Electrocardiographic changes following intravenous administration of thioridazine to macaque monkeys.
Treatment with thioridazine has been associated with electrocardiographic abnormalities, and there are individual case reports of fatal cardiac arrhythmias in patients taking thioridazine. Thioridazine or its metabolites can cause T-wave changes, but there is no evidence for a causal relationship between exposure to thioridazine and the occurrence of arrhythmias. In this study, the authors administered up to 6.7 mg/kg of thioridazine intravenously to macaque monkeys. Two of the animals had minimal T-wave changes immediately after the thioridazine injections and premature ventricular contractions a week later. The premature beats disappeared immediately after the next injection of thioridazine was administered. The authors suggest that when thioridazine has minimal effects on the T-wave, it may have both antiarrhythmic and arrhythmic activity. This could explain why cardiac arrhythmias have not been demonstrated in patients receiving regular, frequent doses of thioridazine, and suggests that arrhythmias may occur more frequently in patients with minimal T-wave changes.


Adolescents' Sexual Encounters With Either Romantic or Casual Partners and the Quality of Their Romantic Relationships Four Years Later.
Adolescent sexual behavior was examined within a health perspective. Assuming a developmental perspective, the current study investigated the associations between sexual behavior in either stable relationships or in casual encounters, and the quality of romantic relationships and affect 4 years later. Data were collected from 144 Israeli adolescents aged 16-18 years (mean age 16.57 years). Participants completed diary data over a period of 10 days and reported on the quality of their romantic encounters and their emotions, and on their sexual behavior in stable relationships or casual encounters. Four years later, they were asked to complete diary data again for 10 consecutive days and report on the quality of their romantic relationships and their positive and negative affect. Findings indicate that involvement in sexual behavior in stable romantic relationships was associated only with future romantic partner support. In contrast, earlier involvement in casual sexual behavior was associated with a number of future indices: lower partner support, greater negative affect as well as greater relationship tension, and dyadic hurtful behavior 4 years later. The differential role of sexuality within a stable relationship or casual encounters among adolescents for their future romantic development is discussed within a developmental framework.


Classification of fall risk across the lifespan using gait derived features from a wearable device.
Falls are one of the leading factors of injury and fatality in older adults. Given the importance of early detection of adults at higher risk of falls, we evaluated the ability of machine learning to classify fall risk in adults across the lifespan using wearable sensors embedded in a smartshirt. We evaluated the classification performance of binary and multiclass fall risk classifier models using SciKit Digital Health in adults across the lifespan. Using a k-fold and group k-fold cross-validation strategy, we demonstrate the feasibility of fall risk classification using accelerometer data from 10 second epochs of treadmill walking data from adults across the lifespan. We achieved an 88% accuracy in a binary clasifier of fallers vs. non-fallers, and an 86% accuracy in a multiclass classifier comparing non-fallers, fallers, and recurrent fallers using retrospective fall histories. Comparing group k-fold vs. k-fold cross-validation strategies, we find a 22-27% drop-off in accuracy performance. Furthering the evaluation framework presented in this study would be valuable to the development of more robust and clinically relevant models used in the prediction of fall risk. These models could one day be applied in clinical settings to help better diagnose and monitor fall risk among older adults, improving the care of at-risk individuals and reducing the injury and associated cost of falls.


No small slam: increasing incidents of genitourinary injury from toilets and toilet seats.
To describe the epidemiology of genitourinary (GU) injury from toilets that present to USA Emergency rooms (ERs). The National Electronic Injury Surveillance System (NEISS) is a stratified probability sample of hospital ER visits for USA consumer product-related injuries. NEISS was used to estimate total toilet- and toilet seat-related GU injury for the years 2002-2010, as well as to describe demographics and injury characteristics. Analyses were performed using strata, primary sampling units and sample weights to accommodate the complex sample survey design. Data are reported as national estimates with 95% confidence intervals (CIs) provided. In all, 13 175 (95% CI 10 185-16 165) GU injuries related to toilets presented to ERs during 2002-2010. The most common mechanism involved crush from accidental fall of toilet seat, described in 9011 (68.4%, 95% CI 6907-11 115) cases. Most crush injuries were isolated to the penis (98.1%). Of crush injuries, 81.7% occurred in children aged 2-3 years and 99.3% occurred in the home. Crush injuries increased over the period 2002-2010 (P = 0.017) by ≈100 per year, ending with an estimated 1707 (95% CI 1011-2402) by 2010. Most patients who sustained toilet- and toilet seat-related GU injuries were treated in the ER and then discharged. While penile crush injury related to a toilet seat is an uncommon mechanism of urological injury in children, the number of incidents appears to be rising. These findings support educational efforts and interventions, such as exchange of heavy toilet seats with slow-close toilet seat technology.


Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact?
Differentiation of stem cells toward a neuronal lineage normally involves a gradually progressive restriction in developmental potential and is regulated by a diverse set of specific and temporally precise genetic events. However, recent studies have indicated that both rodent and human bone marrow stromal cells (MSCs) can be rapidly (within minutes to hours) induced to differentiate into neurons in vitro by relatively simple chemical means (using beta-mercaptoethanol [BME] or dimethylsulfoxide [DMSO] and butylated hydroxyanisol [BHA]; Woodbury et al. [ 2000] J. Neurosci. Res. 61:364-370). The ability to transdifferentiate an easily accessible cell source into neurons could have substantial potential for promoting neural repair. We therefore explored the potential of simple chemical methods to transdifferentiate other cell types, including primary rat fibroblasts, primary human keratinocytes, HEK293 cells, rat PC-12 cells, and as positive control rat bone marrow stromal (BMS) cells. Surprisingly, all cells except for keratinocytes adopted at least partial "neuron-like" pyramidal cell morphology with fine-cellular extensions resembling neurites upon stimulation with BME or DMSO/BHA. However, time-lapse microscopy indicated that the chemical exposure of MSCs did not result in new neurite growth but rather cellular shrinkage, with retraction of the majority of existing cell extensions, leaving only few, fine neurite-like processes. To determine whether the chemically induced transdifferentiation resulted from simple cellular toxicity, MSCs were exposed to various stressors, including detergents, high-molarity sodium chloride, and extremes of pH. In all cases, cellular shrinkage and adoption of pseudoneuronal morphology were observed. Concomitantly with cellular shrinkage, apparent increases in immunolabeling for the neuronal markers NSE and NeuN were detected in the cell soma that could not be confirmed by RT-PCR. Furthermore, blockade of protein synthesis with cycloheximide did not prevent cells from adopting "neuron-like" morphology after chemical induction. Thus, morphological changes and increases in immunolabeling for certain cellular markers upon "chemical induction" of MSCs are likely the result of cellular toxicity, cell shrinkage, and changes in the cytoskeleton and do not represent regulated steps in a complicated cellular differentiation process.


Adverse effects of amantadine and oseltamivir used during respiratory outbreaks in a center for developmentally disabled adults.
Antiviral prophylaxis is recommended for the control of institutional influenza A outbreaks. In long-term-care institutions other than nursing homes, neither the seriousness of influenza nor the risks and benefits of antiviral prophylaxis is clearly understood. We studied the severity of illness due to influenza among adults residing in a center for the developmentally disabled and assessed adverse reactions to amantadine and oseltamivir prophylaxis. Data were collected from the charts of consenting residents. Complications of upper respiratory tract illness were recorded. Potential adverse events were documented during amantadine and oseltamivir therapy, and during a baseline period with neither medication. The median age of the 287 participants was 46.4 years. Only 15 (5%) were older than 65 years, and 69 (24%) had chronic underlying medical illness placing them at high risk for influenza. Of the 122 residents with an upper respiratory tract infection, 16 (13%) developed pneumonia, 12 (9.8%) were hospitalized, and 5 (4%) died. Twenty-eight (25%) of 112 residents had an adverse neurologic event while receiving amantadine prophylaxis, compared with 3 (2.7%) receiving no antiviral medication and 5 (4.5%) receiving oseltamivir (P < .001). Sixteen percent of the residents discontinued amantadine due to adverse events; in contrast, adverse events were identified in 2.9% of the residents prescribed oseltamivir, and none discontinued therapy. Viral respiratory tract infections are associated with a high risk of complications in this population. The rate of adverse neurologic events associated with amantadine was significantly higher than that associated with oseltamivir.


Evaluation of Meropenem-Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance.
Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.


Carotid artery dissections: thrombosis of the false lumen.
Carotid artery dissections are the second leading cause of stroke in young adults. The hemostatic response to a dissection involves exposure of the subendothelium to the intravascular environment. Platelet activation/aggregation superimposed by secondary coagulation cascade activity attempts to heal the injury. Failure of the hemostatic response to heal the injury may lead to further rupture of the intimal and medial layers, which allows for the blood to penetrate these layers to create a false lumen. Continued hemorrhaging into the false lumen may result in dissection progression or obstruction of blood supply to the true lumen and downstream blood vessels. The effects of thrombosis in the true versus false lumen may lead to opposite consequences. True lumen clotting may lead to ischemic complications of downstream cerebral vasculature, whereas false lumen clotting may lead to dissection healing. Current information on clinical outcomes and degree of false lumen clotting in a carotid dissection model is limited, and most of the available information on this controversial topic has been inferred from aortic dissections. Therefore in this report we summarize the present state of knowledge of the pathophysiology, detailed hemostatic response to the injury, clinical presentation and treatment of carotid dissections. We also emphasize the need for future studies to investigate the degree of false lumen clotting on the clinical outcomes of carotid dissections.


Importance of Extraintestinal Manifestations in Early Diagnosis of Gardner Syndrome.
Gardner's syndrome is an autosomal dominant disease caused by a mutation in the APC gene with 20-30% of cases presenting de novo. This entity is a variant of familial adenomatous polyposis, with a prevalence of 3/100,000 habitants. It may present as early as 2 months of age with a variety of both colonic and extracolonic symptoms. We report a case of a 21-year-old man, without any known family history, presenting with microcytic hypochromic anemia and constitutional symptoms for two months. Ultimately, after the etiological study, Gardner syndrome diagnosis was established as an index primary familiar case. Gardner syndrome is a clinical challenge which requires a prompt suspicion in order to reach its diagnosis. Given the malignant evolution of adenomas in 100% of untreated patients, early identification of extraintestinal manifestations (identifiable prior to colonic symptoms) is of the essence. A consequent endoscopic study to confirm gastrointestinal involvement is essential for a more favorable prognosis.


Effects of the axis of rotation and primordially solicited limb of high level athletes in a mental rotation task.
A recent set of studies has investigated the selective effects of particular physical activities that require full-body rotations, such as gymnastics and wrestling (Moreau, Clerc, Mansy-Dannay, & Guerrien, 2012; Steggemann, Engbert, & Weigelt, 2011), and demonstrated that practicing these activities imparts a clear advantage in in-plane body rotation performance. Other athletes, such as handball and soccer players, whose activities do require body rotations may have more experience with in-depth rotations. The present study examined the effect of two components that are differently solicited in sport practices on the mental rotation ability: the rotation axis (in-plane, in-depth) and the predominantly used limb (arms, legs). Handball players, soccer players, and gymnasts were asked to rotate handball and soccer strike images mentally, which were presented in different in-plane and in-depth orientations. The results revealed that handball and soccer players performed the in-depth rotations faster than in-plane rotations; however, the two rotation axes did not differ in gymnasts. In addition, soccer players performed the mental rotations of handball strike images slower. Our findings suggest that the development of mental rotation tasks that involve the major components of a physical activity allows and is necessary for specifying the links between this activity and the mental rotation performance.


A new superfamily of cell surface proteins related to the nerve growth factor receptor.
In this article Susan Mallett and Neil Barclay discuss the molecular and functional features of a new superfamily of membrane proteins defined by the presence of cysteine-rich motifs originally identified in the low-affinity nerve growth factor receptor. This superfamily includes two lymphocyte proteins of unknown function and two receptors for tumor necrosis factor.


Mitigation of epidermal growth factor receptor inhibitor-induced side effects utilizing melanin and vascular-specific lasers: A case report series.
The advent of targeted chemotherapy has led to the emergence of new dermatologic toxicities. We sought to use lasers and light devices to treat recalcitrant cutaneous adverse effects related to cancer treatment. Three stage III or IV cancer patients with cutaneous complications due to epidermal growth factor receptor (EGFR) inhibitors were treated with melanin and vascular-specific laser and light technologies. Two patients reported reduction in papulopustular eruption following pulse dye laser (PDL) treatment. Two patients noted reduction in hair growth following intense pulsed light (IPL) and/or Alexandrite laser treatments. One patient was treated with both the PDL and IPL and reported improvement of both EGFR-induced hypertrichosis and papulopustular eruption. Laser and light devices targeting melanin and hemoglobin can be utilized to mitigate the cutaneous adverse effects associated with EGFR inhibitors in patients who have failed traditional therapies. This represents a new option for the cancer patient who is suffering from chemotherapy-induced side effects.


Psychiatric symptoms in adults with phenylketonuria.
The objective of this study was to identify psychiatric symptom patterns reported by individuals with phenylketonuria (PKU) in the outpatient clinic setting. Brief Symptom Inventory (BSI) results, phenylalanine (phe) levels, and demographic information were collected through a retrospective chart review on 64 participants in the study, "A Diversified Approach for PKU Treatment" (ADAPT). The number of BSI scores meeting clinical threshold was significantly elevated for all global indexes and 6 out of 7 symptom subscales in patients with PKU. Recent and mean phe levels were correlated with age at the time of screening (R(2)=0.10, R(2)=0.10, respectively; p<0.05). Psychoticism and the Positive Symptom Distress Index (PSDI) scores were associated with metabolic control. The results of this study demonstrate a positive correlation between phe levels and psychiatric symptom severity in individuals with PKU.


[Discrepancies between verbal information and the records in pregnant woman card, a neglected instrument].
To compare the filling out of the prenatal care card of pregnant women at a school-service and other services, as well as to verify the concordance between these records and verbal information provided by the puerperae. A two-stage epidemiological, cross-sectional study was performed with stratified sampling, proportional to number of births. In the first stage, the information recorded on the prenatal care card in the school-service was compared to that recorded in units not linked to higher health education in Recife (PE). In the second stage, the information about prenatal care was collected with a semi-structured questionnaire applied to women during the puerperal period. A total of 262 puerperae older than 19 years, who had a prenatal care card at the time of delivery were included in the study from May to July 2008. Data were analyzed statistically by the χ(2) test, Student's t-test or Mann-Whitney test, all one-sided to the right, with the level of significance set at 5%. The information more often recorded on the prenatal care card in the school-service was: schooling (86.5 versus 70.3%; p=0.002), marital status, (83.7 versus 70.9%; p=0.01), weight prior to pregnancy (72.1 versus 46.8%; p<0.001), height (62.5 versus 45.6%; p=0.007), and educational practices (76.9 versus 11.4%; p<0.001) and, at other services, only birth weight <2,500 g (15.4 versus 27.2% at the school-service; p=0.02). There were significant discrepancies between data obtained by verbal information and the prenatal care records of the pregnant women. At the school-service, 40.3% of pregnant women received adequate prenatal care versus 20.3% at other units. In all services, there was a predominance of recorded information directly related to delivery, while information about actions with preventive characteristics during prenatal care was neglected.


MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma.
Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance. Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC. Expert opinion: Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance, MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.


Diversity of deep-water cetaceans in relation to temperature: implications for ocean warming.
Understanding the effects of natural environmental variation on biodiversity can help predict response to future anthropogenic change. Here we analyse a large, long-term data set of sightings of deep-water cetaceans from the Atlantic, Pacific and Indian Oceans. Seasonal and geographic changes in the diversity of these genera are well predicted by a convex function of sea-surface temperature peaking at c. 21 degrees C. Thus, diversity is highest at intermediate latitudes - an emerging general pattern for the pelagic ocean. When applied to a range of Intergovernmental Panel on Climate Change global change scenarios, the predicted response is a decline of cetacean diversity across the tropics and increases at higher latitudes. This suggests that deep-water oceanic communities that dominate > 60% of the planet's surface may reorganize in response to ocean warming, with low-latitude losses of diversity and resilience.


Implantable cardiac pacemaker electromagnetic compatibility testing in a novel security system simulator.
This paper describes a novel simulator to perform electromagnetic compatibility (EMC) tests for active implantable medical devices (AIMDs) with electromagnetic fields emitted by security systems. The security system simulator was developed in response to over 100 incident reports over 17 years related to the interference of AIMD's with security systems and the lack of a standardized test method. The simulator was evaluated regarding field homogeneity, signal distortion, and maximum magnetic field strength levels. Small three-axis probes and a three-axis scanning system were designed to determine the spatial and temporal characteristics of the fields emitted by 12 different types of walk through metal detectors (WTMDs). Tests were performed on four implanted pacemakers with a saline phantom and correlated to a newly developed test method performed "in air" (without the phantom). Comparison of the simulator thresholds with tests performed in real WTMDs showed that the simulator is able to mimic the pacemaker interference. The interference thresholds found in the simulator indicate that pulsed magnetic fields are more likely to cause interference in pacemakers than sinusoidal fields. The security system simulator will help biomedical engineers, manufacturers of medical devices, and manufacturers of security systems to identify incompatible combinations of WTMDs and AIMDs early in the development stage.


An automatic CT-guided adaptive radiation therapy technique by online modification of multileaf collimator leaf positions for prostate cancer.
To propose and evaluate online adaptive radiation therapy (ART) using in-room computed tomography (CT) imaging that detects changes in the target position and shape of the prostate and seminal vesicles (SVs) and then automatically modifies the multileaf collimator (MLC) leaf pairs in a slice-by-slice fashion. For intensity-modulated radiation therapy (IMRT) using a coplanar beam arrangement, each MLC leaf pair projects onto a specific anatomic slice. The proposed strategy assumes that shape deformation is a function of only the superior-inferior (SI) position. That is, there is no shape change within a CT slice, but each slice can be displaced in the anteroposterior (AP) or right-left (RL) direction relative to adjacent slices. First, global shifts (in SI, AP, and RL directions) were calculated by three-dimensional (3D) registration of the bulk of the prostate in the treatment planning CT images with the daily CT images taken immediately before treatment. Local shifts in the AP direction were then found using slice-by-slice registration, in which the CT slices were individually registered. The translational shift within a slice could then be projected to a translational shift in the position of the corresponding MLC leaf pair for each treatment segment for each gantry angle. Global shifts in the SI direction were accounted for by moving the open portal superiorly or inferiorly by an integral number of leaf pairs. The proposed slice-by-slice registration technique was tested by using daily CT images from 46 CT image sets (23 each from 2 patients) taken before the standard delivery of IMRT for prostate cancer. A dosimetric evaluation was carried out by using an 8-field IMRT plan. The shifts and shape change of the prostate and SVs could be separated into 3D global shifts in the RL, AP, and SI directions, plus local shifts in the AP direction, which were different for each CT slice. The MLC leaf positions were successfully modified to compensate for these global shifts and local shape variations. The ART method improved geometric coverage of the prostate and SVs compared with the couch-shift method, particularly for the superior part of the prostate and all the SVs, for which the interfraction shape change was the largest. The dosimetric comparison showed that the ART method covered the target better and reduced the rectal dose more than a simple couch-translation method. ART corrected for interfraction changes in the position and shape of the prostate and SVs and gave dose distributions that were considerably closer to the planned dose distributions than could be achieved with simple alignment strategies that neglect shape change. The ART proposed in this investigation requires neither contouring of the daily CT images nor extensive calculations; therefore, it may prove to be an effective and clinically practical solution to the problem of interfraction shape changes.


Using Rasch modeling to re-evaluate three scales related to physical activity: enjoyment, perceived benefits and perceived barriers.
Studies suggest that enjoyment, perceived benefits and perceived barriers may be important mediators of physical activity. However, the psychometric properties of these scales have not been assessed using Rasch modeling. The purpose of this study was to use Rasch modeling to evaluate the properties of three scales commonly used in physical activity studies: the Physical Activity Enjoyment Scale, the Benefits of Physical Activity Scale and the Barriers to Physical Activity Scale. The scales were administered to 378 healthy adults, aged 25-75 years (50% women, 62% Whites), at the baseline assessment for a lifestyle physical activity intervention trial. The ConQuest software was used to assess model fit, item difficulty, item functioning and standard error of measurement. For all scales, the partial credit model fit the data. Item content of one scale did not adequately cover all respondents. Response options of each scale were not targeting respondents appropriately, and standard error of measurement varied across the total score continuum of each scale. These findings indicate that each scale's effectiveness at detecting differences among individuals may be limited unless changes in scale content and response format are made.


Preliminary observations on the pathogenesis of experimental bovine spongiform encephalopathy (BSE): an update.
Further preliminary observations are reported of an experiment to examine the spread of infectivity and the occurrence of pathological changes in cattle exposed orally to infection with bovine spongiform encephalopathy. Calves were dosed at four months of age and clinically monitored groups were killed sequentially from two to 40 months after inoculation. Tissues were collected for bioassay, for histopathological examinations and for the detection of PrP. Previous reported observations have included the presence of infectivity in the distal ileum of cattle killed after six to 18 months, the earliest onset of clinical signs in an exposed animal after 35 months, and diagnostic histopathological changes in the brain, in association with clinical disease, after 36, 38 and 40 months. In spite of the relative inefficiency of the bioassay of scrapie-like agents across a species barrier the new observations confirm that the onset of clinical signs and pathological changes in the central nervous system (CNS) occur at approximately the same time. The earliest pathological change, the presence of abnormal PrP 32 months after inoculation, coincided with the earliest detected infectivity in the CNS and occurred shortly before there was evidence of typical spongiform changes in the brain 36 months after inoculation. Infectivity has now been demonstrated in the peripheral nervous system, in the cervical and thoracic dorsal root ganglia 32 to 40 months after inoculation and in the trigeminal ganglion 36 and 38 months after inoculation. At the time of writing evidence of infectivity in other tissues is confined to the distal ileum, not only after six to 18 months but also after 38 and 40 months, but these findings may be supplemented by the results of further mouse assays. Nevertheless, they are in general agreement with current knowledge of the pathogenesis of scrapie.


A review of oral transmucosal fentanyl citrate: potent, rapid and noninvasive opioid analgesia.
The physiochemical characteristics of the potent synthetic opioid agonist fentanyl make it ideal for noninvasive transmucosal delivery. Studies of oral transmucosal fentanyl citrate (OTFC), a candied matrix formulation administered orally as a palatable lozenge on a stick, have investigated and determined this analgesic's pharmacokinetics and pharmacodynamics in a number of clinical settings, including premedication before surgery, acute analgesia for painful medical procedures, and, most recently, for the control of breakthrough cancer pain. The onset to meaningful pain relief in patients with acute pain from surgery or breakthrough pain from cancer is between 5 and 10 minutes after initiating OTFC use, equivalent to intravenous morphine. Analgesic dose equivalency studies suggest that OTFC is, on average, about 10 times more potent than morphine, although, in randomized, controlled, and blinded studies, many patients who were using relatively high doses of opioid anlagesics on an around the- clock schedule for control of cancer pain reported that even a low dose of OTFC (i.e., 200 microg) provided adequate relief from breakthrough pain. Side effects from OTFC are similar in character and frequency to other opioids, including sedation, nausea, and pruritus. These effects appear to wane rapidly with repeated use of this medication. To date there have been no reported serious adverse events in any of the population groups studied or treated with OTFC.


Dynamics of demographically open mutualists: immigration, intraspecific competition, and predation impact goby populations.
Although it is now recognized that mutualistic species are common and can have stable populations, the forces controlling their persistence are poorly understood. To better understand the mechanisms that impact the stability of obligate mutualists, I conducted several field experiments within a sandy coral reef lagoon in Moorea, French Polynesia that manipulated densities of fish (gobies) that interact mutualistically with shrimp. Obligate, mutualistic partnerships of gobies and shrimp are common on Indo-Pacific coral reefs and have been shown previously to interact as follows: shrimp construct burrows in which both species reside, and gobies warn shrimp of predators through tactile communication. Augmentation of gobies by up to 100% above ambient densities within 9 m2 plots produced no change in overall density of gobies or shrimp because gobies competed intraspecifically for a limited number of shrimp burrows and smaller gobies were outcompeted by larger individuals. I used predators to assess the impact of goby removal on the stability of goby and shrimp populations. First, although surveys taken throughout the lagoon revealed no relationship between goby and predator densities, predators correlated negatively with the proportion of adult gobies and positively with the proportion of small gobies paired with large shrimp. Second, experimental augmentation of predators resulted in a dramatic reduction of adult gobies within predator-addition plots, but had no impact on overall densities as immigrants rapidly replaced the missing adult gobies. Furthermore, goby turnover resulted in an increase in the proportion of small gobies paired with large shrimp because body sizes of gobies and shrimp in a burrow were similar prior to predator introduction, and predators apparently had a greater impact on gobies than shrimp. The mechanisms that prevent expansion (intraspecific competition) and collapse (immigration) of goby-shrimp populations likely contribute to local-scale stability of mutualistic populations in other terrestrial and aquatic environments.


[The role of adherent cells in supporting natural cytotoxicity reactions].
The cytotoxic activity of natural killer (NK) cells and interferon-alpha (IFN-alpha) production by NK cells were studied. It was shown that in healthy donors adherent cells (AC) play an important role in reactions of natural cytotoxicity: they provide the main IFN production in the NK system. AC suppresses the cytotoxic activity of NK cells in patients with scleroderma and AC has a high cytotoxic activity in patients with multiple sclerosis. The role of AC in appearance and development of NK immunodeficiency in these pathologies was discussed.


Laser-induced graphene on cross-linked sodium alginate.
Laser-induced graphene (LIG) possesses desirable properties for numerous applications. However, LIG formation on biocompatible substrates is needed to further augment the integration of LIG-based technologies into nanobiotechnology. Here, LIG formation on cross-linked sodium alginate is reported. The LIG is systematically investigated, providing a comprehensive understanding of the physicochemical characteristics of the material. Raman spectroscopy, scanning electron microscopy with energy-dispersive X-ray analysis, X-ray diffraction, transmission electron microscopy, Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy techniques confirm the successful generation of oxidized graphene on the surface of cross-linked sodium alginate. The influence of laser parameters and the amount of crosslinker incorporated into the alginate substrate is explored, revealing that lower laser speed, higher resolution, and increased CaCl2 content leads to LIG with lower electrical resistance. These findings could have significant implications for the fabrication of LIG on alginate with tailored conductive properties, but they could also play a guiding role for LIG formation on other biocompatible substrates.


Incidence of intraoperative hypotension in older patients undergoing total intravenous anesthesia by remimazolam versus propofol: A randomized controlled trial.
An increase in the frequency of surgeries among older individuals is observed in some countries. Hypotension is common and exaggerated in older patients and can lead to increased morbidity and mortality. Total intravenous anesthesia is commonly administered with propofol, while remimazolam has been suggested as an alternative to propofol because of advantages such as a more stable hemodynamic profile and less respiratory suppression. We conducted a single-blind, parallel-group randomized controlled trial to compare the incidence of intraoperative hypotension between patients administered with remimazolam and propofol. A total of 132 patients, aged between 65 to 80 years and undergoing laparoscopic cholecystectomy or transurethral resection of bladder tumors were randomly assigned to the propofol or remimazolam group with a permuted block system while being blinded to the hypnotic agent. Remifentanil was administered via target-controlled infusion in both groups, with an initial effect-site concentration of 3.0 ng/mL and titration range of 1.5 to 4.0 ng/mL intraoperatively. The primary outcome of this study was the overall incidence of hypotension during general anesthesia. Patients in the propofol group experienced higher intraoperative hypotension than those in the remimazolam group (59.7% vs 33.3%, P = .006). Multivariate logistic regression analysis showed that remimazolam administration was associated with reduced hypotension (adjusted odds ratio, 0.34; 95% CI, 0.16-0.73). Secondary outcomes such as recovery time, delirium, and postoperative nausea and vomiting were comparable in both groups. Total intravenous anesthesia with remimazolam was associated with less intraoperative hypotension than propofol in older patients, with a comparable recovery profile.


High-Content Analysis--CHI's Seventh Annual Conference--Flow Cytometry in Drug Discovery and Development.
CHI's Seventh Annual Conference on High-Content Analysis, held in San Francisco, included topics covering new developments in the field, including advances in flow cytometry. This conference report highlights selected presentations on strategies to use higher content in flow cytometry as well as tools to enable high content, including mass spectrometry, surface-enhanced Raman scattering (SERS) and hyperspectral analysis. Very high-throughput systems are also discussed.


Volume-sensitive outwardly rectifying chloride channel in white adipocytes from normal and diabetic mice.
The volume-sensitive outwardly rectifying (VSOR) chloride channel is ubiquitously expressed and involved in cell volume regulation after osmotic swelling, called regulatory volume decrease (RVD), in various cell types. In adipocytes, the expression of the VSOR channel has not been explored to date. Here, by employing the whole-cell patch-clamp technique, we examined whether or not the VSOR channel is expressed in white adipocytes freshly isolated from epididymal fat pads of normal (C57BL/6 or KK) and diabetic (KKA(y)) mice. Whole cell voltage-clamp recordings revealed that Cl(-) currents were gradually activated upon cell swelling induced by application of a hypotonic solution, both in normal and diabetic adipocytes. Although both the mean cell size (or cell capacitance) and the current magnitude in KKA(y) adipocytes were larger than those in C57BL/6 cells, the current density was significantly lower in KKA(y) adipocytes (23.32 +/- 1.94 pA in C57BL/6 adipocytes vs. 13.04 +/- 2.41 pA in KKA(y) adipocytes at +100 mV). Similarly, the current density in diabetic KKA(y) adipocytes was lower than that in adipocytes from KK mice (a parental strain of KKA(y) mice), which do not present diabetes until an older age. The current was inhibited by Cl(-) channel blockers, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and glibenclamide, or hypertonic solution, and showed outward rectification and inactivation kinetics at large positive potentials. These electrophysiological and pharmacological properties are consistent with those of the VSOR channel in other cell types. Moreover, adipocytes showed RVD, which was inhibited by NPPB. In KKA(y) adipocytes, RVD was significantly slower (tau; 8.42 min in C57BL/6 adipocytes vs. 11.97 min in KKA(y) adipocytes) and incomplete during the recording period (25 min). It is concluded that the VSOR channel is functionally expressed and involved in volume regulation in white adipocytes. RVD is largely impaired in adipocytes from diabetic mice, presumably as a consequence of the lower density of the functional VSOR channel in the plasma membrane.


Choroidal neovascularization not associated with age-related macular degeneration.
Choroidal neovascularization (CNV) is an important clinical finding that is associated with many ocular conditions, including inflammatory, infectious, degenerative, hereditary, and congenital disorders, ocular tumors, trauma, and a few miscellaneous disorders. The growth of new choroidal vessels beneath the retinal pigment epithelium is associated with specific clinical signs. The clinical recognition of CNV plays a key role in the prognosis and management of these disorders. The clinical presentation of each disorder associated with CNV is reviewed in this paper, with comments on the location and the frequency of CNV occurrence.


An efficient safety system for radiotherapy treatment rooms to prevent accidental exposure of personnel.
A safeguard system is described which minimizes the hazard of accidental exposure of radiotherapy and servicing staff. Upon entrance of the treatment room, each person other than the patient has to take a safety card from a box. After patient set-up, the radiation beam cannot be turned on unless all cards are properly returned to the box. Unlike the commonly used interlocks, which do not actually check the treatment area for unnoticed occupancy, the current system inhibits the radiation beam until every user has left. The issue of personal responsibility is clear-cut: people who use the safeguard system correctly are fully protected against accidental irradiation while anyone who disregards it is held responsible for possible self-exposure. This unambiguous message is contained in the concise instructions posted above the card box. A resetting procedure has been incorporated that successfully discourages any misuse of the system.


Diet and Hygiene in Modulating Autoimmunity During the Pandemic Era.
The immune system is an efficiently toned machinery that discriminates between friends and foes for achieving both host defense and homeostasis. Deviation of immune recognition from foreign to self and/or long-lasting inflammatory responses results in the breakdown of tolerance. Meanwhile, educating the immune system and developing immunological memory are crucial for mounting defensive immune responses while protecting against autoimmunity. Still to elucidate is how diverse environmental factors could shape autoimmunity. The emergence of a world pandemic such as SARS-CoV-2 (COVID-19) not only threatens the more vulnerable individuals including those with autoimmune conditions but also promotes an unprecedented shift in people's dietary approaches while urging for extraordinary hygiene measures that likely contribute to the development or exacerbation of autoimmunity. Thus, there is an urgent need to understand how environmental factors modulate systemic autoimmunity to better mitigate the incidence and or severity of COVID-19 among the more vulnerable populations. Here, we discuss the effects of diet (macronutrients and micronutrients) and hygiene (the use of disinfectants) on autoimmunity with a focus on systemic lupus erythematosus.


Antitumor effect of suberoylanilide hydroxamic acid and topotecan in renal cancer cells.
The treatment modality for advanced renal cancer is limited. The development of novel systemic therapies has long been waited for. Suberoylanilide hydroxamic acid (SAHA) is one of the most potent histone deacetylase (HDAC) inhibitors, which are promising novel anticancer agents. SAHA has already been tested in phase II clinical trials; however, its effectiveness has been found to be limited. Recently, the combination of SAHA and topoisomerase I inhibitor, topotecan, was shown to be effective, but this treatment strategy has not been tested in renal cancer cells. In the present study, we found that the combination of SAHA and topotecan effectively inhibited the growth of renal cancer cells by suppressing the expression of cyclin-dependent kinase (CDK) 4 and cyclin D1, and promoting retinoblastoma protein (Rb) dephosphorylation. Furthermore, the combination therapy was found to inhibit both the function and expression of HDACs, which may be one of the main mechanisms of the combination therapy. To the best of our knowledge, this is the first report that has revealed the combined beneficial effect of SAHA and topotecan on renal cancer cells. Combining SAHA and topotecan is thus a promising approach to the treatment of renal cancer.


Enteropathogenic Escherichia coli-induced epidermal growth factor receptor activation contributes to physiological alterations in intestinal epithelial cells.
The diarrheagenic pathogen enteropathogenic Escherichia coli (EPEC) is responsible for significant infant mortality and morbidity, particularly in developing countries. EPEC pathogenesis relies on a type III secretion system-mediated transfer of virulence effectors into host cells. EPEC modulates host cell survival and inflammation, although the proximal signaling pathways have not been well defined. We therefore examined the effect of EPEC on the epidermal growth factor receptor (EGFR), a known upstream activator of both the prosurvival phosphoinositide 3-kinase/Akt and proinflammatory mitogen-activated protein (MAP) kinase pathways. EPEC induced the autophosphorylation of EGFR in intestinal epithelial cells within 15 min postinfection, with maximal phosphorylation being observed at 4 h. Filter-sterilized supernatants of EPEC cultures also stimulated EGFR phosphorylation, suggesting that a secreted component(s) contributes to this activity. EPEC-induced EGFR phosphorylation was blocked by the pharmacological inhibitor tyrphostin AG1478, as well as by EGFR-neutralizing antibodies. Inhibition of EGFR phosphorylation by AG1478 had no effect on bacterial adherence, actin recruitment to sites of attachment, or EPEC-induced epithelial barrier function alteration. EPEC-mediated Akt phosphorylation, however, was inhibited by both AG1478 and EGFR-neutralizing antibodies. Correspondingly, inhibition of EGFR activation increased the apoptosis/necrosis of infected epithelial cells. Inhibition of EGFR phosphorylation also curtailed EPEC-induced ERK1/2 (MAP kinase) phosphorylation and, correspondingly, the production of the proinflammatory cytokine interleukin-8 by infected epithelial cells. Our studies suggest that EGFR is a key proximal signaling molecule during EPEC pathogenesis.


Importance of passive diffusion in the uptake of polychlorinated biphenyls by phagotrophic protozoa.
Unicellular protozoan grazers represent a size class of organisms where a transition in the mechanism of chlorobiphenyl (CB) introduction, from diffusion through surface membranes to ingestion of contaminated prey, could occur. This study compares the relative importance of these two processes in the overall uptake of polychlorinated biphenyls by protists. Uptake rates and steady-state concentrations were compared in laboratory cultures of grazing and nongrazing protozoa. These experiments were conducted with a 10-microm marine scuticociliate (Uronema sp.), bacterial prey (Halomonas halodurans), and a suite of 21 CB congeners spanning a range of aqueous solubilities. The dominant pathway of CB uptake by both grazing and nongrazing protozoa was diffusion. Organic-carbon-normalized CB concentrations (in the protozoan cell) were equivalent in grazing and nongrazing protozoa for all congeners studied. Rate constants for uptake into and loss from the protozoan cell were independently determined by using [3,3',4, 4'-(14)C]tetrachlorobiphenyl (IUPAC no. 77), 0.38 +/- 0.03 min(-1) and (1.1 +/- 0.1) x 10(-5) (g of organic carbon)(-1) min(-1), respectively. Magnitudes of the uptake and loss processes were calculated and compared by using a numerical model. The model result was consistent with data from the bioaccumulation experiment and supported the hypothesis that diffusive uptake is faster than ingestive uptake in phagotrophic unicellular protozoa.


Systematic Analysis of Molecular Subtypes Based on the Expression Profile of Immune-Related Genes in Pancreatic Cancer.
Immunotherapy has a good therapeutic effect and provides a new approach for cancer treatment. However, only limited studies have focused on the use of molecular typing to construct an immune characteristic index for gene expression in pancreatic adenocarcinoma (PAAD) and to assess the effectiveness of immunotherapy in patients with PAAD. Clinical follow-up data and gene expression profile of PAAD patients were retrieved from The Cancer Genome Atlas (TCGA) database. Based on 184 immune features, molecular subtypes of pancreatic cancer were found by the "ConsensusClusterPlus" package, and the association between clinical features and immune cell subtype distribution was analysed. In addition, the relationship between the proportion of immune subtypes and the expression of immune checkpoints was analysed. The CIBERSORT algorithm was introduced to evaluate the immune scores of different molecular subtypes. We used the tumor immune dysfunction and exclusion (TIDE) algorithm to assess the potential clinical effect of immunotherapy interventions on single-molecule subtypes. In addition, the oxidative stress index was constructed by linear discriminant analysis DNA (LDA), and weighted correlation network analysis was performed to identify the core module of the index and its characteristic genes. Expression of hub genes was verified by immunohistochemical analysis in an independent PAAD cohort. Pancreatic cancer is divided into three molecular subtypes (IS1, IS2, and IS3), with significant differences in prognosis between multiple cohorts. Expression of immune checkpoint-associated genes was significantly reduced in IS3 and higher in IS1 and IS2, suggesting that the three subgroups have different responsiveness to immunotherapy interventions. The results of the CIBERSORT analysis showed that IS1 exhibited the highest levels of immune infiltration, whereas the results of the TIDE analysis showed that the T-cell dysfunction score of IS1 was higher than that of IS2 and IS3. Furthermore, IS3 was found to be more sensitive to 5-FU and to have a higher immune signature index than IS1 and IS2. Based on WGCNA analysis, 10 potential gene markers were identified, and their expression at the protein level was verified by immunohistochemical analysis. Specific molecular expression patterns in pancreatic cancer can predict the efficacy of immunotherapy and influence the prognosis of patients.


High-frequency stimulation of the subthalamic nucleus potentiates L-DOPA-induced neurochemical changes in the striatum in a rat model of Parkinson's disease.
This study examined the cellular changes produced in the striatum by chronic L-DOPA treatment and prolonged subthalamic nucleus high-frequency stimulation (STN-HFS) applied separately, successively, or in association, in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). Only animals showing severe L-DOPA-induced dyskinesias (LIDs) were included, and STN-HFS was applied for 5 d at an intensity efficient for alleviating akinesia without inducing dyskinesias. L-DOPA treatment alone induced FosB/deltaFosB immunoreactivity, exacerbated the postlesional increase in preproenkephalin, reversed the decrease in preprotachykinin, and markedly increased mRNA levels of preprodynorphin and of the glial glutamate transporter GLT1, which were respectively decreased and unaffected by the dopamine lesion. STN-HFS did not affect per se the postlesion changes in any of these markers. However, when applied in association with L-DOPA treatment, it potentiated the positive modulation exerted by L-DOPA on all of the markers examined and tended to exacerbate LIDs. After 5 d of L-DOPA withdrawal, the only persisting drug-induced responses were an elevation in preprodynorphin mRNA levels and in the number of FosB/deltaFosB-immunoreactive neurons. Selective additional increases in these two markers were measured when STN-HFS was applied subsequently to L-DOPA treatment. These data provide the first evidence that STN-HFS exacerbates the responsiveness of striatal cells to L-DOPA medication and suggest that STN-HFS acts specifically through an L-DOPA-modulated signal transduction pathway associated with LIDs in the striatum. They point to striatal cells as a primary site for the complex interactions between these two therapeutic approaches in PD and argue against a direct anti-dyskinetic action of STN-HFS.


Cast of the left bronchial tree.
A 59-year old woman presented with hemoptysis of thick blood clots and fever of two days duration. Her medical history included sarcoidosis for which she was on chronic steroids. Computed tomography imaging revealed stage IV sarcoidosis with diffuse cystic and fibrotic changes bilaterally, worse in the right lung. She underwent bronchoscopy to attempt to localize a source but none was clearly found; no biopsies were performed. Immediately post-procedure she developed massive hemoptysis with hypoxia leading to cardiopulmonary arrest. She was intubated and stabilized with the spontaneous cessation of her bleeding. Immediate angiography revealed no active extravasation, but localized embolization was performed on the right main and right accessory bronchial arteries because these appeared hypertrophied and irregular. Two days later, she again developed spontaneous massive hemoptysis leading to cardiopulmonary arrest. Manual ventilation through the endotracheal tube became impossible. Immediate bronchoscopy identified a blood clot extending from the main carina into the left main stem bronchus. This was removed with a cryoprobe and ventilation could then be achieved easily. Examination of the blood clot demonstrated it to be a cast of the proximal left bronchial tree. Despite the return of spontaneous circulation via resuscitative efforts, the patient developed acute respiratory distress syndrome and later expired.


EFFECT OF THIOL-BINDING REAGENTS ON THE METABOLISM OF THIOSULFATE AND TETRATHIONATE BY THIOBACILLUS NEAPOLITANUS.
Trudinger, P. A. (Division of Plant Industry, Canberra, Australia). Effect of thiol-binding reagents on the metabolism of thiosulfate and tetrathionate by Thiobacillus neapolitanus. J. Bacteriol. 89:617-625. 1965.-Iodoacetamide, N-ethyl maleimide (NEM), p-chloromercuribenzoate (CMB), Mercurochrome, and HgCl(2) inhibited the oxidation of thiosulfate to sulfate by Thiobacillus neapolitanus; tetrathionate accumulated under these conditions. High concentrations of the thiol-binding reagents lowered the rate of oxidation of thiosulfate to tetrathionate; inhibition by CMB was reversed by high concentrations of thiosulfate. Relatively low concentrations of the thiol-binding reagents completely inhibited the oxidation and anaerobic metabolism of tetrathionate. Similar reagents had no effect on a soluble thiosulfate-oxidizing enzyme. Inhibition by thiol-binding reagents was overcome by washing the bacteria with Na(2)S or thioethanol after their exposure to the inhibitors. Under some conditions, the addition of thiosulfate or tetrathionate to bacterial suspensions before the addition of the thiol-binding reagents prevented the inhibition of thiosulfate and tetrathionate metabolism by these reagents. Thiosulfate catalyzed a rapid chemical breakdown of NEM and reacted with iodoacetamide. A complex between thiosulfate and mercuribenzoate was demonstrated. Three types of thiol group appear to be associated with the metabolism of thiosulfate and tetrathionate; one of these types may be located at the bacterial cell membrane. The results are consistent with the hypothesis that thiols (or disulfide groups) are binding sites for the substrates.


Detection of gonadotropin-releasing hormone receptor and its mRNA in primary human epithelial ovarian cancers.
The hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) serves a key role in regulating mammalian reproductive function. An extrapituitary role for GnRH in the normal and malignant reproductive tissues has been postulated. The purpose of our study is to demonstrate the presence and levels of GnRH receptor (RGnRH) protein and its mRNA in normal and malignant tissues of ovary. Normal human ovarian tissues (n = 13), as well as epithelial ovarian cancer specimens from stages I-IV (n = 39), were obtained from appropriate patients at operation room. Monoclonal antibodies against RGnRH were used for immunohistochemical evaluation of paraffin-embedded ovarian tissue sections by methods of streptavidin-biotin immunostaining. The molecular size and levels of RGnRH were determined by enhanced chemiluminescence-Western blot assay. The amount of RGnRH mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The rate of positive immunostaining in ovarian cancers was 53.8% (21/39). The rate of positive staining in the late stage (stages III and IV) was significantly higher than that in the early stage (stages I and II). A single band of molecular weight of about 60 kDa was detected from protein extracts of ovarian cancer as well as from normal ovary. The mean values of fold increase of signal intensities of 60 kDa detected by Western blots in stages I-IV ovarian cancers were 2.39, 2.42, 2.78, and 3.62, respectively, as compared with normal ovarian tissues. The overall positive rate of Western blot analysis for ovarian cancers was 59% (23/39). The mean values of signal intensity of RT-PCR products of RGnRH mRNA in stages I-IV were 2.24, 2.58, 3.10, and 3.20, respectively. The positive rate of overexpression of RGnRH mRNA in ovarian cancer was 70% (21/30). The differences of mean values of signal intensities of Western blot staining (2.41 versus 2.85) as well as RT-PCR products (2.40 versus 3.11) between the early stage and the late stage of ovarian cancers were statistically nonsignificant. Mechanism of autocrine regulation of tumor growth in human epithelial ovarian cancer can be explained by the coexistence of GnRH, RGnRH, and its mRNA, according to our own and other studies. The level of RGnRH expressed by ovarian cancer might be used for targeting chemotherapeutic agents to those patients who harbor RGnRH-positive tumors.


Systematic literature review of traits and outcomes reported in randomised controlled trials of asthma with regular dosing of inhaled corticosteroids with short-acting β2-agonist reliever, as-needed ICS/formoterol, or ICS/formoterol maintenance and reliever therapy.
Asthma treatments based solely on diagnostic label do not benefit patients equally. To identify patient traits that may be associated with improved treatment response to regular inhaled corticosteroid (ICSs) dosing with short-acting β2-agonist reliever or ICS/formoterol-containing therapy, a systematic literature review (SLR) was conducted. Searches of databases including MEDLINE and Embase identified randomised controlled trials (RCTs) of patients with asthma, aged ≥12 years, published 1998-2022, containing ≥1 regular ICS dosing or ICS/formoterol-containing treatment arm, and reporting patient traits and outcomes of interest. Relevant data was extracted and underwent a feasibility assessment to determine suitability for meta-analysis. The SLR identified 39 RCTs of 72,740 patients and 90 treatment arms, reporting 11 traits and 11 outcomes. Five patient traits (age, body mass index, FEV1, smoking history, asthma control) and five outcomes (exacerbation rate, lung function, asthma control, adherence, time to first exacerbation) were deemed feasible for inclusion in meta-analyses due to sufficient comparable reporting. Subgroups of clinical outcomes stratified by levels of patient traits were reported in 16 RCTs. A systematic review of studies of regular ICS dosing with SABA or ICS/formoterol-containing treatment strategies in asthma identified consistent reporting of five traits and outcomes, allowing exploration of associations with treatment response. Conversely, many other traits and outcomes, although being potentially relevant, were inconsistently reported and limited subgroup reporting meant analyses of treatment response for subgroups of traits was not possible. We recommend more consistent measurement and reporting of clinically relevant patient traits and outcomes in respiratory RCTs.


Study Protocol: A randomized controlled trial of suicide risk reduction in the year following jail release (the SPIRIT Trial).
This article describes the protocol for a randomized effectiveness and cost-effectiveness trial of Stanley and Brown's Safety Planning Intervention (SPI) during pretrial jail detention to reduce post-release suicide events (suicide attempts, suicide behaviors, and suicide-related hospitalizations). With 10 million admissions per year and short stays (often days), U.S. jails touch many individuals at risk for suicide, providing an important opportunity for suicide prevention that is currently being missed. This study (N = 800) is the first randomized evaluation of an intervention to reduce suicide risk in the vulnerable year after jail release. Given that roughly 10% of all suicides in the U.S. with known circumstances occur in the context of a criminal legal stressor, reducing suicide risk in the year after arrest and jail detention could have a noticeable impact on national suicide rates. Pretrial jail detainees at risk for suicide were randomized to SPI during jail detention plus post-release phone follow-up or to enhanced Standard Care. Outcomes assessed through 12 months post-release include suicide events, suicide attempts, weeks of active suicide ideation, severity of suicide ideation, time to first event, psychiatric symptoms, functioning, and cost-effectiveness. Methods accommodate short jail stays and maximize trial safety and follow-up in a large sample with severe suicide risk, access to lethal means including substances and firearms, high rates of psychiatric illness, and unstable circumstances. Adequate funding was important to create the infrastructure needed to run this large trial cleanly. We encourage funders to provide adequate resources to ensure clean, well-run trials.


Gas-phase synthesis of nanoparticles: current application challenges and instrumentation development responses.
Nanoparticles constitute fundamental building blocks required in several fields of application with current global importance. To fully exploit nanoparticle properties specifically determined by the size, shape, chemical composition and interfacial configuration, rigorous nanoparticle growth and deposition control is needed. Gas-phase synthesis, in particular magnetron-sputtering inert-gas condensation, provides unique opportunities to realise engineered nanoparticles optimised for the desired use case. Here, we provide an overview of recent nanoparticle growth experiments via this technique, how the latter can meet application-specific requirements, and what challenges might impede the wide-spread adoption for scalable industrial synthesis. More specifically, we discuss the timely topics of energy, catalysis, and sensing applications enabled by gas-phase synthesised nanoparticles, as well as recently emerging advances in neuromorphic devices for unconventional computing. Having identified the most relevant challenges and limiting factors, we outline how advances in nanoparticle source instrumentation and/or in situ diagnostics can address current shortcomings. Eventually we identify common trends and directions, giving our perspective on the most promising and impactful applications of gas-phase synthesised nanoparticles in the future.


Interaction of human laminin receptor with Sup35, the [PSI⁺] prion-forming protein from S. cerevisiae: a yeast model for studies of LamR interactions with amyloidogenic proteins.
The laminin receptor (LamR) is a cell surface receptor for extracellular matrix laminin, whereas the same protein within the cell interacts with ribosomes, nuclear proteins and cytoskeletal fibers. LamR has been shown to be a receptor for several bacteria and viruses. Furthermore, LamR interacts with both cellular and infectious forms of the prion protein, PrP(C) and PrP(Sc). Indeed, LamR is a receptor for PrP(C). Whether LamR interacts with PrP(Sc) exclusively in a capacity of the PrP receptor, or LamR specifically recognizes prion determinants of PrP(Sc), is unclear. In order to explore whether LamR has a propensity to interact with prions and amyloids, we examined LamR interaction with the yeast prion-forming protein, Sup35. Sup35 is a translation termination factor with no homology or functional relationship to PrP. Plasmids expressing LamR or LamR fused with the green fluorescent protein (GFP) were transformed into yeast strain variants differing by the presence or absence of the prion conformation of Sup35, respectively [PSI⁺] and [psi⁻]. Analyses by immunoprecipitation, centrifugal fractionation and fluorescent microscopy reveal interaction between LamR and Sup35 in [PSI⁺] strains. The presence of [PSI⁺] promotes LamR co-precipitation with Sup35 as well as LamR aggregation. In [PSI⁺] cells, LamR tagged with GFP or mCherry forms bright fluorescent aggregates that co-localize with visible [PSI⁺] foci. The yeast prion model will facilitate studying the interaction of LamR with amyloidogenic prions in a safe and easily manipulated system that may lead to a better understanding and treatment of amyloid diseases.


The clinical presentation of preterm cerebellar haemorrhage.
The objective of this study was to evaluate clinical symptoms and findings on cranial ultrasound (CUS) in preterm infants with cerebellar haemorrhage through retrospective analysis of all preterm infants with a postnatal CUS or MRI diagnosis of cerebellar haemorrhage admitted in a tertiary care centre between January 2002 and June 2009. Fifteen infants were identified; median gestational age was 25 2/7 weeks and median birth weight 730 g. We discerned six types of haemorrhage: subarachnoid (n = 3), folial (n = 1), lobar (n = 9, of which 4 bilateral), giant lobar (n = 1, including vermis) and contusional (n = 1). Especially in infants with lobar cerebellar haemorrhage, CUS showed preceding or concurrent lateral ventricle dilatation, mostly without intraventricular haemorrhage (IVH). Thirteen infants suffered from notable, otherwise unexplained motor agitation in the days preceding the diagnosis. In conclusion, motor agitation may be a presenting symptom of cerebellar haemorrhage in preterm infants. Unexplained ventriculomegaly can be a first sign of cerebellar haemorrhage and should instigate sonographic exploration of the cerebellum.


optix functions as a link between the retinal determination network and the dpp pathway to control morphogenetic furrow progression in Drosophila.
optix, the Drosophila ortholog of the SIX3/6 gene family in vertebrate, encodes a homeodomain protein with a SIX protein-protein interaction domain. In vertebrates, Six3/6 genes are required for normal eye as well as brain development. However, the normal function of optix in Drosophila remains unknown due to lack of loss-of-function mutation. Previous studies suggest that optix is likely to play an important role as part of the retinal determination (RD) network. To elucidate normal optix function during retinal development, multiple null alleles for optix have been generated. Loss-of-function mutations in optix result in lethality at the pupae stage. Surprisingly, close examination of its function during eye development reveals that, unlike other members of the RD network, optix is required only for morphogenetic furrow (MF) progression, but not initiation. The mechanisms by which optix regulates MF progression is likely through regulation of signaling molecules in the furrow. Specifically, although unaffected during MF initiation, expression of dpp in the MF is dramatically reduced in optix mutant clones. In parallel, we find that optix is regulated by sine oculis and eyes absent, key members of the RD network. Furthermore, positive feedback between optix and sine oculis and eyes absent is observed, which is likely mediated through dpp signaling pathway. Together with the observation that optix expression does not depend on hh or dpp, we propose that optix functions together with hh to regulate dpp in the MF, serving as a link between the RD network and the patterning pathways controlling normal retinal development.


Organometallic mediated radical polymerization of vinyl acetate using bis(imino)pyridine vanadium trichloride complexes.
The synthesis and characterization of one novel proligand and six novel vanadium(III) trichloride complexes is described. The controlled radical polymerization activity towards vinyl acetate of these, and eight other bis(imino)pyridine vanadium trichloride complexes previously reported, is investigated. Those complexes possessing variation at the N-aryl para-position with no steric protection offered by ortho-substituents (4 examples) result in poor control over poly(vinyl acetate) polymerization. Control is improved with increasing steric bulk at the ortho-position of the N-aryl substituent (4 examples) although attempts to increase steric bulk past isopropyl were unsuccessful. Synthesizing bis(imino)pyridine vanadium trichloride complexes with substituted imine backbones restores polymerization control when aliphatic substituents are used (4 examples) but ceases to make any drastic improvements on catalyst lifetime. Modification of the polymerization conditions is also investigated, in an attempt to improve the catalyst lifetime. Expansion of the monomer scope to include other vinyl esters, particularly those derived from renewable resources, shows promising results.


Cytotoxicity of VEGF(121)/rGel on vascular endothelial cells resulting in inhibition of angiogenesis is mediated via VEGFR-2.
The fusion protein VEGF(121)/rGel composed of the growth factor VEGF(121) and the plant toxin gelonin targets the tumor neovasculature and exerts impressive anti-vascular effects. We have previously shown that VEGF(121)/rGel is cytotoxic to endothelial cells overexpressing VEGFR-2 but not to endothelial cells overexpressing VEGFR-1. In this study, we examined the basis for the specific toxicity of this construct and assessed its intracellular effects in vitro and in vivo. We investigated the binding, cytotoxicity and internalization profile of VEGF(121)/rGel on endothelial cells expressing VEGFR-1 or VEGFR-2, identified its effects on angiogenesis models in vitro and ex vivo, and explored its intracellular effects on a number of molecular pathways using microarray analysis. Incubation of PAE/VEGFR-2 and PAE/VEGFR-1 cells with (125)I-VEGF(121)/rGel demonstrated binding specificity that was competed with unlabeled VEGF(121)/rGel but not with unlabeled gelonin. Assessment of the effect of VEGF(121)/rGel on blocking tube formation in vitro revealed a 100-fold difference in IC(50) levels between PAE/VEGFR-2 (1 nM) and PAE/VEGFR-1 (100 nM) cells. VEGF(121)/rGel entered PAE/VEGFR-2 cells within one hour of treatment but was not detected in PAE/VEGFR-1 cells up to 24 hours after treatment. In vascularization studies using chicken chorioallantoic membranes, 1 nM VEGF(121)/rGel completely inhibited bFGF-stimulated neovascular growth. The cytotoxic effects of VEGF(121)/rGel were not apoptotic since treated cells were TUNEL-negative with no evidence of PARP cleavage or alteration in the protein levels of select apoptotic markers. Microarray analysis of VEGF(121)/rGel-treated HUVECs revealed the upregulation of a unique "fingerprint" profile of 22 genes that control cell adhesion, apoptosis, transcription regulation, chemotaxis, and inflammatory response. Taken together, these data confirm the selectivity of VEGF(121)/rGel for VEGFR-2-overexpressing endothelial cells and represent the first analysis of genes governing intoxication of mammalian endothelial cells by a gelonin-based targeted therapeutic agent.


Impact of clostridial glucosylating toxins on the proteome of colonic cells determined by isotope-coded protein labeling and LC-MALDI.
The anaerobe Clostridium difficile produces two major virulence factors toxin A and B that inactivate Rho proteins by glucosylation of a pivotal threonine residue. Purified toxins induce reorganization of the cytoskeleton and cell death in colonic cells. Whether all toxin effects on target cells depend on catalytic glucosyltransferase activity is unclear at present. Thus, we conducted a proteome approach to compare the protein profile of target cells treated either with wild type toxin A (rTcdA wt) or with a catalytically inactive mutant toxin A (mutant rTcdA). Relative protein quantification was feasible using isotope-coded protein labeling techniques (ICPL) and mass spectrometry (LC-MALDI). Altogether we found a significant differential expression of thirty proteins after treatment with rTcdA wt or mutant rTcdA. Mutant rTcdA caused up-regulation of seven proteins and sixteen proteins were responsive to rTcdA wt after 5 h. Long-term effect of rTcdA wt on protein expression was the down-regulation of eleven proteins. Up- or down-regulation of several proteins was verified by western blot analysis confirming the MS results. Our results indicate incubation time-dependent effects of the clostridial glucosylating toxin A on colonic cells. The rTcdA wt impact more cellular functions than actin cytoskeleton reorganization and apoptosis. Furthermore, these data give insight into glucosyltransferase independent effects of clostridial glucosylating toxins on target cells after short incubation time. Additionally, our data reveal pro-inflammatory and proliferative effects of mutant rTcdA after short-term incubation.


The rRNA-processing function of the yeast U14 small nucleolar RNA can be rescued by a conserved RNA helicase-like protein.
The phylogenetically conserved U14 small nucleolar RNA is required for processing of rRNA, and this function involves base pairing with conserved complementary sequences in 18S RNA. With a view to identifying other important U14 interactions, a stem-loop domain required for activity of Saccharomyces cerevisiae U14 RNAs (the Y domain) was first subjected to detailed mutational analysis. The mapping results showed that most nucleotides of the Y domain can be replaced without affecting function, except for loop nucleotides conserved among five different yeast species. Defective variants were then used to identify both intragenic and extragenic suppressor mutations. All of the intragenic mutations mapped within six nucleotides of the primary mutation, suggesting that suppression involves a change in conformation and that the loop element is involved in an essential intermolecular interaction rather than intramolecular base pairing. A high-copy extragenic suppressor gene, designated DBP4 (DEAD box protein 4), encodes an essential, putative RNA helicase of the DEAD-DEXH box family. Suppression by DBP4 (initially CA4 [T.-H. Chang, J. Arenas, and J. Abelson, Proc. Natl. Acad. Sci. USA 87:1571-1575, 1990]) restores the level of 18S rRNA and is specific for the Y domain but is not allele specific. DBP4 is predicted to function either in assembly of the U14 small nucleolar RNP or, more likely, in its interaction with other components of the rRNA processing apparatus. Mediating the interaction of U14 with precursor 18S RNA is an especially attractive possibility.


Functional genomics-based studies of the microbial ecology of hyperthermophilic micro-organisms.
Although much attention has been paid to the genetic, biochemical and physiological aspects of individual hyperthermophiles, how these unique micro-organisms relate to each other and to their natural habitats must be addressed in order to develop a comprehensive understanding of life at high temperatures. Phylogenetic 16 S rRNA-based profiling of samples from various geothermal sites has provided insights into community structure, but this must be complemented with efforts to relate metabolic strategies to biotic and abiotic characteristics in high-temperature habitats. Described here are functional genomics-based approaches, using cDNA microarrays, to gain insight into how ecological features such as biofilm formation, species interaction, and possibly even gene transfer may occur in native environments, as well as to determine what genes or sets of genes may be tied to environmental functionality.


[Evolution and impact of the infodemic on the child population in times of COVID-19Evolução e impacto da infodemia na população infantil em tempos de COVID-19].
The provision of timely, clear, correct information is an important strategy for controlling panic and containing a pandemic outbreak. However, as this task has not been prioritized in the context of the SARS-CoV-2 pandemic, a new lethal enemy has emerged that now poses another crisis, namely, the "infodemic", with consequences that have affected the entire population worldwide. In particular, it has increased the vulnerability of a group that is not often discussed: children, who constitute our study population.This article provides an analysis aimed at demystifying false constructs about the low impact of the COVID-19 pandemic on the child population. It gives a chronological description of the different events that were the building blocks of the infodemic, affecting this population in three phases: first, at the onset of the pandemic, when its effects on children were ignored altogether; second, when children were stigmatized as "super-spreaders"; and third, when the crisis resulting from a failure to transmit information to this population group became evident.The world is facing both the pandemic and a pressing need for communicative justice, which includes children as a primary target group. Taking a social determinants approach, this article proposes a new normal that includes using accurate and clear information to empower children to combat the infodemic virus from an early age.


Safety of biologic therapy in combination with methotrexate in moderate to severe psoriasis: a cohort study from the BIOBADADERM registry.
Safety is an important consideration in decisions on treatment for patients with moderate to severe psoriasis and its study is the main purpose of the BIOBADADERM Registry. The combination of a biologic agent and a conventional systemic drug- generally methotrexate (MTX)-is a common treatment in clinical practice. However, there is a paucity of evidence from real-world practice on the safety of such combination regimens in psoriasis. The primary objective of this study was to ascertain whether the use of regimens combining biologic drugs with MTX in the management of moderate to severe psoriasis increases the risk of adverse events (AEs) or serious AEs (SAEs). We compared monotherapy with tumour necrosis factor (TNF), interleukin-17 and interleukin-23 inhibitors with the use of the same drugs in combination with MTX. Using data from the BIOBADADERM Registry, we compared biologic monotherapies with MTX combined therapies. We estimated crude and adjusted incidence rate ratios using a random effects Poisson regression with 95% confidence intervals for all AEs, SAEs, infections and serious infections, and several organ class systems. We analysed data from 2,829 patients and 5,441 treatment cycles, a total of 12,853 patient-years. The combination of a biologic with MTX was not associated with statistically significant increases in overall risk of AEs or SAEs in any treatment group. No increase in the total number of infections or serious infections in patients receiving combined therapy was observed for any group. However, treatment with a TNF inhibitor plus MTX was associated with an increase in the incidence of gastrointestinal AEs. The risk of AEs and SAEs was not significantly increased in patients with moderate to severe psoriasis receiving different classes of biologic drugs plus MTX compared to those on biologic monotherapy.


Institutional care and iron deficiency increase ADHD symptomology and lower IQ 2.5-5 years post-adoption.
Increased ADHD symptomology and lower IQ have been reported in internationally adopted (IA) children compared to non-adopted peers (Hostinar, Stellern, Schaefer, Carlson & Gunnar, 2012; Kreppner, O'Connor & Rutter, 2001). However, it is unclear whether these outcomes are due to institutional deprivation specifically or to co-occurring micronutrient deficiencies that disrupt brain development (Fuglestad, Rao & Georgieff, 2008b). In this study, IA children were compared to children raised in their biological families to examine differences in ADHD symptomology and IQ 2.5-5 years post-adoption and to assess the contributions of iron deficiency (ID) and duration of deprivation to these cognitive outcomes. ADHD symptoms (parent- and experimenter-reported) and IQ were evaluated in 88 IA (M = 62.1 months, SD = 2.4) and 35 non-adopted children (M = 61.4 months, SD = 1.6). IA children were assessed 29-64 months post-adoption (M = 41.9 months, SD = 10.2). ID was assessed during the initial post-adoption medical visit in 69 children, and children were classified into four groups by iron status, ranging from normal to ID anemia (most severe). IA children had greater ADHD symptomology, p < .01, and lower IQ, p = .001, than non-adopted children. Within the IA group, children with more severe ID at adoption had greater ADHD symptomology, r(69) = 0.40, p = .001, and lower IQ, r(68) = -0.28, p < .05. Duration of institutional care was positively correlated with ADHD symptoms, r(86) = .28, p < .01, but not IQ, r(85) = -.08, p = .52. Longitudinal results indicate improvement in IQ from 12 months post-adoption to age 5 for children with greater ID severity at adoption and longer duration of institutional care but no improvement in ADHD symptoms. These results signify continuing effects of early deprivation and ID on ADHD symptoms and IQ years after adoption. A video abstract of this article can be viewed at http://www.youtube.com/watch?v=vUFDAS3DD1c.


Infants' visual system nonretinotopically integrates color signals along a motion trajectory.
Whereas early visual processing has been considered primarily retinotopic, recent studies have revealed significant contributions of nonretinotopic processing to the human perception of fundamental visual features. For adult vision, it has been shown that information about color, shape, and size is nonretinotipically integrated along the motion trajectory, which could bring about clear and unblurred perception of a moving object. Since this nonretinotopic processing presumably includes tight and elaborated cooperation among functional cortical modules for different visual attributes, how this processing matures in the course of brain development is an important unexplored question. Here we show that the nonretinotopic integration of color signals is fully developed in infants at five months of age. Using preferential looking, we found significantly better temporal segregation of colors for moving patterns than for flickering patterns, even when the retinal color alternation rate was the same. This effect could be ascribed to the integration of color signals along a motion trajectory. Furthermore, the infants' color segmentation performance was comparable to that of human adults. Given that both the motion processing and color vision of 5-month-old infants are still under development, our findings suggest that nonretinotopic color processing develops concurrently with basic color and motion processing. Our findings not only support the notion of an early presence of cross-modal interactions in the brain, but also indicate the early development of a purposive cross-module interaction for elegant visual computation.


Comparing Zwitterionic and PEG Exteriors of Polyelectrolyte Complex Micelles.
A series of model polyelectrolyte complex micelles (PCMs) was prepared to investigate the consequences of neutral and zwitterionic chemistries and distinct charged cores on the size and stability of nanocarriers. Using aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization, we synthesized a well-defined diblock polyelectrolyte system, poly(2-methacryloyloxyethyl phosphorylcholine methacrylate)-block-poly((vinylbenzyl) trimethylammonium) (PMPC-PVBTMA), at various neutral and charged block lengths to compare directly against PCM structure-property relationships centered on poly(ethylene glycol)-block-poly((vinylbenzyl) trimethylammonium) (PEG-PVBTMA) and poly(ethylene glycol)-block-poly(l-lysine) (PEG-PLK). After complexation with a common polyanion, poly(sodium acrylate), the resulting PCMs were characterized by dynamic light scattering (DLS) and small angle X-ray scattering (SAXS). We observed uniform assemblies of spherical micelles with a diameter ~1.5-2× larger when PMPC-PVBTMA was used compared to PEG-PLK and PEG-PVBTMA via SAXS and DLS. In addition, PEG-PLK PCMs proved most resistant to dissolution by both monovalent and divalent salt, followed by PEG-PVBTMA then PMPC-PVBTMA. All micelle systems were serum stable in 100% fetal bovine serum over the course of 8 h by time-resolved DLS, demonstrating minimal interactions with serum proteins and potential as in vivo drug delivery vehicles. This thorough study of the synthesis, assembly, and characterization of zwitterionic polymers in PCMs advances the design space for charge-driven micelle assemblies.


Relationship between psychological profile and cardiological variables in chronic heart failure. The role of patient subjectivity.
To analyse the relationships between the psychological profile, the satisfaction profile and cardiological variables in patients with chronic heart failure. One hundred and fifty-two male patients with chronic heart failure in a stable clinical condition underwent cardiological evaluation and psychological assessment by means of two instruments: the Cognitive Behavioural Assessment 2.0 Battery and the Satisfaction Profile. Patients scored higher than healthy subjects in terms of psychophysiological disorders and depression. Patients in NYHA class III reported higher anxiety and depression scores and had more frequent problems in daily life than patients in NYHA classes I and II. Class III patients also reported lower satisfaction levels in many aspects of psychological and physical functioning. Pulmonary resistances >2.5 Wood units, pulmonary capillary wedge pressure >0. 18 mmHg and a diagnosis of ischaemic cardiomyopathy were associated with low satisfaction levels in the Satisfaction Profile 'physical functioning' factor. To be listed for heart transplantation and a history of more than three hospitalizations were related to low satisfaction levels in many items of the Satisfaction Profile. Finally, stepwise multiple regression showed that NYHA class, depression score and pulmonary capillary resistance accounted for 32% of the variance in the Satisfaction Profile physical functioning factor score. On the basis of chronic heart failure diagnosis only, a generic pattern of psychological distress can be predicted, common to many severe chronic diseases. Shifting from objective mental health measures towards the domain of subjective satisfaction, the only link which emerges is between objective cardiological data and satisfaction with physical functioning. Satisfaction in terms of other life aspects does not seem to be related to cardiological variables. These results support the importance of subjectivity in health related quality of life, as well as objective measures.


Employment of time-varying sensory evidence to test the mechanisms underlying flexible decision-making.
To make flexible decisions in dynamic environments, the brain must integrate behaviorally relevant information while simultaneously discarding irrelevant information. This study aimed to investigate the mechanisms responsible for discarding irrelevant information during context-dependent decision-making. We trained two macaque monkeys to switch between direction and depth discrimination tasks in successive trials. During decision-making, the strength of the motion or depth signal changes transiently at various times, introducing a brief pulse. We assessed the effects of pulse on behavioral choices. Consistent with previous findings, early relevant pulses, such as motion pulses during direction discrimination, had a significantly larger effect compared to late pulses. Critically, the effects of irrelevant pulses, such as motion pulses during depth discrimination, exhibited an initial minimal effect, followed by an increase and subsequent decrease as a function of pulse timing. Gating mechanisms alone, aimed at discarding irrelevant information, did not account for the observed time course of pulse effects. Instead, the observed increase in the effects of irrelevant pulses with time suggested the involvement of a leaky integration mechanism. The results suggested that the brain controls the amount of disposal in accumulating sensory evidence during flexible decision-making.


Heterogeneity of human thymocytes and a malignant T-lymphoblast cell line, MOLT-3.
The purpose of this paper was to study the heterogeneity of human thymocytes and leukemic cells of the T-cell line MOLT-3 by velocity sedimentation. Analysis of the subpopulations of thymocytes demonstrated that they represent a heterogeneous population of cells with respect to their size, proliferative activity, and presence and quantities of terminal deoxynucleotidyl transferase and human thymus leukemia-associated antigen, a thymic isozyme of adenosine deaminase (HThy-L/ADA). Only a minor subpopulation of thymocytes (large cells) was in active cycle. The highest level of HThy-L/ADA was associated with the main subpopulation of thymocytes sedimenting at 3 to 4 mm/hr while low amounts of the HThy-L/ADA antigen (enzyme) were found in the minor fractions of the small and large cells. The distribution of terminal deoxynucleotidyl transferase-positive cells indicated that most, but not all, thymocytes contain the enzyme. Analysis of the T-cell line MOLT-3 showed that these cells could be separated into subpopulations with different biochemical and biological properties. More than one subpopulation of cells was capable of DNA synthesis. In contrast to the thymocytes, all fractions of MOLT-3 cells contained high amounts of HThy-L/ADA. The proportion of terminal deoxynucleotidyl transferase-positive cells as a function of sedimentation velocity was also quite constant although there was a slight but reproducible drop in the percentage of these cells in the slowly sedimenting fractions. The percentage of cells with receptors for sheep erythrocytes also remained high in fractions separated on the basis of size, although a consistently higher percentage was found in smaller cells. These studies indicated that thymus cells as well as the malignant T-cell line MOLT-3 can be separated on the basis of sedimentation velocity into subpopulations with different biological and biochemical properties. The data also indicated that the heterogeneity of MOLT-3 line cannot be explained solely on the basis of volume changes due to cell cycle, suggesting that they may represent heterogeneous populations of cells.


Risk factors for inadequate antibody response to primary rabies vaccination in dogs under one year of age.
Ensuring the adequacy of response to rabies vaccination in dogs is important, particularly in the context of pet travel. Few studies have examined the factors associated with dogs' failure to achieve an adequate antibody titer after vaccination (0.5 IU/ml). This study evaluated rabies antibody titers in dogs after primary vaccination. Dogs under one year of age whose serum was submitted to a reference laboratory for routine diagnostics, and which had no prior documented history of vaccination were enrolled (n = 8,011). Geometric mean titers (GMT) were calculated and univariate analysis was performed to assess factors associated with failure to achieve 0.5 IU/mL. Dogs vaccinated at >16 weeks of age had a significantly higher GMT compared to dogs vaccinated at a younger age (1.64 IU/ml, 1.57-1.72, ANOVA p < 0.01). There was no statistical difference in GMT between dogs vaccinated <12 weeks and dogs vaccinated 12-16 weeks (1.22 IU/ml and 1.21 IU/ml). The majority of dogs failed to reach an adequate titer within the first 3 days of primary vaccination; failure rates were also high if the interval from vaccination to titer check was greater than 90 days. Over 90% of dogs that failed primary vaccination were able to achieve adequate titers after booster vaccination. The ideal timing for blood draw is 8-30 days after primary vaccination. In the event of a failure, most dogs will achieve an adequate serologic response upon a repeat titer (in the absence of booster vaccination). Booster vaccination after failure provided the highest probability of an acceptable titer.


Post-translation modification of proteins in tears.
This is the first 2-DE study using sequential dyes to analyse phospho-, glyco- and total tear protein profiles (Pro-Q Diamond for phosphoprotein, Pro-Q Emerald for glycoprotein and Sypro Ruby for total protein). This method minimised the gel-gel variations, allowing better comparisons among the three profiles and generated a whole map of PTM profiles of tear protein. A novel tear protein, dermcidin, was identified for the first time in this study. The identification of this antimicrobial protein suggests a new model of defence in tears. In addition, we are able to present the first experimental evidence of the presence of glycosylated lipocalin 1 and cystatin S. Nucleobindin 2 was only detected using phospho staining, suggesting it is only phosphorylated in tears. This study provides the groundwork for understanding the PTM of tear proteins and consequently these methods could be useful in the search for biomarkers in tears.


White Blood Cell Counts, Alcoholism, and Cirrhosis in Pneumococcal Pneumonia.
An elevated white blood cell (WBC) count is a characteristic finding in pneumococcal pneumonia. Very low WBC counts, occurring in some cases, are often associated with overwhelming pneumonia and have been attributed to alcohol-induced suppression of bone marrow. However, a systematic study of neutropenia, leukocytosis, alcohol ingestion, and cirrhosis in pneumococcal pneumonia has not been previously reported. Using a database of patients with pneumococcal pneumonia at our medical center, we extracted data on WBC counts at admission, differential counts, alcohol ingestion, and cirrhosis, and we related these to 7-day and 30-day mortality. White blood cell counts were <6000/mm3 in 49 of 481 patients (10.2%) with pneumococcal pneumonia and >25000/mm3 in 40 (8.3%). Mortality at 7 days was 18.4% and 12.5%, respectively, 5-fold and 3-fold greater in patients with WBC <6000 or >25000 than in those with WBC counts between 6000 and 25000 (P < .001). Increased band forms were not associated with a worse outcome (P = .12). Alcohol use and cirrhosis were not associated with WBC counts <6000 (P = .63 and P = .41, respectively). In a large series of cases of pneumococcal pneumonia, WBC counts <6000 or >25000 correlated significantly with increased 7-day mortality. More than 10% band forms was not associated with a poor outcome. Alcohol abuse was not associated with low WBC or increased mortality. Our findings suggest that greater consideration be given to more intense care for patients with bacterial pneumonia who have very high or very low WBC counts at the time of hospital admission.