be applicable to other organisms via the use of suitable reporter proteins, as well as to the analysis of complex mixtures of fusion proteins.


Effects of forskolin on bone in organ culture.
The effects of forskolin, which directly activates adenylate cyclase in most systems, have been compared with the actions of parathyroid hormone and calcitonin, both of which have been suggested to utilize cAMP as a second messenger in their actions on bone. Forskolin alone stimulated calcium release from neonatal mouse calvaria and fetal rat limb bones in vitro in a dose-dependent manner. The effect was maximal at 10(-6) M in both systems. At higher concentrations forskolin completely inhibited stimulated bone resorption, although with submaximal concentrations the inhibition was only partially sustained up to 72 h. Forskolin directly stimulated cAMP release from calvaria into the medium at concentrations up to 10(-4) M. Forskolin had no effect on the interaction between parathyroid hormone and calcitonin, while calcitonin inhibited the stimulatory effect of forskolin comparably with its inhibition of parathyroid hormone-stimulated bone resorption. The results indicate that forskolin has dual effects on bone and can mimic responses of both parathyroid hormone and calcitonin in both bone culture systems. The observed response depends on the concentration of forskolin used and the length of treatment with the drug.


Pulmonary lesions in experimental ophidian paramyxovirus pneumonia of Aruba Island rattlesnakes, Crotalus unicolor.
Histologic and ultrastructural changes were observed in the respiratory portions of lung in five 29-40-month-old Aruba Island rattlesnakes, Crotalus unicolor, that were inoculated with an Aruba Island Rattlesnake virus (AIV) strain of ophidian paramyxovirus (OPMV) isolated from an Aruba Island rattlesnake. Lungs from one non-infected and three mock-infected Aruba Island rattlesnakes were examined also. From 4 to 22 days following intratracheal inoculation, progressive microscopic changes were seen in the lung. Initially, increased numbers of heterophils were observed in the interstitium followed by proliferation and vacuolation of epithelial cells lining faveoli. The changes appeared to progress from cranial to caudal portions of the respiratory lung following inoculation. Beginning at 4 days postinoculation, viral antigen was demonstrated in epithelial cells lining faveoli with an immunofluorescent technique using a rabbit anti-AIV polyclonal antibody. Electron microscopy revealed loss of type I cells, hyperplasia of type II cells, and interstitial infiltrates of heterophils and mononuclear cells. Viral nucleocapsid material was seen within the cytoplasm and mature virus was seen budding from cytoplasmic membranes of infected type I and type II cells from 8 to 19 days after infection. A virus consistent with AIV was isolated from lung tissues of infected rattlesnakes, thus fulfilling Koch's postulates.


Association of Intracranial Hypertension With Calvarial and Skull Base Thinning.
Determine if patients with increased opening pressure (OP) on lumbar puncture (LP) have thinner calvaria and skull bases. Retrospective cohort study. Tertiary referral center. Patients (≥18 yr of age) who had a recorded OP on LP and high-resolution computed tomography imaging of the head. Patient age, sex, body mass index were calculated. Intracranial hypertension (IH) was defined with an OP≥25 cm-H2O and low intracranial pressure with an OP<15 cm-H2O. Measurement of calvarial, zygoma, and skull base thickness when blinded to OP with three-dimensional slicer and radiologic calipers. Association of calvarial, skull base, and zygoma thickness with OP and age. Fifty-eight patients were included with a mean (SD) age of 53.1 (16.2) years and average (SD) body mass index of 30.1 (9.1) kg/m. Patients with IH had thinner mean (SD) calvaria (3.01 [0.81] versus 2.70 [0.58] mm; p = 0.036) and skull bases (5.17 [1.22] versus 4.60 [1.42] mm; p = 0.043) when compared with patients without IH. The mean (SD) extracranial zygoma thickness was similar between the two groups (5.09 [0.76] versus 5.00 [0.73] mm; p = 0.56). General linear model regression demonstrated advancing age was associated with increasing calvarial thickness in patients without IH and calvarial thinning in patients with IH (p = 0.038). IH is independently associated with intracranial bone (calvaria and skull base) thinning and not extracranial (zygoma) thinning. Skull thinning occurs with IH and advancing age. These findings support a possible role of increased ICP in the pathophysiologic development of spontaneous cerebrospinal fluid leaks.


Noninvasive temperature estimation based on the energy of backscattered ultrasound.
Hyperthermia has been used as a cancer treatment in which tumors are elevated to cytotoxic temperatures to aid in their control. A noninvasive method for volumetrically determining temperature distribution during treatment would greatly enhance the ability to uniformly heat tumors at therapeutic levels. Ultrasound is an attractive modality for this purpose. We investigated changes in backscattered energy (CBE) from pulsed ultrasound with temperature. Our predicted changes in backscattered energy were matched by in vitro measurements in samples of bovine liver, turkey breast, and pork rib muscle. We studied CBE in tissue regions with multiple scatterers, of isolated individual scatterers, and in collections of individual scatterers. The latter appears to have the most potential. We measured the CBE with a focused circular transducer with a center frequency of 7.5 MHz. The standard deviation of the CBE of 75-125 scattering regions from 0.3 to 0.5 cm3 volumes increased nearly monotonically from 37 degrees C to 50 degrees C in each tissue type. Although the slopes were different, the curve for each type of tissue was well matched by a second-degree polynomial, with a correlation coefficient of 0.99 in each case. Thus the use of the CBE of ultrasound for temperature estimation may have clinical promise with a convenient, low cost modality. Because our approach exploits the inhomogeneities present in tissue, we believe that if it is successful in vitro, it holds promise for in vivo application.


A systematic review of the non-operative treatment of nightstick fractures of the ulna.
Most patients with a nightstick fracture of the ulna are treated conservatively. Various techniques of immobilisation or early mobilisation have been studied. We performed a systematic review of all published randomised controlled trials and observational studies that have assessed the outcome of these fractures following above- or below-elbow immobilisation, bracing and early mobilisation. We searched multiple electronic databases, related bibliographies and other studies. We included 27 studies comprising 1629 fractures in the final analysis. The data relating to the time to radiological union and the rates of delayed union and nonunion could be pooled and analysed statistically. We found that early mobilisation produced the shortest radiological time to union (mean 8.0 weeks) and the lowest mean rate of nonunion (0.6%). Fractures treated with above- or below-elbow immobilisation and braces had longer mean radiological times to union (9.2 weeks, 9.2 weeks and 8.7 weeks, respectively) and higher mean rates of nonunion (3.8%, 2.1% and 0.8%, respectively). There was no statistically significant difference in the rate of non- or delayed union between those treated by early mobilisation and the three forms of immobilisation (p = 0.142 to p = 1.000, respectively). All the studies had significant biases, but until a robust randomised controlled trial is undertaken the best advice for the treatment of undisplaced or partially displaced nightstick fractures appears to be early mobilisation, with a removable forearm support for comfort as required.


A small stem-loop structure of the Ebola virus trailer is essential for replication and interacts with heat-shock protein A8.
Ebola virus (EBOV) is a single-stranded negative-sense RNA virus belonging to the Filoviridae family. The leader and trailer non-coding regions of the EBOV genome likely regulate its transcription, replication, and progeny genome packaging. We investigated the cis-acting RNA signals involved in RNA-RNA and RNA-protein interactions that regulate replication of eGFP-encoding EBOV minigenomic RNA and identified heat shock cognate protein family A (HSC70) member 8 (HSPA8) as an EBOV trailer-interacting host protein. Mutational analysis of the trailer HSPA8 binding motif revealed that this interaction is essential for EBOV minigenome replication. Selective 2'-hydroxyl acylation analyzed by primer extension analysis of the secondary structure of the EBOV minigenomic RNA indicates formation of a small stem-loop composed of the HSPA8 motif, a 3' stem-loop (nucleotides 1868-1890) that is similar to a previously identified structure in the replicative intermediate (RI) RNA and a panhandle domain involving a trailer-to-leader interaction. Results of minigenome assays and an EBOV reverse genetic system rescue support a role for both the panhandle domain and HSPA8 motif 1 in virus replication.


Oviposition-site preference in Drosophila following interspecific gene transfer of the Alcohol dehydrogenase locus.
The preference of Drosophila females to lay eggs on substrates that do or do not contain alcohol is an excellent system to study the evolutionary genetics of behavior, because (1) there is variation in this behavior within and among species, (2) the behavior is amenable to laboratory investigation, and (3) the behavior presumably has a direct relationship to reproductive fitness. Moreover, a key genetic component of the system, the Alcohol dehydrogenase (Adh) locus, is arguably the most well characterized gene known. However, because the Adh gene and its genetic background are inseparable in reproductively isolated species, it is difficult to establish its role in behavioral divergence. By transgene coplacement, we created pairs of strains of D. melanogaster expressing an Adh allele from either D. melanogaster or D. affinidisjuncta, a Hawaiian species with very low levels of ADH in adults. When raised on ethanol-containing medium, the affinidisjuncta-Adh strains experience high mortality relative to the melanogaster-Adh strains. However, affinidisjuncta-Adh females show the same preference for oviposition on ethanol-containing medium as melanogaster-Adh females. Thus, preference for ethanol in these strains is not determined primarily by Adh genotype.


Health-related quality of life and its predictors among patients with rheumatoid arthritis.
Limited studies have examined the predictors of HRQoL among patients with rheumatoid arthritis. This study helped to ascertain the predictors of HRQoL from the pool of influencing factors identified by previous studies. This study investigated the health-related quality of life (HRQoL) of adult patients with rheumatoid arthritis and its predictors. Using a descriptive correlational design, this study explored the relationship between HRQoL and pain, functional disability, anxiety, depression, medication adherence and social support. Eligible outpatients (n=108) were recruited via their attending doctors who were co-investigators of this study. Informed consent forms were distributed and questionnaires administered in a teaching hub by the main researcher. Significant correlations were found between HRQoL and all of the study variables. Pain, functional disability and depression were main predictors of HRQoL. Future evidence-based interventions focusing on pain relief, delaying disability or improving functional ability and reducing depressive symptoms are required to enhance the HRQoL of patients with rheumatoid arthritis.


Inhibition of induced DNA oxidative damage by beers: correlation with the content of polyphenols and melanoidins.
Beers are a source of dietary flavonoids; however, there exist differences in composition, alcohol concentration, and beneficial activities. To characterize these differences, three kinds of lager beer of habitual consumption in Spain, dark, blond, and alcohol-free, were assayed for total phenolic content, antioxidant activity, superoxide and hydroxyl radical scavenging activities, and in vitro inhibitory effect on DNA oxidative damage. Furthermore, their melanoidin content and correlation with antioxidant activity were evaluated. Dark beer contained the highest total phenolic (489 +/- 52 mg/L) and melanoidin (1.49 +/- 0.02 g/L) contents with a 2-fold difference observed when compared to the alcohol-free beer. For the three kinds of beer, the antioxidant activity measured as N,N-dimethyl-p-phenylenediamine dihydrochloride concentration was strongly correlated with the total polyphenol content (R(2) = 0.91102, p < 0.005) and with the melanoidin content (R(2) = 0.7999, p < 0.05). The results support a positive effect of beers on the protection of DNA oxidative damage, by decreasing the deoxyribose degradation, DNA scission (measured by electrophoresis), and inhibition of 8-hydroxydeoxyguanosine (8-OH-dG) formation. Furthermore, a correlation between the total melanoidin content (R(2) = 0.7309, p < 0.01) and inhibition of 8-OH-dG was observed.


Developing the ethical framework of end-stage kidney disease care: from practice to policy.
Ethical issues relating to end-stage kidney disease (ESKD) care are increasingly being discussed by clinicians and ethicists but are still infrequently considered at a policy level or in the education and training of health care professionals. In most lower-income countries, access to kidney replacement therapies such as dialysis is not universal, leading to overt or implicit rationing of resources and potential exclusion from care of those who are unable to sustain out-of-pocket payments. These circumstances create significant inequities in access to ESKD care within and between countries and impose emotional and moral burdens on patients, families, and health care workers involved in decision-making and provision of care. End-of-life decision-making in the context of ESKD care in all countries may also create ethical dilemmas for policy makers, professionals, patients, and their families. This review outlines several ethical implications of the complex challenges that arise in the management of ESKD care around the world. We argue that more work is required to develop the ethics of ESKD care, so as to provide ethical guidance in decision-making and education and training for professionals that will support ethical practice in delivery of ESKD care. We briefly review steps that may be required to accomplish this goal, discussing potential barriers and strategies for success.


Assessing the consistency assumption by exploring treatment by covariate interactions in mixed treatment comparison meta-analysis: individual patient-level covariates versus aggregate trial-level covariates.
Mixed treatment comparison (MTC) meta-analysis allows several treatments to be compared in a single analysis while utilising direct and indirect evidence. Treatment by covariate interactions can be included in MTC models to explore how the covariate modifies the treatment effects. If interactions exist, the assumptions underlying MTCs may be invalidated. For conventional pair-wise meta-analysis, important benefits regarding the investigation of such interactions, gained from using individual patient data (IPD) rather than aggregate data (AD), have been described. We aim to compare IPD MTC models including patient-level covariates with AD MTC models including study-level covariates. IPD and AD random-effects MTC models for dichotomous outcomes are specified. Three assumptions are made regarding the interactions (i.e. independent, exchangeable and common interactions). The models are applied to a dataset to compare four drugs for treating malaria (i.e. amodiaquine-artesunate, dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine and chlorproguanil-dapsone plus artesunate) using the outcome unadjusted treatment success at day 28. The treatment effects and regression coefficients for interactions from the IPD models were more precise than those from AD models. Using IPD, assuming independent or exchangeable interactions, the regression coefficient for chlorproguanil-dapsone plus artesunate versus DHAPQ was statistically significant and assuming common interactions, the common coefficient was significant; whereas using AD, no coefficients were significant. Using IPD, DHAPQ was the best drug; whereas using AD, the best drug varied. Using AD models, there was no evidence that the consistency assumption was invalid; whereas, the assumption was questionable based on the IPD models. The AD analyses were misleading.


[Associated lesions in closed injuries of the thorax: right bronchial rupture, rupture of the right subclavian artery, and bilateral fracture of the 1st rib].
A patient presented with rupture of right bronchus associated with rupture of the homolateral subclavian artery (diagnosed secondarily at the false aneurysm stage) and bilateral fracture of the 1st rib. Two stage repair operation provided lasting recovery. This case is used as a basis for emphasizing the diagnostic problems raised by combined endothoracic lesions, the need for systematic investigation of possible presence of a lesion of subclavian artery in patients with fracture of 1st rib, and finally various operative tactics (in the framework of false aneurysms of proximal subclavian vessels).


Evidence for induced synthesis of an active transport factor for mandelate in Pseudomonas putida.
1. At low concentrations of mandelate there is a lag before induction of the mandelate regulon begins at a sub-maximum rate. Cells preinduced with a saturating concentration of inducer do not exhibit this lag when they are transferred to sub-maximum inducer concentrations and are able to maintain a high rate of induction under these conditions. 2. Chloramphenicol was used to show that a protein is synthesized during the lag period that is probably responsible for the maintenance effects observed in batch and continuous cultures. 3. Direct measurements appear to show that induced cells possess an active transport factor for mandelate, sensitive to dinitrophenol, and this is presumably responsible for the maintenance effect. Mandelate is accumulated unchanged against a concentration gradient from media containing low concentrations. At higher external concentrations no accumulation occurs and only a rapid equilibration is noted. Uninduced cells merely equilibrate mandelate.


Media activism and Internet use by people with HIV/AIDS.
This paper seeks to understand better the media practices of people who are directly affected by an illness or health problem. Internet sites that have been created by people with HIV/AIDS are examined as a strategy for self-representation. This analysis identifies four prominent 'organising themes' in Internet sites: autobiography; expertise; self promotion; and dissent. It is argued that there is a connection between media activism within the contemporary AIDS movement and Internet use among people with HIV/AIDS. This paper discusses the potential of the Internet, as a form of media activism, to raise the private troubles of people with health problems as public issues through a revitalisation of the public sphere in contemporary post-industrial societies.


Validity of observer ratings of the five-factor model of personality traits: a meta-analysis.
Conclusions reached in previous research about the magnitude and nature of personality-performance linkages have been based almost exclusively on self-report measures of personality. The purpose of this study is to address this void in the literature by conducting a meta-analysis of the relationship between observer ratings of the five-factor model (FFM) personality traits and overall job performance. Our results show that the operational validities of FFM traits based on observer ratings are higher than those based on self-report ratings. In addition, the results show that when based on observer ratings, all FFM traits are significant predictors of overall performance. Further, observer ratings of FFM traits show meaningful incremental validity over self-reports of corresponding FFM traits in predicting overall performance, but the reverse is not true. We conclude that the validity of FFM traits in predicting overall performance is higher than previously believed, and our results underscore the importance of disentangling the validity of personality traits from the method of measurement of the traits.


Analytical estimation of laser phase noise induced BER floor in coherent receiver with digital signal processing.
The Bit-Error-Ratio (BER) floor caused by the laser phase noise in the optical fiber communication system with differential quadrature phase shift keying (DQPSK) and coherent detection followed by digital signal processing (DSP) is analytically evaluated. An in-phase and quadrature (I&Q) receiver with a carrier phase recovery using DSP is considered. The carrier phase recovery is based on a phase estimation of a finite sum (block) of the signal samples raised to the power of four and the phase unwrapping at transitions between blocks. It is demonstrated that errors generated at block transitions cause the dominating contribution to the system BER floor when the impact of the additive noise is negligibly small in comparison with the effect of the laser phase noise. Even the BER floor in the case when the phase unwrapping is omitted is analytically derived and applied to emphasize the crucial importance of this signal processing operation. The analytical results are verified by full Monte Carlo simulations. The BER for another type of DQPSK receiver operation, which is based on differential phase detection, is also obtained in the analytical form using the principle of conditional probability. The principle of conditional probability is justified in the case of differential phase detection due to statistical independency of the laser phase noise induced signal phase error and the additive noise contributions. Based on the achieved analytical results the laser linewidth tolerance is calculated for different system cases.


Measurement of normal and pathological mandibular and temporomandibular joint kinematics: A systematic review.
Motion of the mandible and temporomandibular joint (TMJ) plays a pivotal role in the function of the dentition and associated hard and soft tissue structures, and facilitates mastication, oral communication and access to respiratory and digestive systems. Quantification of TMJ kinematics is clinically relevant in cases of prosthetic rehabilitations, TMJ disorders, osteoarthritis, trauma, tumour resection and congenital abnormalities, which are known to directly influence mandibular motion and loading. The objective of this systematic review was to critically investigate published literature on historic and contemporary measurement modalities used to quantify in vivo mandibular and TMJ kinematics in six degrees of freedom. The electronic databases of Scopus, Web of Science, Medline, Embase and Central were searched and 109 relevant articles identified. Publication quality was documented using a modified Downs and Black checklist. Axiography and ultrasonic tracking are commonly employed in the clinical setting due to their simplicity and capacity to rapidly acquire low-fidelity mandibular motion data. Magnetic and optoelectronic tracking have been used in combination with dental splints to produce higher accuracy measurements while minimising skin motion artefact, but at the expense of setup time and cost. Four-dimensional computed tomography provides direct 3D measurement of mandibular and TMJ motion while circumventing skin motion artefact entirely, but employs ionising radiation, is restricted to low sampling frequencies, and requires time-consuming image processing. Recent advances in magnetic tracking using miniature sensors adhered to the teeth in combination with intraoral scanning may facilitate rapid and high precision mandibular kinematics measurement in the clinical setting. The findings of this review will guide selection and application of mandibular and TMJ kinematic measurement for both clinical and research applications.


Synchronous tracheostomy and gastrostomy placement results in shorter length of stay in traumatic brain injury patients.
American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines recommend gastrostomy for patients suspected to require enteral access device for 4-6 weeks. Our hypothesis was that traumatic brain injury (TBI) patients undergoing synchronous tracheostomy/gastrostomy (SYNC) compared to tracheostomy first (DELAY) have shorter length of stay (LOS) but higher rates of unnecessary gastrostomy. Retrospective review of TBI patients requiring tracheostomy in 2017-2022 at a Level 1 trauma center was conducted. SYNC and DELAY patients were compared, and CoxPH analysis was performed for LOS. 394 patients were included [mean age: 42 (SD:18); mortality: 9 %]. The DELAY group had longer LOS (39 vs 32 days, p < 0.001). There was no significant difference in unnecessary gastrostomy rate between groups (p = 0.1331). In adjusted hazard analysis, SYNC predicted shorter LOS (HR:1.54; 95 % CI:1.20-1.98, p < 0.001). Synchronous gastrostomy was associated with shorter length of stay and similar rates of unnecessary gastrostomy in TBI patients.


Zwitterionic chitooligosaccharide-modified ink-blue titanium dioxide nanoparticles with inherent immune activation for enhanced photothermal therapy.
Photothermal therapy (PTT) can trigger massive apoptosis of cancer cells, and this sharply increasing local apoptotic rate may recruit plenty of tumor-associated macrophages (TAMs). Although TAMs are recognized to display an M2-like subtype, which encourages tumor ontogenesis, they can be re-educated to a tumoricidal M1-like subtype by immunomodulatory reagents. Chitooligosaccharides (COSs) are endowed with immunomodulatory ability, but the positive electrical property limits their application; besides, their re-educating ability on TAMs is uncertain. Therefore, we proposed whether the combination of zwitterionic COS with a photothermal material can impair the undesirable tumor promotion of TAMs, thus enhancing the PTT treatment outcome. Herein, zwitterionic COS was obtained via the carboxymethylate method and then, the obtained COS was modified on the surface of ink-blue titanium dioxide (BTiO2) with photothermal ability to synthesize BTC NPs. In vitro, the immunofluorescence staining and cell survival assays indicated that BTC NPs could re-educate 87% of the M2-like RAW264.7 macrophages stimulated by apoptotic tumor cell secretion and significantly inhibit the liver tumor cell proliferation. Notably, in a mouse H22 liver cancer model, compared with mono PTT with BTiO2, the PTT treatment of BTC could reverse the ratio of M2 : M1 from 3.3 : 1 to 0.5 : 1, thus leading to 20.7% increase in the tumor inhibition rate. In general, our study demonstrated that zwitterionic COS can act as a potent immune activator to re-educate TAMs to M1. Furthermore, equipping the photothermal material with zwitterionic COS can be a potential treatment paradigm to achieve more forceful PTT.


Synchronization of neuronal activity promotes survival of individual rat neocortical neurons in early development.
Neural activity is thought to play a significant role during the development of the cerebral cortex. In this study, we examined the effects of global activity block or enhancement and the effects of patterned firing on the ability of cultured rat neocortical neurons to survive during the second week in vitro, beyond the beginning of synaptogenesis. Blockade of neuronal activity by adding tetrodotoxin (TTX) and increasing magnesium concentration in the medium strongly reduced the survival of cortical cells. Increasing neuronal activity by raising the external potassium concentration significantly improved the survival of cortical neurons. We postulated that in a developing neuronal network the survival of nerve cells is regulated by synaptically mediated events that involve changes in the intracellular calcium concentration. To examine this question further, we monitored the activity of the developing network by optically recording the intracellular calcium signals of many neurons simultaneously. These recordings show that in low magnesium neocortical neurons express synchronized oscillation of their intracellular calcium concentration. The ability of a network to synchronize the changes in intracellular calcium of multiple cells appeared gradually during the second week in culture, paralleled by both an increase in the synaptic density and a decline in the number of surviving neurons. By examining the fate of identified cells several days after a recording session, we found that those nerve cells that were co-activated with other neurons had a significantly higher chance to survive than cells that did not participate in synchronized events. These experiments demonstrate that during early cortical network development cortical neurons show synchronized firing activity and that the survival of neurons is at least partially dependent on this pattern of neuronal activity.


Modelling flavoenzymatic charge transfer events: development of catalytic indole deuteration strategies.
The formation and chemistry of flavin-indole charge transfer (CT) complexes has been studied using a model cationic flavin. The ability to form a CT complex is sensitive to indole structure as gauged by spectroscopic, kinetics and crystallographic studies. Single crystals of sufficient quality of a flavin-indole CT complex, suitable for X-ray diffraction, have been grown, allowing solid-state structural analysis. When CT complex formation is conducted in d4-methanol, an efficient and synthetically useful C-3 indole deuteration is observed.


Reevaluating the safety profile of pediatrics: a comparison of computerized adverse drug event surveillance and voluntary reporting in the pediatric environment.
Children are at exceptionally high risk for adverse drug events. At Duke University Hospital, computerized adverse drug event surveillance and voluntary safety reporting systems work synergistically to identify adverse drug events. Here we identify the most deleterious drug classes to pediatric inpatients and determine which detection methodology provides the greatest opportunity to reduce harm. We evaluated all of the medication-related events detected by our computerized surveillance and safety reporting systems over a 1-year period for Duke University Hospital pediatric inpatients. Events from both systems were scored for severity and assigned a drug event category. Surveillance events were additionally scored for causality. A total of 849 medication-related reports were entered into the safety reporting system, and 93 caused patient harm, resulting in an adverse drug event rate of 1.8 events per 1000 pediatric patient-days. Seventy eight of the 1537 medication-related events detected by surveillance resulted in patient harm, giving a rate of 1.6 events per 1000 patient-days. The most common events identified by the safety reporting system were failures in the medication use process (26.9%), drug omissions (16.1%), and dose- or rate-related events (12.9%). The most frequent adverse drug event surveillance categories were nephrotoxins (20.7%), narcotics and benzodiazepines (19.3%), and hypoglycemia (11.5%). Most voluntarily reported events originated in ICUs (72.0%), whereas surveillance events were split evenly across intensive and general care. There was little overlap between methodologies. The epidemiology of pediatric adverse drug events is best addressed by using voluntary reporting in tandem with other strategies, such as computerized surveillance and targeted chart review. Although voluntary reporting excels at identifying administration errors, surveillance excels at detecting adverse drug events caused by high-risk medications and identifies evolving conditions that may provoke imminent patient harm. Surveillance underperformed in pediatrics when compared with adult detection rates, suggesting that tailored rules may be necessary for a robust pediatric adverse drug event surveillance system.


Ciprofloxacin 0.3% + dexamethasone 0.1% for the treatment for otitis media.
Ciprofloxacin 0.3% with dexamethasone 0.1% (ciprofloxacin/dexamethasone) is an ototopical preparation for acute otitis externa, otorrhea with tympanostomy tubes, and is frequently used to treat chronic suppurative otitis media (CSOM). The advantage of topical therapy is the ability to deliver higher concentration of antibiotics to the treatment site when compared with oral or parenteral antibiotics. The delivery of a high concentration of antibiotics significantly decreases treatment failure and makes the development of resistant organisms unlikely. Previous ototopical preparations contained antibiotics such as aminoglycosides that are known to be ototoxic making treatment of otic infections without an intact tympanic membrane difficulty. A literature search of PubMed was performed as the basis for a literature-based discussion on the clinical efficacy of ciprofloxacin/dexamethasone compared to oral antibiotics and ototopical therapy without a steroid component. The potential ototoxicity of ototopical therapies is discussed, including evidence demonstrating the lack of ototoxicity of fluoroquinolone and dexamethasone containing drops. Because multiple studies have demonstrated that fluoroquinolones are not ototoxic, fluoroquinolone ototopical drops should be a first-line treatment for otorrhea without an intact membrane. The addition of dexamethasone 0.1% to ciprofloxacin 0.3% has been shown to decrease granulation tissue, improve clinical cure and achieve greater rates of bacterial eradication when compared to ciprofloxacin 0.3% alone.


Moyamoya disease and coronary artery disease--case report.
A 26-year-old female with idiopathic moyamoya disease developed chest pain with concomitant ST depression on electrocardiography. Coronary angiography detected no stenotic lesions in the epicardial coronary arteries. The clinical diagnosis was vasospastic angina pectoris. She was medicated with calcium antagonists, which reduced the frequency of chest pain episodes. Angina pectoris is a rare occurrence in young patients with moyamoya disease. Coronary artery disease and moyamoya disease may have common etiological factors.


Closed-loop insulin delivery for treatment of type 1 diabetes.
Type 1 diabetes is one of the most common endocrine problems in childhood and adolescence, and remains a serious chronic disorder with increased morbidity and mortality, and reduced quality of life. Technological innovations positively affect the management of type 1 diabetes. Closed-loop insulin delivery (artificial pancreas) is a recent medical innovation, aiming to reduce the risk of hypoglycemia while achieving tight control of glucose. Characterized by real-time glucose-responsive insulin administration, closed-loop systems combine glucose-sensing and insulin-delivery components. In the most viable and researched configuration, a disposable sensor measures interstitial glucose levels, which are fed into a control algorithm controlling delivery of a rapid-acting insulin analog into the subcutaneous tissue by an insulin pump. Research progress builds on an increasing use of insulin pumps and availability of glucose monitors. We review the current status of insulin delivery, focusing on clinical evaluations of closed-loop systems. Future goals are outlined, and benefits and limitations of closed-loop therapy contrasted. The clinical utility of these systems is constrained by inaccuracies in glucose sensing, inter- and intra-patient variability, and delays due to absorption of insulin from the subcutaneous tissue, all of which are being gradually addressed.


Cost of open access publishing in otolaryngology-head and neck surgery.
Open access (OA) publishing makes research more accessible but is associated with steep article processing charges (APCs). The study objective was to characterize the APCs of OA publishing in otolaryngology-head and neck surgery (OHNS) journals. We conducted a cross-sectional analysis of published policies of 110 OHNS journals collated from three databases. The primary outcomes were the publishing model, APC for original research, and APC waiver policy. We identified 110 OHNS journals (57 fully OA, 47 hybrid, 2 subscription-only, 4 unknown model). After excluding 12 journals (2 subscription-only, 4 unknown model, 5 OA with unspecified APCs, and 1 OA that accepts publications only from society members), we analyzed 98 journals, 23 of which did not charge APCs. Among 75 journals with nonzero APCs, the mean and median APCs were $2452 and $2900 (interquartile range: $1082-3520). Twenty-five journals (33.3%) offered APC subsidies for authors in low- and middle-income countries (LMICs) and/or on a case-by-case basis. Eighty-five and 25 journals were based in high-income countries (HICs) and LMICs, respectively. The mean APC was higher among HIC journals than LMIC journals ($2606 vs. $958, p < 0.001). APCs range from tens to thousands of dollars with limited waivers for authors in LMICs.


Algorithmic Design of 3D Wireframe RNA Polyhedra.
We address the problem of de novo design and synthesis of nucleic acid nanostructures, a challenge that has been considered in the area of DNA nanotechnology since the 1980s and more recently in the area of RNA nanotechnology. Toward this goal, we introduce a general algorithmic design process and software pipeline for rendering 3D wireframe polyhedral nanostructures in single-stranded RNA. To initiate the pipeline, the user creates a model of the desired polyhedron using standard 3D graphic design software. As its output, the pipeline produces an RNA nucleotide sequence whose corresponding RNA primary structure can be transcribed from a DNA template and folded in the laboratory. As case examples, we design and characterize experimentally three 3D RNA nanostructures: a tetrahedron, a triangular bipyramid, and a triangular prism. The design software is openly available and also provides an export of the targeted 3D structure into the oxDNA molecular dynamics simulator for easy simulation and visualization.


[Microbiological aspects of identification of patients with drug-resistant tuberculosis].
This review discusses controversial issues, such as definitions of drug resistance, the conditions laboratory drug-susceptibility testing in all new patients is justified, and the requirements for the optimum turnaround time of laboratory reports. It also analyses the advantages and disadvantages of different methods for drug susceptibility testing, including those based on cultivation in the solid and liquid media, as well as molecular phenotypic and genotypic methods. While molecular genotypic methods represent the most promising direction for future development, their application in the clinical laboratory setting today is limited to the initial preliminary screening for rifampicin resistance as a marker for possible MDR and as an indicator for the need for subsequent testing with other drugs. The direct susceptibility test in the solid media (at least that with rifampicin and isoniazid) represents the most affordable method that allows timely adjustment in the treatment regimen if drug resistance is detected. The total turnaround time can be as short as three weeks for 85-90% of smear-positive specimens when the agar plate technique is used for a direct test. Introduction of a liquid media system is the next step to achieving the expected results in all patients.


A multiplex assay for the detection and mapping of complex glycerol kinase deficiency.
Glycerol kinase deficiency (GKD) is an X-linked recessive disorder that presents in both isolated and complex forms. The contiguous deletion that leads to GKD also commonly affects NR0B1 (DAX1), the gene associated with adrenal hypoplasia congenita, and DMD, the Duchenne muscular dystrophy gene. Molecular testing to delineate this deletion is expensive and has only limited availability. We designed a multiplex PCR assay for the detection and mapping of a contiguous deletion potentially affecting the IL1RAPL1, NR0B1, GK, and DMD genes in a 29-month-old male patient with GKD. Multiplex PCR detected a contiguous deletion that involved the IL1RAPL1, NR0B1, GK, and DMD genes. Although the patient had a creatine kinase concentration within the reference interval, further mapping with PCR revealed that exon 74 was the last intact exon at the 3' end of the DMD gene. Multiplex PCR is an effective and inexpensive way to detect and map the contiguous deletion in cases of complex GKD. The extension of a deletion to include DMD exon 75 in a patient with a creatine kinase concentration within the reference interval suggests that this region of the gene may not be essential for protein function.


Prenatal diagnosis of retroperitoneal teratoma: a case report and review of the literature.
We report a case of retroperitoneal teratoma diagnosed prenatally by serial sonographic examinations in the third trimester. A 29-year-old woman was referred for sonographic evaluation at 33 weeks' gestation because of a fetal intra-abdominal mass. Our initial sonographic image suggested a neuroblastoma. Repeat ultrasound images demonstrated an increase in size of the tumor, while the content of the tumor became predominantly solid with areas of calcification. Teratoma should be considered on detection of any cystic or mixed semisolid mass, especially when calcification is present. The fetus was prenatally diagnosed with retroperitoneal teratoma. After birth at 39 weeks, the tumor was removed and histological analysis revealed an immature retroperitoneal teratoma. Intensive monitoring of the changes in ultrasound images of the tumor should provide ground for a precise antenatal diagnosis.


The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones.
Tenascin-X (TNX) is an extracellular matrix glycoprotein with anti-adhesive properties in skin and joints. Here we report the novel finding that TNX is expressed in human and mouse gut tissue where it is exclusive to specific subpopulations of neurones. Our studies with TNX-deficient mice show impaired defecation and neural control of distal colonic motility that can be rescued with a 5-HT4 receptor agonist. However, colonic secretion is unchanged. They are also susceptible to internal rectal intussusception. Colonic afferent sensitivity is increased in TNX-deficient mice. Correspondingly, there is increased density of and sensitivity of putative nociceptive fibres in TNX-deficient mucosa. A group of TNX-deficient patients report symptoms highly consistent with those in the mouse model. These findings suggest TNX plays entirely different roles in gut to non-visceral tissues - firstly a role in enteric motor neurones and secondly a role influencing nociceptive sensory neurones Studying further the mechanisms by which TNX influences neuronal function will lead to new targets for future treatment. The extracellular matrix (ECM) is not only an integral structural molecule, but is also critical for a wide range of cellular functions. The glycoprotein tenascin-X (TNX) predominates in the ECM of tissues like skin and regulates tissue structure through anti-adhesive interactions with collagen. Monogenic TNX deficiency causes painful joint hypermobility and skin hyperelasticity, symptoms characteristic of hypermobility Ehlers Danlos syndrome (hEDS). hEDS patients also report consistently increased visceral pain and gastrointestinal (GI) dysfunction. We investigated whether there is a direct link between TNX deficiency and GI pain or motor dysfunction. We set out first to learn where TNX is expressed in human and mouse, then determine how GI function, specifically in the colon, is disordered in TNX-deficient mice and humans of either sex. In human and mouse tissue, TNX was predominantly associated with cholinergic colonic enteric neurones, which are involved in motor control. TNX was absent from extrinsic nociceptive peptidergic neurones. TNX-deficient mice had internal rectal prolapse and a loss of distal colonic contractility which could be rescued by prokinetic drug treatment. TNX-deficient patients reported increased sensory and motor GI symptoms including abdominal pain and constipation compared to controls. Despite absence of TNX from nociceptive colonic neurones, neuronal sprouting and hyper-responsiveness to colonic distension was observed in the TNX-deficient mice. We conclude that ECM molecules are not merely support structures but an integral part of the microenvironment particularly for specific populations of colonic motor neurones where TNX exerts functional influences.


Rapidly transported organelles containing membrane and cytoskeletal components: their relation to axonal growth.
We have examined the movements, composition, and cellular origin of phase-dense varicosities in cultures of chick sympathetic and sensory neurons. These organelles are variable in diameter (typically between 0.2 and 2 microns) and undergo saltatory movements both towards and away from the neuronal cell body. Their mean velocities vary inversely with the size of the organelle and are greater in the retrograde than the anterograde direction. Organelles stain with the lipophilic dye 1, 1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine and with antibodies to cytoskeletal components. In cultures double-stained with antibodies to alpha-tubulin and 70-kD neurofilament protein (NF-L), approximately 40% of the organelles stain for tubulin, 30% stain for NF-L, 10% stain for both tubulin and NF-L, and 40% show no staining with either antibody. The association of cytoskeletal proteins with the organelles shows that these proteins are able to move by a form of rapid axonal transport. Under most culture conditions the predominant direction of movement is towards the cell body, suggesting that the organelles are produced at or near the growth cone. Retrograde movements continue in culture medium lacking protein or high molecular mass components and increase under conditions in which the advance of the growth cone is arrested. There is a fourfold increase in the number of organelles moving retrogradely in neurites that encounter a substratum-associated barrier to elongation; retrograde movements increase similarly in cultures exposed to cytochalasin at levels known to block growth cone advance. No previously described organelle shows behavior coordinated with axonal growth in this way. We propose that the organelles contain membrane and cytoskeletal components that have been delivered to the growth cone, by slow or fast anterograde transport, in excess of the amounts required to synthesize more axon. In view of their rapid mobility and variable contents, we suggest that they be called "neuronal parcels."


Ecological effects of the invasive giant madagascar day gecko on endemic mauritian geckos: applications of binomial-mixture and species distribution models.
The invasion of the giant Madagascar day gecko Phelsuma grandis has increased the threats to the four endemic Mauritian day geckos (Phelsuma spp.) that have survived on mainland Mauritius. We had two main aims: (i) to predict the spatial distribution and overlap of P. grandis and the endemic geckos at a landscape level; and (ii) to investigate the effects of P. grandis on the abundance and risks of extinction of the endemic geckos at a local scale. An ensemble forecasting approach was used to predict the spatial distribution and overlap of P. grandis and the endemic geckos. We used hierarchical binomial mixture models and repeated visual estimate surveys to calculate the abundance of the endemic geckos in sites with and without P. grandis. The predicted range of each species varied from 85 km2 to 376 km2. Sixty percent of the predicted range of P. grandis overlapped with the combined predicted ranges of the four endemic geckos; 15% of the combined predicted ranges of the four endemic geckos overlapped with P. grandis. Levin's niche breadth varied from 0.140 to 0.652 between P. grandis and the four endemic geckos. The abundance of endemic geckos was 89% lower in sites with P. grandis compared to sites without P. grandis, and the endemic geckos had been extirpated at four of ten sites we surveyed with P. grandis. Species Distribution Modelling, together with the breadth metrics, predicted that P. grandis can partly share the equivalent niche with endemic species and survive in a range of environmental conditions. We provide strong evidence that smaller endemic geckos are unlikely to survive in sympatry with P. grandis. This is a cause of concern in both Mauritius and other countries with endemic species of Phelsuma.


Depression Among Patients with Type 2 Diabetes Mellitus: Prevalence and Associated Factors in Hue City, Vietnam.
Depression is common in people with type 2 diabetes mellitus. The association of depression and diabetes has negative effects on patients. This study investigated the prevalence of depression in individuals with type 2 diabetes mellitus and examined the social, psychological and clinical factors associated with depression. The study included 216 inpatients with type 2 diabetes mellitus at the Department of Endocrinology and Neurology, Hue Central Hospital and the Department of General Internal Medicine, Hue University Hospital. This descriptive cross-sectional study evaluated depression using the Patient Health Questionnaire-9 (PHQ-9). Data were collected on patients' socio-demographic factors such as sex, age, marital and economic status, level of education and clinical factors including duration of type 2 diabetes mellitus, fasting blood glucose, HbA1C, comorbidities or complications as well as health behavior including alcohol consumption, smoking and physical activities. Logistic regression was used to analyze the factors associated with depression in patients with type 2 diabetes mellitus. 23.2% of the patients had depression. The rates of severe, moderate and mild depression were 0.5, 0.9 and 21.8%, respectively. Multivariate logistic regression analysis indicated several factors associated with depression in participants, including age under 60 years, poor economic status, unstable or part-time work, having stress during the past year, without/poor treatment adherence to type 2 diabetes mellitus, and engaging in heavy physical activity or physical activity less than three days per week. The prevalence of depression among patients with type 2 diabetes mellitus is high. Endocrinologists should be made aware of the increased risk of depression in this patient population and screening individuals for relevant risk factors is highly recommended.


A complete screen for mutations of the rhodopsin gene in a panel of Chinese patients with autosomal dominant retinitis pigmentosa.
To evaluate the prevalence of rhodopsin (RHO) mutations and the genotype-phenotype relationships in Chinese patients with autosomal dominant retinitis pigmentosa (ADRP) by conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing. We have screened the five coding exons and splice sites of RHO gene in 27 probands who had no relativity from Chinese ADRP families and 100 normal controls to identify disease-associated mutations, using CSGE and direct DNA sequencing. Family members of some probands with disease-associated mutations were also genotyped to determine whether the RHO mutations segregated with retinitis pigmentosa (RP) in their families. Two RHO mutations, Pro347Leu and Pro327 (1-bp del), were identified separately in two families, thus the frequency of RHO mutations among this set of Chinese ADRP families is about 7.4% (2/27). Pro347Leu mutation was found in one ADRP proband as well as three her children who also had RP. She had relatively early onset at about 17 years. The only one child without this mutation had no symptom or sign of RP at age of 34. Pro327 (1-bp del) was identified in a late-onset ADRP patient, who appeared night blindness around 30 years old and in her fifties electroretinogram (ERG) has been flat in both scotopic and photopic phases. Family analysis showed that this mutation also existed in her younger daughter and her elder sister, both of them also had RP. Three other family members were genotypically and phenotypically normal. Neither of the two mutations was detected in 100 normal controls. The frequency of RHO mutations in Chinese patients was lower than that in Europe and North America. The phenotype of the patients with Pro347Leu corresponded to type 1 ADRP, with severe rod degeneration and some cone preservation later, while the phenotype of the patients carrying Pro327 (1-bp del) corresponded to type 2 ADRP, with a concomitant loss of rod and cone visual function. CSGE was found to be a sensitive, simple, and practical method for the screening of a large number of samples under highly reproducible conditions, and could be utilized in routine molecular diagnostic laboratories.


Can traditional epidemiology detect cancer risks caused by occupational exposure to pesticides?
In order to investigate the possible relationship between cancer and occupational exposure to pesticides, we reviewed the latest literature of the epidemiological studies in this area coming to the conclusion that, while several studies indicate a link between certain pesticides and certain tumors, this information is still insufficient, and further research on the health consequences of exposure to pesticides is needed. Moreover, provided there is a risk, it is often too limited to be detected by available epidemiological techniques. Therefore, in addition to the epidemiological studies, the development of new biology, gene technology and medical biotechnology methods may significantly enhance the specificity of the epidemiological studies. Thus, the fusion of molecular biology and epidemiology into molecular epidemiology may provide more specific methods for monitoring the occupational dependent carcinogenic risk of individuals and groups.


Preliminary characterisation of two early meiotic wheat proteins after identification through 2D gel electrophoresis proteomics.
Various genetic-based approaches including mutant population screens, microarray analyses, cloning and transgenesis have broadened our knowledge of gene function during meiosis in plants. Nonetheless, these genetic tools are not without inherent limitations. One alternative approach to studying plant meiosis, especially in polyploids such as Triticum aestivum L. (bread wheat), is proteomics. However, protein-based approaches using proteomics have seldom been described, with only two attempts at studying early plant meiosis reported. Here, we report the investigation of early bread wheat meiosis using proteomics. Five differentially expressed protein spots were identified using 2D gel electrophoresis (2DGE) on protein extracts from four pooled stages of meiosis and three genotypes (Chinese Spring wild-type, ph1b and ph2a wheat mutant lines). Tandem mass spectrometry (MS/MS) identification of peptides from these protein spots led to the isolation and characterisation of the full-length clones of a wheat Speckle-type POZ protein, an SF21-like protein and HSP70, and a partial coding sequence of a hexose transporter. Significantly, the putative functions of the Speckle-type POZ protein and HSP70 were confirmed using in vitro DNA binding assays. Through the use of a 2DGE proteomics approach, we show that proteomics is a viable alternative to genetic-based approaches when studying meiosis in wheat. More significantly, we report a potential role for a Speckle-type POZ protein and a HSP70 in chromosome pairing during the early stages of meiosis in bread wheat.


Neurocognitive Correlates of Young Drivers' Performance in a Driving Simulator.
Differences in neurocognitive functioning may contribute to driving performance among young drivers. However, few studies have examined this relation. This pilot study investigated whether common neurocognitive measures were associated with driving performance among young drivers in a driving simulator. Young drivers (19.8 years (standard deviation [SD] = 1.9; N = 74)) participated in a battery of neurocognitive assessments measuring general intellectual capacity (Full-Scale Intelligence Quotient, FSIQ) and executive functioning, including the Stroop Color-Word Test (cognitive inhibition), Wisconsin Card Sort Test-64 (cognitive flexibility), and Attention Network Task (alerting, orienting, and executive attention). Participants then drove in a simulated vehicle under two conditions-a baseline and driving challenge. During the driving challenge, participants completed a verbal working memory task to increase demand on executive attention. Multiple regression models were used to evaluate the relations between the neurocognitive measures and driving performance under the two conditions. FSIQ, cognitive inhibition, and alerting were associated with better driving performance at baseline. FSIQ and cognitive inhibition were also associated with better driving performance during the verbal challenge. Measures of cognitive flexibility, orienting, and conflict executive control were not associated with driving performance under either condition. FSIQ and, to some extent, measures of executive function are associated with driving performance in a driving simulator. Further research is needed to determine if executive function is associated with more advanced driving performance under conditions that demand greater cognitive load.


Alterations of constitutive pericentromeric heterochromatin in lymphocytes of cancer patients and lymphocytes exposed to 5-azacytidine is associated with DNA-hypomethylation.
DNA hypomethylation plays a key role in carcinogenesis. The malignant transformation of cells as well as tumor progression is accompanied with increasing DNA hypomethylation in cancer cells. Nevertheless, the evolution of dis-epigenetic genomic alteration in the somatic cellular malignant transformation has not yet been clear. To study the relationship between the pattern of genomic DNA hypomethylation and DNA hyperploidy. The model of 5-azacytidine demethylating DNA treatment of the mitogen-stimulated lymphocytes in parallel with patients with solid cancer has been explored. DNA content was measured by quantitative DAPI and Hoechst 33258 fluorescence in situ hybridization on interphase nuclei. The conventional mitogen-stimulated blood lymphocyte culture development was performed in metaphase chromosomes and interphase nuclei assay. The light and fluorescent cytomorphological microscopy was performed. The model 5-azacytidine induced DNA demethylation results in increased DNA hyperploidy accompanying major pericentromeric heterochromatin (Alu) DNA repeats amplification similar to those during DNA hypomethylation-associated cancer events, and both contributed to nuclear heteropycnosis development. The constitutive pericentromeric heterochromatin consequent morphological disturbance to the latent polytene chromomerization and heteropycnosis development both in cancer patients and in model 5-azacytidine exposured lymphocytes are associated with DNA hypomethylation. We have observed that the induced global DNA hypomethylation triggers dis-epigenetic morphological reprogramming of constitutive pericentromeric heterochromatin on the extrachromosomal organization pathway as seen during the heterochromatin latent polytene features development, which is of importance as one of the mechanism involving DNA hypomethylation in initiation and progression of cancer.


Biclonal Gammopathy in Chronic Lymphocytic Leukemia: Case Report and Review of the Literature.
Monoclonal gammopathies are frequently seen in B-cell malignancies. Monoclonal proteins are seen in a significant proportion of patients with chronic lymphocytic leukemia (CLL), which is a clonal disorder of mature B cells. The use of more sensitive laboratory methods has enabled the detection of monoclonal proteins or light chains in the serum and/or urine in the majority of these patients. The presence of some of these monoclonal proteins may explain the different autoimmune phenomena that are associated with this disease. Some reports indicate that the finding of monoclonal proteins has a negative impact on patients' survival. The presence of two different monoclonal proteins (i.e. biclonal gammopathy) is on the other hand rare. Most of the reported cases in the literature are of patients with plasma cell disorders. In this report, we describe a rare occurrence of biclonal gammopathy in a patient with CLL. Serum protein electrophoresis and immunofixation, which were negative at the time of initial diagnosis, showed biclonal immunoglobin A (IgA) kappa and IgA lambda during the course of the disease. The patient's disease showed steady progression, despite multiple treatments. Although this could just be the result of using more sensitive laboratory techniques, biclonal gammopathy in this patient likely reflects the evolution of another clone, which would explain the encountered resistance to therapy. Because of paucity of reports, the impact of biclonal gammopathies in such patients is not known and an effort to collectively report the presentation and outcome of these patients is needed to further understand the pathophysiology and clinical significance of such a finding.


Signal detection theory applied to three visual search tasks--identification, yes/no detection and localization.
Adding distracters to a display impairs performance on visual tasks (i.e. the set-size effect). While keeping the display characteristics constant, we investigated this effect in three tasks: 2 target identification, yes-no detection with 2 targets, and 8-alternative localization. A Signal Detection Theory (SDT) model, tailored for each task, accounts for the set-size effects observed in identification and localization tasks, and slightly under-predicts the set-size effect in a detection task. Given that sensitivity varies as a function of spatial frequency (SF), we measured performance in each of these three tasks in neutral and peripheral precue conditions for each of six spatial frequencies (0.5-12 cpd). For all spatial frequencies tested, performance on the three tasks decreased as set size increased in the neutral precue condition, and the peripheral precue reduced the effect. Larger set-size effects were observed at low SFs in the identification and localization tasks. This effect can be described using the SDT model, but was not predicted by it. For each of these tasks we also established the extent to which covert attention modulates performance across a range of set sizes. A peripheral precue substantially diminished the set-size effect and improved performance, even at set size 1. These results provide support for distracter exclusion, and suggest that signal enhancement may also be a mechanism by which covert attention can impose its effect.


Analysis of the mechanisms of idiopathic scoliosis progression using finite element simulation.
The mechanisms of idiopathic scoliosis progression are still not fully understood. The aim of this study is to explore, using finite element simulation, effect of the combination of gravity and anterior spinal overgrowth on scoliosis progression. 14 adolescents (10 girls, 4 boys) with an average age of 10.8 years [range 9; 13] were divided in three groups: thoraco-lumbar scoliosis (TL), lumbar scoliosis (L), asymptomatic patients (A). Accurate 3D reconstructions of the spine have been built using bi-planar X-rays. A patient specific validated finite element model has been used. Simulations have been launched with simulation of the combined effect of gravity and growth. The progression during the simulation was defined by a maximal axial rotation movement greater or equal than 4 degrees and a maximal lateral displacement greater or equal than 5 mm ("first order progression" for one criterion, "second order" for the both criteria). In the group TL, we notice an aggravation for 4 patients (Cobb angle increase at least by 4 degrees , mean at 5.9 degrees ). Only three patients of the group L show a progression with a smaller Cobb angle increase (mean 3.9 degrees ). For the group A, no progression is found for 3 and a progression is found for 1. An anterior spinal overgrowth combined with gravity and a pre-existent curve in the spine could lead to a progression of scoliosis. It seems necessary to consider differently lumbar curves from other curves. Numerical simulation with a patient specific model appears as a useful tool to investigate mechanisms of scoliosis aggravation.


Autism and the double empathy problem: Implications for development and mental health.
This article proposes a link between autistic people being misperceived by the neurotypical majority and their being at risk of poor mental health and well-being. We present a transactional account of development in which the misperceptions (and consequent behaviour) of the neurotypical majority influences the perceptions and behaviour of autistic people such that they become increasingly separate and indeed isolated from mainstream society. This jeopardizes their mental health and prevents autistic people from developing to full potential. The situation is not only problematical for the development of autistic people but is also to the detriment of wider society, in so far as autistic people are effectively prevented from contributing fully. This account assumes that some (not necessarily all) autistic people yearn to be included, to be productive and to be useful. It thus directly opposes accounts that view autism as an extreme case of diminished social motivation.


A hepatitis B virus-derived human hepatic cell-specific heparin-binding peptide: identification and application to a drug delivery system.
Viruses are naturally evolved nanocarriers that can evade host immune systems, attach specifically to the surfaces of target cells, enter the cells through endocytosis, escape from endosomes efficiently, and then transfer their genomes to host cells. Hepatitis B virus (HBV) is a ∼42 nm enveloped DNA virus that can specifically infect human hepatic cells. To utilize the HBV-derived early infection machinery in synthetic nanocarriers, the human hepatic cell-binding site (i.e., the sodium taurocholate co-transporting polypeptide (NTCP)-binding site, with myristoylated pre-S1(2-47)) and the low pH-dependent fusogenic domain (pre-S1(9-24)) are indispensable for targeting and endosomal escape, respectively. However, cell-surface NTCP has recently been shown not to be involved in the initial attachment of HBV. In this study, we identified a novel heparin-binding site (pre-S1(30-42)) in the N-terminal half of the pre-S1 region, which presumably interacts with cell-surface heparan sulfate proteoglycan (HSPG) and plays a pivotal role in the initial attachment of HBV to human hepatic cells. The evolutionarily conserved amino acid residues Asp-31, Trp-32, and Asp-33 are indispensable for the heparin-binding activity. Liposomes (LPs) displaying the peptide were endocytosed by human hepatic cells in a cell-surface heparin-dependent manner and delivered doxorubicin to human hepatic cells more efficiently than myristoylated pre-S1(2-47)-displaying LPs. These results demonstrated that the pre-S1(30-42) peptide is the most promising HBV-derived targeting peptide for synthetic nanocarriers, and that this peptide exhibits high specificity for human hepatic cells and efficiently induces endocytosis.


Pelvic ring disruptions with symphysis pubis diastasis. Indications, technique, and limitations of anterior internal fixation.
The management of disruption of the pelvic ring is both complex and controversial. Twenty-four injuries associated with symphysis pubis diastasis were reviewed to evaluate a two-hole plate technique of anterior internal fixation as compared to four-hole plate anterior fixation. The two-hole plate technique appears to be quite acceptable for maintaining reduction of the diastasis and therefore can be used to manage most anteroposterior compression injuries (those without complete posterior disruption). Vertical shear injuries, all of which are grossly unstable, can also be managed with anterior two-hole plates. However, this fixation method must be supplemented with some form of posterior stabilization to maintain pelvic ring reduction.