Rapid T(1) mapping using multislice echo planar imaging.
Determination of neurological pathology in white matter disease can be made in a semiquantitative way from T(1)- or T(2)-weighted images. A higher level of quantification based on measured T(1) or T(2) values has been either limited to specific regions of interest or to low-resolution maps. Higher-resolution T(1) maps have proved difficult to obtain due to the excessively long scan times required using conventional techniques. In this study, clinically acceptable images are obtained by using single-shot echo planar imaging (EPI) with an acquisition scheme that maximizes signal-to-noise while minimizing the scan time. Magn Reson Med 45:630-634, 2001.


Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits.
Multiple Sclerosis (MS) causes neurologic disability due to inflammation, demyelination, and neurodegeneration. Immunosuppressive treatments can modify the disease course but do not effectively promote remyelination or prevent long term neurodegeneration. As a novel approach to mitigate chronic stage pathology, we tested transplantation of mouse induced neural stem cells (iNSCs) into the chronically demyelinated corpus callosum (CC) in adult mice. Male C57BL/6 mice fed 0.3% cuprizone for 12 weeks exhibited CC atrophy with chronic demyelination, astrogliosis, and microglial activation. Syngeneic iNSCs were transplanted into the CC after ending cuprizone and perfused for neuropathology 2 weeks later. Magnetic resonance imaging (MRI) sequences for magnetization transfer ratio (MTR), diffusion-weighted imaging (T2), and diffusion tensor imaging (DTI) quantified CC pathology in live mice before and after iNSC transplantation. Each MRI technique detected progressive CC pathology. Mice that received iNSCs had normalized DTI radial diffusivity, and reduced astrogliosis post-imaging. A motor skill task that engages the CC is Miss-step wheel running, which demonstrated functional deficits from cuprizone demyelination. Transplantation of iNSCs resulted in marked recovery of running velocity. Neuropathology after wheel running showed that iNSC grafts significantly increased host oligodendrocytes and proliferating oligodendrocyte progenitors, while modulating axon damage. Transplanted iNSCs differentiated along astrocyte and oligodendrocyte lineages, without myelinating, and many remained neural stem cells. Our findings demonstrate the applicability of neuroimaging and functional assessments for pre-clinical interventional trials during chronic demyelination and detect improved function from iNSC transplantation. Directly reprogramming fibroblasts into iNSCs facilitates the future translation towards exogenous autologous cell therapies.


67Cu-versus 131I-labeled Lym-1 antibody: comparative pharmacokinetics and dosimetry in patients with non-Hodgkin's lymphoma.
Antilymphoma mouse monoclonal antibody (MoAb) Lym-1, labeled with 67Cu or 131I, has demonstrated promising results in radioimmunotherapy (RIT) for lymphoma. Although 131I has played a central role in RIT thus far, some properties of 67Cu are preferable. A subset of our patients received both 67Cu- and 131I-labeled Lym-1, allowing a comparative evaluation of the two radiopharmaceuticals administered to a matched population of patients. Four patients with B-lymphocytic non-Hodgkin's lymphoma that had progressed despite standard therapy entered trials of 67Cu- and 131I-labeled Lym-1, which were injected 3-26 days apart. Lym-1 was conjugated to 6-[p-(bromoacetamido)benzyl]-1,4,7,11-tetraazacyclotetradecane-N,N ',N",N'"-tetraacetic acid (BAT) via 2-iminothiolane (2IT) and radiolabeled with 67Cu to prepare 67Cu-2IT-BAT-Lym-1; 131I-Lym-1 was preparred by the chloramine-T reaction. Planar imaging was used to quantitate 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1 in organs and tumors daily for 3 days or longer. 67Cu-2IT-BAT-Lym-1 exhibited higher peak concentration in 92% (12 of 13) of tumors and a longer biological half-time in every tumor than 131I-Lym-1. The mean tumor concentration (%ID/g) of 67Cu-2IT-BAT-Lym-1 was 1.7, 2.2, and 2.8 times that of 131I-Lym-1 at 0, 24, and 48 h after injection, respectively. The mean biological half-times of 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 in tumor were 8.8 and 2.3 days, respectively. Consequently, the mean tumor radiation dose delivered by 67Cu-2IT-BAT-Lym-1 was twice that of 131I-Lym-1, 2.8 (range 0.8-6.7), and 1.4 (range 0.4-35) Gy/GBq, respectively. 67Cu-2IT-BAT-Lym-1 delivered a lower marrow radiation dose than 131I-Lym-1; hence, the tumor:marrow therapeutic indices were 29 and 9.7, respectively. Radiation doses from 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 to normal tissues were similar except for liver, which received a higher dose from 67Cu-2IT-BAT-Lym-1. Images obtained with 67Cu-2IT-BAT-Lym-1 were superior. Radiation dosimetry data for 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 agreed with corresponding data from the larger populations of patients from which the matched population for the current study was drawn. In conclusion, 67Cu-2IT-BAT-Lym-1 given to non-Hodgkin's lymphoma patients in close temporal proximity to 131I-Lym-1 exhibited greater uptake and longer retention in tumor, resulting in higher radiation dose and therapeutic index than 131I-Lym-1. These as well as other factors suggest that 67Cu-2IT-BAT-Lym-1 may be superior to 131I-Lym-1 for RIT.


Differential expression of ryanodine receptor isoforms after spinal cord injury.
Ryanodine receptors (RyRs) are highly conductive intracellular Ca2+ release channels and are widely expressed in many tissues, including the central nervous system. RyRs have been implicated in intracellular Ca2+ overload which can drive secondary damage following traumatic injury to the spinal cord (SCI), but the spatiotemporal expression of the three isoforms of RyRs (RyR1-3) after SCI remains unknown. Here, we analyzed the gene and protein expression of RyR isoforms in the murine lumbar dorsal root ganglion (DRG) and the spinal cord lesion site at 1, 2 and 7 d after a mild contusion SCI. Quantitative RT PCR analysis revealed that RyR3 was significantly increased in lumbar DRGs and at the lesion site at 1 and 2 d post contusion compared to sham (laminectomy only) controls. Additionally, RyR2 expression was increased at 1 d post injury within the lesion site. RyR2 and -3 protein expression was localized to lumbar DRG neurons and their spinal projections within the lesion site acutely after SCI. In contrast, RyR1 expression within the DRG and lesion site remained unaltered following trauma. Our study shows that SCI initiates acute differential expression of RyR isoforms in DRG and spinal cord.


Persistent Cryptococcus neoformans pulmonary infection in the rat is associated with intracellular parasitism, decreased inducible nitric oxide synthase expression, and altered antibody responsiveness to cryptococcal polysaccharide.
Fungal pathogens are notorious for causing chronic and latent infections, but the mechanism by which they evade the immune response is poorly understood. A major limitation in the study of chronic fungal infection has been the lack of suitable animal models where the infection is controlled and yet persists. Pulmonary Cryptococcus neoformans infection in rats results in a diffuse pneumonitis that resolves without dissemination or scarring except for the persistence of interstitial and subpleural granulomas that harbor viable cryptococci inside macrophages and epithelioid cells. Infected rats are asymptomatic but remain infected for as long as 18 months after inoculation with C. neoformans. Containment of infection is associated with granuloma formation that can be partially abrogated by glucocorticoid administration. Using this model, we identified several features associated with persistent infection in the rat lung, including (i) localization of C. neoformans to discrete, well-organized granulomas; (ii) intracellular persistence of C. neoformans within macrophages and epithelioid cells; (iii) reduced inducible nitric oxide synthase expression by granulomas harboring C. neoformans; and (iv) reduced antibody responses to cryptococcal polysaccharide. The results show that maintenance of persistent infection is associated with downregulation of both cellular and humoral immune responses.


Benzodiazepines, Codispensed Opioids, and Mortality among Patients Initiating Long-Term In-Center Hemodialysis.
Mortality from benzodiazepine/opioid interactions is a growing concern in light of the opioid epidemic. Patients on hemodialysis suffer from a high burden of physical/psychiatric conditions, which are treated with benzodiazepines, and they are three times more likely to be prescribed opioids than the general population. Therefore, we studied mortality risk associated with short- and long-acting benzodiazepines and their interaction with opioids among adults initiating hemodialysis. The cohort of 69,368 adults initiating hemodialysis (January 2013 to December 2014) was assembled by linking US Renal Data System records to Medicare claims. Medicare claims were used to identify dispensed benzodiazepines and opioids. Using adjusted Cox proportional hazards models, we estimated the mortality risk associated with benzodiazepines (time varying) and tested whether the benzodiazepine-related mortality risk differed by opioid codispensing. Within 1 year of hemodialysis initiation, 10,854 (16%) patients were dispensed a short-acting benzodiazepine, and 3262 (5%) patients were dispensed a long-acting benzodiazepine. Among those who were dispensed a benzodiazepine during follow-up, codispensing of opioids and short-acting benzodiazepines occurred among 3819 (26%) patients, and codispensing of opioids and long-acting benzodiazepines occurred among 1238 (8%) patients. Patients with an opioid prescription were more likely to be subsequently dispensed a short-acting benzodiazepine (adjusted hazard ratio, 1.66; 95% confidence interval, 1.59 to 1.74) or a long-acting benzodiazepine (adjusted hazard ratio, 1.11; 95% confidence interval, 1.03 to 1.20). Patients dispensed a short-acting benzodiazepine were at a 1.45-fold (95% confidence interval, 1.35 to 1.56) higher mortality risk compared with those without a short-acting benzodiazepine; among those with opioid codispensing, this risk was 1.90-fold (95% confidence interval, 1.65 to 2.18; Pinteraction<0.001). In contrast, long-acting benzodiazepine dispensing was inversely associated with mortality (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72 to 0.99) compared with no dispensing of long-acting benzodiazepine; there was no differential risk by opioid dispensing (Pinteraction=0.72). Codispensing of opioids and short-acting benzodiazepines is common among patients on dialysis, and it is associated with higher risk of death.


Controllable multiband terahertz notch filter based on a parallel plate waveguide with a single deep groove.
The influence of the air gap on the response of transmission for a transverse-electric mode parallel plate waveguide with a single deep groove has been experimentally studied. As the air gap is larger than the resonant wavelength of a high-order cavity mode in a single deep grooved waveguide, only the fundamental cavity mode can be excited and the single resonance (band) can be observed in a transmission spectrum. The decrease of the air gap can not only efficiently push the radiation of the fundamental cavity mode into the deep groove but also excite the high-order cavity modes, resulting in multiple resonances (multiband) in the corresponding spectrum. Based on the above observations, a tunable multiband terahertz notch filter has been proposed and the variation of the air gap has turned out to be an effective method to select band number. Experimental data and simulated results verify this band number tunability.


Effect of laparoscopic antireflux surgery on esophageal motility.
The effect of laparoscopic antireflux surgery on esophageal motility is incompletely understood, and any indication for this procedure in patients with motility disorder is disputed in literature. We evaluated the influence of laparoscopic Nissen fundoplication on impaired esophageal motility. In this pathological manometric study, we divided the patients into two groups preoperatively: the hypomotility group (mean amplitude of esophageal contraction wave <40 mm Hg; HYPO group, n = 11) and the normal group (mean amplitude of esophageal contraction wave >40 mm Hg; NORM group, n = 43). The amplitudes of esophageal contraction waves 3 and 8 cm above the lower esophageal sphincter and the percentage of peristaltic contraction waves of the tubular esophagus were analyzed pre- and postoperatively. In total, 54 patients with GERD underwent esophageal manometry before and 6 months after Nissen fundoplication. The length and pressure of the lower esophageal sphincter were increased in both groups postoperatively (p < 0.01). Patients in the HYPO group (n = 11) showed a statistically significant increase of mean amplitude of esophageal contraction (32.8 vs. 57.3 mm Hg; p < 0.01), while no change was found in the NORM group (n = 43). A total of 72% of patients with preoperative motility disorder showed normal postoperative manometry. Nissen fundoplication normalizes esophageal motility, especially in patients with preoperative hypomotility. Patients with impaired esophageal motility should not per se be excluded from antireflux surgery.


Dielectric relaxation and crystallization of nanophase separated 1-propanol-isoamylbromide mixture.
The effects of liquid-liquid phase separation on molecular relaxation of an apparently homogeneous mixture of 1-propanol and isoamylbromide has been studied by dielectric spectroscopy over a broad frequency and temperature range, and its crystallization kinetics investigated in real time. The mixture shows two widely separated relaxation processes, as before, with the faster relaxation due to the orientational diffusion of isoamylbromide and the slower due to that of 1-propanol. In the mixture, the scaled contribution to permittivity from orientation polarization, Deltaepsilon, of isoamylbromide is about the same as in the pure state, but that of 1-propanol decreases by a factor of approximately 3 at 120 K. As the temperature is decreased, this difference remains constant. The relaxation time, tau, of isoamylbromide and its distribution parameter remains the same as for the pure liquid, but that of 1-propanol is longer and increases with decrease in T, becoming approximately 130 times the pure liquid's value at 119 K. This is in contrast to the finding for an isomeric heptanol, whose tau had decreased. Extrapolation suggests that at T>151 K, tau of 1-propanol in the mixture may become less than that in the pure liquid (the isoamylbromide component crystallizes before this temperature could be reached). This indicates that Tg corresponding to tau of 10(3) s for 1-propanol in the mixture would be higher than in the pure liquid. Crystallization of the two components in the mixture occurs at different rates and 1-propanol remains partially uncrystallized while isoamylbromide completely crystallizes. tau of any remaining liquid isoamylbromide does not change in the presence of crystallized states while tau of residual liquid 1-propanol in the mixture is reduced. The mixture phase separates in submicron or nanosize aggregates of the alcohol in isoamylbromide, without affecting the latter's relaxation kinetics, while its own epsilon(s) decreases and tau increases. Consequences of the finding for various relaxation mechanisms are briefly described.


Microfluidic fabrication of microparticles for biomedical applications.
Droplet microfluidics offers exquisite control over the flows of multiple fluids in microscale, enabling fabrication of advanced microparticles with precisely tunable structures and compositions in a high throughput manner. The combination of these remarkable features with proper materials and fabrication methods has enabled high efficiency, direct encapsulation of actives in microparticles whose features and functionalities can be well controlled. These microparticles have great potential in a wide range of bio-related applications including drug delivery, cell-laden matrices, biosensors and even as artificial cells. In this review, we briefly summarize the materials, fabrication methods, and microparticle structures produced with droplet microfluidics. We also provide a comprehensive overview of their recent uses in biomedical applications. Finally, we discuss the existing challenges and perspectives to promote the future development of these engineered microparticles.


Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis.
We assessed axonal loss in the normal appearing white matter of the corpus callosum in postmortem brains of patients with multiple sclerosis, using quantitative measures of both axonal density and white matter atrophy. The calculated total number of axons was reduced significantly (mean +/- SD, 5.4 x 10(7) +/- 3.1 x 10(7)) compared with normal controls (11.6 x 10(7) +/- 2.2 x 10(7), p = 0.001) with a reduction both in axonal density (median, 34%; range, 16-56%; p = 0.004) and area (mean +/- SD: multiple sclerosis, 584 +/- 170 mm2; controls, 871 +/- 163 mm2; p = 0.004). These results confirm substantial axonal loss in the normal appearing white matter and demonstrate that measures of both axonal density and white matter volume are necessary to appreciate the full extent of axonal loss.


Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival.
Endothelial differentiation gene (Edg) proteins are G-protein-coupled receptors activated by lysophospholipid mediators: sphingosine-1-phosphate (S1P) or lysophosphatidic acid. We show that in the CNS, expression of Edg8/S1P5, a high-affinity S1P receptor, is restricted to oligodendrocytes and expressed throughout development from the immature stages to the mature myelin-forming cell. S1P activation of Edg8/S1P5 on O4-positive pre-oligodendrocytes induced process retraction via a Rho kinase/collapsin response-mediated protein signaling pathway, whereas no retraction was elicited by S1P on these cells derived from Edg8/S1P5-deficient mice. Edg8/S1P5-mediated process retraction was restricted to immature cells and was no longer observed at later developmental stages. In contrast, S1P activation promoted the survival of mature oligodendrocytes but not of pre-oligodendrocytes. The S1P-induced survival of mature oligodendrocytes was mediated through a pertussis toxin-sensitive, Akt-dependent pathway. Our data demonstrate that Edg8/S1P5 activation on oligodendroglial cells modulates two distinct functional pathways mediating either process retraction or cell survival and that these effects depend on the developmental stage of the cell.


Adverse events associated with pediatric spinal manipulation: a systematic review.
Spinal manipulation is a noninvasive manual procedure applied to specific body tissues with therapeutic intent. Although spinal manipulation is commonly used in children, there is limited understanding of the pediatric risk estimates. Our goal was to systematically identify and synthesize available data on adverse events associated with pediatric spinal manipulation. A comprehensive search was performed of 8 major electronic databases (eg, Medline, AMED, MANTIS) from inception to June 2004 irrespective of language. Reports were included if they (1) were a primary investigation of spinal manipulation (eg, observation studies, controlled trials, surveys), (2) included a study population of children who were aged 18 years or younger, and (3) reported data on adverse events. Data were summarized to demonstrate the nature and severity of adverse events that may result rather than their incidence. Thirteen studies (2 randomized trials, 11 observational reports) were identified for inclusion. We identified 14 cases of direct adverse events involving neurologic or musculoskeletal events. Nine cases involved serious adverse events (eg, subarachnoidal hemorrhage, paraplegia), 2 involved moderately adverse events that required medical attention (eg, severe headache), and 3 involved minor adverse events (eg, midback soreness). Another 20 cases of indirect adverse events involved delayed diagnosis (eg, diabetes, neuroblastoma) and/or inappropriate provision of spinal manipulation for serious medical conditions (ie, meningitis, rhabdomyosarcoma). Serious adverse events may be associated with pediatric spinal manipulation; neither causation nor incidence rates can be inferred from observational data. Conduct of a prospective population-based active surveillance study is required to properly assess the possibility of rare, yet serious, adverse events as a result of spinal manipulation on pediatric patients.


Effect of race on survival following in-hospital cardiopulmonary resuscitation.
Race has been shown to be a significant predictive factor in a number of treatment decisions and outcomes, including survival following out-of-hospital cardiopulmonary resuscitation (CPR). The goal of this study was to determine whether race is associated with the rate of survival to discharge following in-hospital CPR. Consecutive adult patients undergoing attempted CPR at three teaching hospitals were identified. Demographic, clinical, and laboratory data from the time of admission, information about the resuscitation attempt, and the outcome of CPR were recorded for each patient. The characteristics of black and non-black patients were compared. Logistic regression was used to determine whether race was a significant independent predictor of CPR outcome. A total of 656 patients were identified. Black patients had a higher mean severity of illness as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) III score, were more likely to have an initial rhythm of electromechanical dissociation or asystole, were less likely to have an admitting diagnosis of myocardial infarction or a history of coronary artery disease, and had a higher serum creatinine level, lower serum albumin value, and lower 24-hour urine output for the first 24 hours. There was no difference between black and nonblack patients regarding the rate of survival of the resuscitative effort itself. However, black patients were significantly less likely than nonblack patients to survive to discharge following resuscitation (Mantel-Haenszel odds ratio, 0.31; 95% confidence interval, 0.15 to 0.68). This relationship persisted after adjusting for potential confounders such as age, sex, initial cardiac rhythm, diagnosis of pneumonia, serum creatinine level, hospital, and APACHE III score. Black race is significantly associated with a lower rate of survival to discharge following in-hospital CPR. Further work is needed to explore this association in other settings; to examine the effect of other possible confounding variables, such as tobacco use, socioeconomic status, and marital status; and to further study the determinants of physician decision-making about resuscitation.


Analytical considerations for the use of the paleothermometer tetraether index(86) and the branched vs isoprenoid tetraether index regarding the choice of cleanup and instrumental conditions.
The tetraether index of tetraethers consisting of 86 carbons (TEX(86)) is a novel proxy applied to obtain paleotemperature reconstructions from marine and lacustrine settings. It is usually applied alongside the branched vs isoprenoid tetraether (BIT) index, which provides paleoenvironmental information as well as information on the reliability of TEX(86). Both indices are calculated via the analysis of glycerol dialkyl glycerol tetraethers or GDGTs by means of high-performance liquid chromatography/atmospheric pressure chemical ionization-mass spectrometry (HPLC/APCI-MS). Here we test the performance of alternative methods for sample cleanup and instrumental analysis. In particular, we evaluate using alkaline hydrolysis as an alternative cleanup step to alumina column fractionation and show that the resulting TEX(86) and BIT are statistically equivalent. We also test two different adsorbents in the activated or deactivated state for preparative column fractionation and show that any of them can be used to measure TEX(86) but that a certain discrimination between GDGTs used in the BIT index can occur. Regarding the mass spectrometer design, an ion-trap is shown to be as precise as a quadrupole mass spectrometer for GDGT analysis. Some differences are observed for TEX(86) and especially for BIT values obtained from both MS designs. We provide evidence that the APCI conditions are at least partly responsible for these differences. We recommend caution when comparing BIT values among laboratories as this index seems to be especially sensitive to analytical conditions.


Regulation of miRNA strand selection: follow the leader?
miRNA strand selection is the process that determines which of the two strands in a miRNA duplex becomes the active strand that is incorporated into the RISC (RNA-induced silencing complex) (named the guide strand, leading strand or miR) and which one gets degraded (the passenger strand or miR*). Thermodynamic features of the duplex appear to play an important role in this decision; the strand with the weakest binding at its 5'-end is more likely to become the guide strand. Other key characteristics of human miRNA guide strands are a U-bias at the 5'-end and an excess of purines, whereas the passenger strands have a C-bias at the 5'-end and an excess of pyrimidines. Several proteins are known to play a role in strand selection [Ago (Argonaute), DICER, TRBP (trans-activation response RNA-binding protein), PACT (protein activator of dsRNA-dependent protein kinase) and Xrn-1/2]; however, the mechanisms by which these proteins act are largely unknown. For several miRNAs the miR/miR* ratio varies dependent on cell type, developmental stage and in different disease states, suggesting that strand selection is a tightly controlled process. The present review discusses our current knowledge regarding the factors and processes involved in strand selection and the many questions that still remain.


Current concepts in the management Radial Longitudinal Deficiency.
Radial longitudinal deficiency represents a spectrum of musculoskeletal hypoplasia and dysplasia affecting the upper limb involving mainly the radial aspect of the forearm, wrist, and hand and not infrequently the proximal arm. 2/3rd of the patients with this condition suffer from an associated medical or musculoskeletal disorder and 1/3rd of them show features of a well-known syndrome with systemic manifestations. Hence it is mandatory to do a detailed clinical, radiological and laboratory evaluation which should also include genetic counselling and assessment. Its management has evolved greatly since the beginning of last century. The vast variations developed for the treatment only reflects on the persisting controversy on the ideal treatment which still eludes the medical fraternity. Current treatment options for wrist deformities include radialization or centralization with or without distraction which unfortunately has often shown poor outcomes with high rates of recurrence and poor growth of ulna leading some workers to suggest alternative techniques, which include microsurgical reconstruction using the proximal fibula and the second toe. The management of the associated hypoplastic thumb has been encouraging with recent improvements in classifications and increased options for milder deformities. The article reviews the management options available for this common condition with respect to the recent developments in literature.


Structure-function analysis of STRUBBELIG, an Arabidopsis atypical receptor-like kinase involved in tissue morphogenesis.
Tissue morphogenesis in plants requires the coordination of cellular behavior across clonally distinct histogenic layers. The underlying signaling mechanisms are presently being unraveled and are known to include the cell surface leucine-rich repeat receptor-like kinase STRUBBELIG in Arabidopsis. To understand better its mode of action an extensive structure-function analysis of STRUBBELIG was performed. The phenotypes of 20 EMS and T-DNA-induced strubbelig alleles were assessed and homology modeling was applied to rationalize their possible effects on STRUBBELIG protein structure. The analysis was complemented by phenotypic, cell biological, and pharmacological investigations of a strubbelig null allele carrying genomic rescue constructs encoding fusions between various mutated STRUBBELIG proteins and GFP. The results indicate that STRUBBELIG accepts quite some sequence variation, reveal the biological importance for the STRUBBELIG N-capping domain, and reinforce the notion that kinase activity is not essential for its function in vivo. Furthermore, individual protein domains of STRUBBELIG cannot be related to specific STRUBBELIG-dependent biological processes suggesting that process specificity is mediated by factors acting together with or downstream of STRUBBELIG. In addition, the evidence indicates that biogenesis of a functional STRUBBELIG receptor is subject to endoplasmic reticulum-mediated quality control, and that an MG132-sensitive process regulates its stability. Finally, STRUBBELIG and the receptor-like kinase gene ERECTA interact synergistically in the control of internode length. The data provide genetic and molecular insight into how STRUBBELIG regulates intercellular communication in tissue morphogenesis.


Microbicide clinical trial adherence: insights for introduction.
After two decades of microbicide clinical trials it remains uncertain if vaginally- delivered products will be clearly shown to reduce the risk of HIV infection in women and girls. Furthermore, a microbicide product with demonstrated clinical efficacy must be used correctly and consistently if it is to prevent infection. Information on adherence that can be gleaned from microbicide trials is relevant for future microbicide safety and efficacy trials, pre-licensure implementation trials, Phase IV post-marketing research, and microbicide introduction and delivery. Drawing primarily from data and experience that has emerged from the large-scale microbicide efficacy trials completed to-date, the paper identifies six broad areas of adherence lessons learned: (1) Adherence measurement in clinical trials, (2) Comprehension of use instructions/Instructions for use, (3) Unknown efficacy and its effect on adherence/Messages regarding effectiveness, (4) Partner influence on use, (5) Retention and continuation and (6) Generalizability of trial participants' adherence behavior. Each is discussed, with examples provided from microbicide trials. For each of these adherence topics, recommendations are provided for using trial findings to prepare for future microbicide safety and efficacy trials, Phase IV post-marketing research, and microbicide introduction and delivery programs.


Brief deprivation of vision after unilateral lesions of the frontal eye field prevents contralateral inattention.
Brief deprivation of vision after unilateral lesions of the frontal eye field prevents the appearance of contralateral inattention to visual, auditory, and somatosensory stimuli. The forced circling that accompanies inattention, however, is not affected. An equivalent preoperative period in the dark only partly reduces inattention symptoms. Visual deprivation does not reduce or prevent inattention resulting from lesions of the superior colliculus.


Bucco-lingual crestal bone changes after immediate and delayed implant placement.
Implants placed immediately after tooth extraction offer several advantages, but many authors have reported problems in filling the residual gap between the implant and the socket walls. Barrier and grafting techniques have been tested and yield varying results, so it has been suggested that the timing of implant placement may be important for success. The aim of this study was to analyze bone healing and coronal bone remodeling around 35 implants, 20 placed immediately after tooth removal and 15 placed 6 to 8 weeks after extraction. All the implants were submerged and placed within the alveoli confines, leaving circumferential defects because the implants did not contact the bone at their coronal aspects; stabilization was achieved in the bone apically. After implant placement the mean distance from buccal bone to lingual bone was 10 mm (SD 1.522) for immediate implants and 8.86 mm (SD 2.356) for delayed implants. No membrane or filling materials were used. Primary flap closure was accomplished in all cases. At second-stage surgery all peri-implant defects were filled, and the mean distance from buccal bone to lingual bone was 8.1 mm (SD 1.334) for immediate implants and 5.8 mm (SD 1.265) for delayed implants. This pattern of coronal bone remodeling, showing a narrowing of the bucco-lingual width, was clinically similar for the two groups, although it should be noted that the delayed implants exhibited smaller bucco-lingual bone width already at the first measurement: it can be speculated that early remodeling may start immediately after tooth extraction and continue, non-uniformly, even after delayed implant placement. This study suggests that circumferential defects could heal clinically without any guided bone regeneration (GBR) in both experimental groups, and that the procedure was virtually free from complications in the postoperative period, probably because of the absence of barrier membranes and/or grafting materials. Histologically, peri-implant defects of over 1.5 mm heal by connective tissue apposition, rather than by direct bone-to-implant contact, but clinically this healing may be very successful. No histological analysis was carried out in the present study, but even the largest residual gaps were filled with hard tissue that could not be probed. Thus, such outcomes can be considered clinically successful. The different rate of bone remodeling around immediate or delayed implants could have implications for the preferred timing of implant placement in sites of high esthetic concern.


Expression of tissue kallikrein in human kidney.
1. We studied the distribution of human tissue kallikrein mRNA in normal and diseased kidney, using in situ hybridization, together with immunohistochemical localization of renal kallikrein protein. Materials studied were (a) normal tissue from kidneys removed because of localized renal carcinoma, (b) kidneys removed because of post-traumatic haemorrhage and (c) renal biopsy specimens from patients with membranous glomerulonephritis and nephrotic syndrome. 2. A 1.35 kb EcoRI fragment of human tissue kallikrein cDNA was labelled with [32P]dCTP using the random-primer technique, and used for in situ hybridization. A specific rabbit antibody to active human urinary kallikrein was employed for immunocytochemistry, using a peroxidase-antiperoxidase method. 3. By in situ hybridization, no tissue kallikrein gene expression was seen in the carcinoma nephrectomy specimens. Positive expression was seen in the trauma nephrectomy tissue, and in four of five nephrotic syndrome biopsies. In all kidneys, expression was confined to the renal cortex. The dominant site of gene expression was the distal tubule. Apart from one area of positive signal related to an epithelial cell of Bowman's capsule, expression was not observed in glomeruli. Expression was also seen in the walls of large- and medium-sized blood vessels. 4. By immunohistochemistry, the dominant site of immunoreactivity was the distal tubule. Dense staining was also seen in granular peripolar cells and in isolated parietal epithelial cells close to the vascular pole. Isolated immunoreactive cells were seen in the media of large- and medium-sized arteries. 5. The tissue kallikrein gene in the kidney may not be constitutively expressed, but is expressed in response to physiological or pathological stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibition of human immunodeficiency virus type 1 reverse transcriptase, RNase H, and integrase activities by hydroxytropolones.
Human immunodeficiency virus type I reverse transcriptase (RT) possesses distinct DNA polymerase and RNase H sites, whereas integrase (IN) uses the same active site to perform 3'-end processing and strand transfer of the proviral DNA. These four enzymatic activities are essential for viral replication and require metal ions. Two Mg2+ ions are present in the RT polymerase site, and one or two Mg2+ ions are required for the catalytic activities of RNase H and IN. We tested the possibility of inhibition of the RT polymerase and RNase H as well as the IN 3'-end processing and transfer activities of purified enzymes by a series of 3,7-dihydroxytropolones designed to target two Mg2+ ions separated by approximately 3.7 angstroms. The RT polymerase and IN 3' processing and strand transfer activities were inhibited at submicromolar concentrations, while the RNase H activity was inhibited in the low micromolar range. In all cases, the lack of inhibition by tropolones and O-methylated 3,7-dihydroxytropolones was consistent with the active molecules binding the metal ions in the active site. In addition, inhibition of the DNA polymerase activity was shown to depend on the Mg2+ concentration. Furthermore, selective inhibitors were identified for several of the activities tested, leaving some potential for design of improved inhibitors. However, all tested compounds exhibited cellular toxicity that presently limits their applications.


Joint Symposium of Korean Cancer Association & UICC-ARO-Cross-boundary cancer studies: cancer and Universal Health Coverage (UHC) in Asia.
On 16 June 2016, the Korean Cancer Association (KCA) and Union for International Cancer Control-Asia Regional Office (UICC-ARO) organized a joint symposium as part of the official program of the 42nd Annual Meeting of the Korean Cancer Association to discuss the topic 'Cross-boundary Cancer Studies: Cancer and Universal Health Coverage (UHC) in Asia.' Universal Health Coverage is included in the Sustainable Development Goals adopted by the United Nations as part of the 2030 Agenda for Sustainable Development. The objectives of UHC are to ensure that all people can receive high-quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The participants discussed the growing cost of cancer in the Asian region and the challenges that this poses to the establishment and deployment of UHC in the countries of Asia, all of which face budgetary and other systemic constraints in controlling cancer in the region. Representatives from Korea, Japan and Indonesia reported on the status of UHC in their countries and the challenges that are being faced, many of which are common to other countries in Asia. In addition to country-specific presentations about the progress of and challenges facing UHC, there were also presentations from WHO Kobe Centre concerning advancing UHC in non-communicable diseases and prospects for further collaboration and research on UHC. A presentation from the University of Tokyo also highlighted the need to focus on multidisciplinary studies in an age of globalization and digitization.


Metabolism and DNA interaction of 2',3'-didehydro-2',3'-dideoxythymidine in human bone marrow cells.
2',3'-Didehydro-2',3'-dideoxythymidine (D4T) is a potent inhibitor of human immunodeficiency virus (HIV), with low hematological toxicity. In the present study, the cellular pharmacology of D4T was investigated in human bone marrow cells (BMC), in an attempt to understand the mechanism of the observed low bone marrow toxicity. After exposure of human BMC to 10 microM [3H]D4T for 24 hr, D4T-5'-triphosphate (D4T-TP) was the predominant metabolite, reaching a concentration of 0.3 pmol/10(6) cells. The D4T-5'-monophosphate levels were slightly lower, whereas the D4T-5'-diphosphate levels were about 6-fold lower than those of D4T-TP at 24 hr. Nucleic acids of human BMC exposed to 10 microM [3H]D4T for 24 hr were purified and analyzed by cesium sulfate density gradient centrifugation. No radioactivity was detected in the RNA region, whereas a limited amount was associated with the DNA region. The amount of label incorporated into DNA correlated with the extracellular D4T concentration and the length of incubation time. Enzymatic hydrolysis of radiolabeled DNA and subsequent analysis by high performance liquid chromatography demonstrated incorporation of both D4T and thymidine (dThd) into DNA. Degradation of D4T to thymine and subsequent formation of labeled dThd was also detected in human BMC. Pulse (24 hr)-chase (48 hr) experiments with 10 microM [3H]D4T demonstrated that the amount of radiolabel from D4T in DNA decreased over time during the chase. Under similar conditions, [3H]3'-azido-3'-deoxythymidine (AZT) incorporated into DNA of human BMC did not decrease during the chase. Although D4T-TP standard was demonstrated to be unstable at 37 degrees and neutral pH, D4T was much more stable in solution when incorporated into newly synthesized DNA isolated from human BMC, suggesting that enzymatic excision may be the mechanism for D4T removal from DNA. In summary, although higher concentrations of D4T-TP, compared with AZT-5'-triphosphate, are observed in human BMC, after exposure of cells to similar extracellular concentrations of parent drug, steady state levels of D4T incorporated into DNA are 10-50-fold lower, compared with AZT. Competition with dTTP formed by D4T metabolism and excision of D4T from DNA may be responsible, in part, for these effects. This study further demonstrates that incorporation of 2',3'-dideoxynucleosides into nuclear DNA of human BMC may be related to the ability of these anti-HIV agents to induce hematological side effects.


Domains in cell plasma membranes investigated by near-field scanning optical microscopy.
Near-field scanning optical microscopy (NSOM) uses the near-field interaction of light from a sharp fiber-optic probe with a sample of interest to image surfaces at a resolution beyond the diffraction limit of conventional optics. We used NSOM to image fluorescently labeled plasma membranes of fixed human skin fibroblasts, either dried or in buffer. A patchy distribution of a fluorescent lipid analog suggestive of lipid domains was observed in the fixed, dried cells. The sizes of these patches were consistent with the sizes of domains implied by fluorescence photobleaching recovery measurements. Patches of fluorescent lipid analog were not spatially correlated with patches of transmembrane proteins, HLA class I molecules labeled with fluorescent antibody; the patchiness of the HLA class I molecules was on a smaller scale and was not localized to the same regions of membrane as the lipid analog. Sizes of HLA patches were deduced from a two-dimensional spatial autocorrelation analysis of NSOM images that resolved patches with radii of approximately 70 and approximately 600 nm on fixed, dried cells labeled with IgG and 300-600 nm on cells labeled with Fab and imaged in buffer. The large-size patches were also resolved by far-field microscopy. Both the spatial autocorrelation analysis and estimates from fluorescence intensity indicate that the small patches seen on fixed, dried cells contain approximately 25-125 HLA-I molecules each.


Is serial testing required to diagnose imported malaria in the era of rapid diagnostic tests?
Exclusion of malaria traditionally requires three negative serial thick and thin blood films. However, many clinical laboratories now routinely perform rapid diagnostic tests (RDTs) in addition to blood films when malaria is suspected. We sought to determine whether serial testing is necessary in this setting. We examined 388 cases of malaria diagnosed during 1999-2010 at three laboratories in Melbourne, Australia. For each case, we ascertained whether the diagnosis was made on initial or follow-up testing. Nine cases (3.5%) were diagnosed after a negative initial blood film and RDT: 7 Plasmodium vivax, 1 P. ovale, and 1 P. falciparum. Of four case-patients with P. vivax in which clinical data were available, all had recent exposure to antimalarial medication. Our data suggest that among patients who have not received recent anti-malarial therapy, and when RDTs are performed and blood films are prepared, most malaria diagnoses are made by using the first set of tests.


Positive regulation of CXCR4 expression and signaling by interleukin-7 in CD4+ mature thymocytes correlates with their capacity to favor human immunodeficiency X4 virus replication.
The emergence of X4 human immunodeficiency virus type 1 (HIV-1) variants in infected individuals is associated with poor prognosis. One of the possible causes of this emergence might be the selection of X4 variants in some specific tissue compartment. We demonstrate that the thymic microenvironment favors the replication of X4 variants by positively modulating the expression and signaling of CXCR4 in mature CD4(+) CD8(-) CD3(+) thymocytes. Here, we show that the interaction of thymic epithelial cells (TEC) with these thymocytes in culture induces an upregulation of CXCR4 expression. The cytokine secreted by TEC, interleukin-7 (IL-7), increases cell surface expression of CXCR4 and efficiently overcomes the downregulation induced by SDF-1 alpha, also produced by TEC. IL-7 also potentiates CXCR4 signaling, leading to actin polymerization, a process necessary for virus entry. In contrast, in intermediate CD4(+) CD8(-) CD3(-) thymocytes, the other subpopulation known to allow virus replication, TEC or IL-7 has little or no effect on CXCR4 expression and signaling. CCR5 is expressed at similarly low levels in the two thymocyte subpopulations, and neither its expression nor its signaling was modified by the cytokines tested. This positive regulation of CXCR4 by IL-7 in mature CD4(+) thymocytes correlates with their high capacity to favor X4 virus replication compared with intermediate thymocytes or peripheral blood mononuclear cells. Indeed, we observed an enrichment of X4 viruses after replication in thymocytes initially infected with a mixture of X4 (NL4-3) and R5 (NLAD8) HIV strains and after the emergence of X4 variants from an R5 primary isolate during culture in mature thymocytes.


Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy.
Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity. Sixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0-48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0-48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 μg.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations. A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR. ClinicalTrials.gov Identifier: NCT00640887.


Combining transcranial ultrasound with intelligent communication methods to enhance the remote assessment and management of stroke patients: Framework for a technology demonstrator.
With over 150,000 strokes in the United Kingdom every year, and more than 1 million living survivors, stroke is the third most common cause of death and the leading cause of severe physical disability among adults. A major challenge in administering timely treatment is determining whether the stroke is due to vascular blockage (ischaemic) or haemorrhage. For patients with ischaemic stroke, thrombolysis (i.e. pharmacological 'clot-busting') can improve outcomes when delivered swiftly after onset, and current National Health Service Quality Improvement Scotland guidelines are for thrombolytic therapy to be provided to at least 80 per cent of eligible patients within 60 min of arrival at hospital. Thrombolysis in haemorrhagic stroke could severely compound the brain damage, so administration of thrombolytic therapy currently requires near-immediate care in a hospital, rapid consultation with a physician and access to imaging services (X-ray computed tomography or magnetic resonance imaging) and intensive care services. This is near impossible in remote and rural areas, and stroke mortality rates in Scotland are 50 per cent higher than in London. We here describe our current project developing a technology demonstrator with ultrasound imaging linked to an intelligent, multi-channel communication device - connecting to multiple 2G/3G/4G networks and/or satellites - in order to stream live ultrasound images, video and two-way audio streams to hospital-based specialists who can guide and advise ambulance clinicians regarding diagnosis. With portable ultrasound machines located in ambulances or general practices, use of such technology is not confined to stroke, although this is our current focus. Ultrasound assessment is useful in many other immediate care situations, suggesting potential wider applicability for this remote support system. Although our research programme is driven by rural need, the ideas are potentially applicable to urban areas where access to imaging and definitive treatment can be restricted by a range of operational factors.


Thermus thermophilus L11 methyltransferase, PrmA, is dispensable for growth and preferentially modifies free ribosomal protein L11 prior to ribosome assembly.
The ribosomal protein L11 in bacteria is posttranslationally trimethylated at multiple amino acid positions by the L11 methyltransferase PrmA, the product of the prmA gene. The role of L11 methylation in ribosome function or assembly has yet to be determined, although the deletion of Escherichia coli prmA has no apparent phenotype. We have constructed a mutant of the extreme thermophile Thermus thermophilus in which the prmA gene has been disrupted with the htk gene encoding a heat-stable kanamycin adenyltransferase. This mutant shows no growth defects, indicating that T. thermophilus PrmA, like its E. coli homolog, is dispensable. Ribosomes prepared from this mutant contain unmethylated L11, as determined by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and are effective substrates for in vitro methylation by cloned and purified T. thermophilus PrmA. MALDI-TOF MS also revealed that T. thermophilus L11 contains a total of 12 methyl groups, in contrast to the 9 methyl groups found in E. coli L11. Finally, we found that, as with the E. coli methyltransferase, the ribosomal protein L11 dissociated from ribosomes is a more efficient substrate for in vitro methylation by PrmA than intact 70S ribosomes, suggesting that methylation in vivo occurs on free L11 prior to its incorporation into ribosomes.


Design and Characterization of a Fabric-Based Softness Display.
To enable a realistic tactile interaction with remote or virtual objects, softness information represents a fundamental property to be rendered via haptic devices. What is challenging is to reduce the complexity of such an information as it arises from contact mechanics and to find suitable simplifications that can lead an effective development of softness displays. A possible approach is to surrogate detailed tactile cues with information on the rate of spread of the contact area between the object and the finger as the contact force increases, i.e. force/area relation. This paradigm is called contact area spread rate. In this paper we discuss how such a paradigm has inspired the design of a tactile device (hereinafter referred to as Fabric Yielding Display, FYD-2), which exploits the elasticity of a fabric to mimic different levels of stiffness, while the contact area on the finger indenting the fabric is measured. In this manner, the FYD-2 can be controlled to reproduce force-area characteristics. In this work, we describe the FYD-2 architecture and report a psychophysical characterization. FYD-2 is shown to be able to accurately reproduce force-area curves of typical objects and to enable a reliable softness discrimination in human users.


Regeneration of acini in submandibular gland autografts.
Regeneration of submandibular gland (SMG) secretory parenchyma is remarkably impaired in salivary gland diseases and under experimental conditions such as in tissue culture and after isografting. In our study acinar regeneration was found to depend on the site where the SMG tissue was implanted. Implantation of several 2-3 mm3 fragments of SMG subcutaneously in the back of the same donor adult male rat resulted in initial necrosis and mononuclear cell infiltration of the autograft. Then there was epithelial proliferation with the appearance within 28 days of lobules which contained numerous duct-like structures and only a few or no acini. In contrast, implanting SMG fragments in the anatomical bed of the donor gland resulted in the appearance of a more differentiated autograft. Although the initial tissue changes were similar to those seen in the autografts in the subcutaneous tissues of the back, the SMG autograft in the neck also contained numerous acini by 42 and 56 days after implantation. These data support the view that the implantation site influences the course of cytodifferentiation in SMG autografts.


Polarization of cell growth in yeast. I. Establishment and maintenance of polarity states.
The ability to polarize is a fundamental property of cells. The yeast Saccharomyces cerevisiae has proven to be a fertile ground for dissecting the molecular mechanisms that regulate cell polarity during growth. Here we discuss the signaling pathways that regulate polarity. In the second installment of this two-part commentary, which appears in the next issue of Journal of Cell Science, we discuss how the actin cytoskeleton responds to these signals and guides the polarity of essentially all events in the yeast cell cycle. During the cell cycle, yeast cells assume alternative states of polarized growth, which range from tightly focused apical growth to non-focused isotropic growth. RhoGTPases, and in particular Cdc42p, are essential to guiding this polarity. The distribution of Cdc42p at the cell cortex establishes cell polarity. Cyclin-dependent protein kinase, Ras, and heterotrimeric G proteins all modulate yeast cell polarity in part by altering the distribution of Cdc42p. In turn, Cdc42p generates feedback signals to these molecules in order to establish stable polarity states and coordinate cytoskeletal organization with the cell cycle. Given that many of these signaling pathways are present in both fungi and animals, they are probably ancient and conserved mechanisms for regulating polarity.


Frequency analyses of prephonological spellings as predictors of success in conventional spelling.
The present study explored how children's prephonological writing foretells differential learning outcomes in primary school. The authors asked Portuguese-speaking preschool children in Brazil (mean age 4 year 3 months) to spell 12 words. Monte Carlo tests were used to identify the 31 children whose writing was not based on spellings or sounds of the target words. Two and a half years later, the children took a standardized spelling test. The more closely the digram (two-letter sequence) frequencies in the preschool task correlated with those in children's books, the better scores the children had in primary school, and the more preschoolers used letters from their own name, the lower their subsequent scores. Thus, preschoolers whose prephonological writing revealed attentiveness to the statistical properties of text subsequently performed better in conventional spelling. These analytic techniques may help in the early identification of children at risk for spelling difficulties.


A vertebrate gene, ticrr, is an essential checkpoint and replication regulator.
Eukaryotes have numerous checkpoint pathways to protect genome fidelity during normal cell division and in response to DNA damage. Through a screen for G2/M checkpoint regulators in zebrafish, we identified ticrr (for TopBP1-interacting, checkpoint, and replication regulator), a previously uncharacterized gene that is required to prevent mitotic entry after treatment with ionizing radiation. Ticrr deficiency is embryonic-lethal in the absence of exogenous DNA damage because it is essential for normal cell cycle progression. Specifically, the loss of ticrr impairs DNA replication and disrupts the S/M checkpoint, leading to premature mitotic entry and mitotic catastrophe. We show that the human TICRR ortholog associates with TopBP1, a known checkpoint protein and a core component of the DNA replication preinitiation complex (pre-IC), and that the TICRR-TopBP1 interaction is stable without chromatin and requires BRCT motifs essential for TopBP1's replication and checkpoint functions. Most importantly, we find that ticrr deficiency disrupts chromatin binding of pre-IC, but not prereplication complex, components. Taken together, our data show that TICRR acts in association with TopBP1 and plays an essential role in pre-IC formation. It remains to be determined whether Ticrr represents the vertebrate ortholog of the yeast pre-IC component Sld3, or a hitherto unknown metazoan replication and checkpoint regulator.


Primary cutaneous melanoma: an 18-year study.
Primary cutaneous melanoma still constitutes the main cause of skin cancer death in developed countries, and its incidence in recent years has been increasing in a steady, worrisome manner. This study evaluated the clinical, epidemiological and demographic aspects of this disease, and correlated them with patient prognosis. Using epidemiologic and clinical data, we analyzed 84 patients with mild to severe primary cutaneous melanoma treated between 1990 and 2007. Slides containing surgical specimens were analyzed, and new slides were made from archived paraffin sections when necessary. The melanoma incidence was higher in areas of sun exposure, with lesions commonly observed in the trunk for males, and lower limbs for females. In addition to Breslow's thickness and ulceration (p = 0.043 and p < 0.001, respectively), the mitotic rate per mm(2) also correlated with worse patient outcome (p = 0.0007). The sum of ulceration (0 when absent or 1 when present), the Breslow index (1 when <1 mm, 2 when >1 mm and <4 mm, 3 when >4 mm) and the mitotic index (0 when absent or 1 when > or =1 per mm(2)) allowed the establishment of a prognostic score: if the sum was equal to or over three, nearly all (91.7%) patients had systemic disease. The 5-year survival was approximately seventy percent. Because American Join Committee of Cancer Staging will update the classification of malignant tumors (TNM) staging in the near future, and introduce mitosis as a prognostic factor, our results show the importance of such a feature. Additional studies are necessary to confirm the importance of a prognostic score as proposed herein.


Association between number of cell phone contracts and brain tumor incidence in nineteen U.S. States.
Some concern has arisen about adverse health effects of cell phones, especially the possibility that the low power microwave-frequency signal transmitted by the antennas on handsets might cause brain tumors or accelerate the growth of subclinical tumors. We analyzed data from the Statistical Report: Primary Brain Tumors in the United States, 2000-2004 and 2007 cell phone subscription data from the Governing State and Local Sourcebook. There was a significant correlation between number of cell phone subscriptions and brain tumors in nineteen US states (r = 0.950, P < 0.001). Because increased numbers of both cell phone subscriptions and brain tumors could be due solely to the fact that some states, such as New York, have much larger populations than other states, such as North Dakota, multiple linear regression was performed with number of brain tumors as the dependent variable, cell phone subscriptions, population, mean family income and mean age as independent variables. The effect of cell phone subscriptions was significant (P = 0.017), and independent of the effect of mean family income (P = 0.894), population (P = 0.003) and age (0.499). The very linear relationship between cell phone usage and brain tumor incidence is disturbing and certainly needs further epidemiological evaluation. In the meantime, it would be prudent to limit exposure to all sources of electro-magnetic radiation.


Cardioprotective Role of Heat Shock Proteins in Atrial Fibrillation: From Mechanism of Action to Therapeutic and Diagnostic Target.
Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia worldwide and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Unfortunately, current AF therapy is only moderately effective and does not prevent AF progression from recurrent intermittent episodes (paroxysmal) to persistent and finally permanent AF. It has been recognized that AF persistence is related to the presence of electropathology. Electropathology is defined as structural damage, including degradation of sarcomere structures, in the atrial tissue which, in turn, impairs electrical conduction and subsequently the contractile function of atrial cardiomyocytes. Recent research findings indicate that derailed proteostasis underlies structural damage and, consequently, electrical conduction impairment. A healthy proteostasis is of vital importance for proper function of cells, including cardiomyocytes. Cells respond to a loss of proteostatic control by inducing a heat shock response (HSR), which results in heat shock protein (HSP) expression. Emerging clinical evidence indicates that AF-induced proteostasis derailment is rooted in exhaustion of HSPs. Cardiomyocytes lose defense against structural damage-inducing pathways, which drives progression of AF and induction of HSP expression. In particular, small HSPB1 conserves sarcomere structures by preventing their degradation by proteases, and overexpression of HSPB1 accelerates recovery from structural damage in experimental AF model systems. In this review, we provide an overview of the mechanisms of action of HSPs in preventing AF and discuss the therapeutic potential of HSP-inducing compounds in clinical AF, as well as the potential of HSPs as biomarkers to discriminate between the various stages of AF and recurrence of AF after treatment.


Meteorological normalisation and non-parametric smoothing for quality assessment and trend analysis of tropospheric ozone data.
Despite extensive efforts to ensure that sampling and installation and maintenance of instruments are as efficient as possible when monitoring air pollution data, there is still an indisputable need for statistical post processing (quality assessment). We examined data on tropospheric ozone and found that meteorological normalisation can reveal (i) errors that have not been eliminated by established procedures for quality assurance and control of collected data, as well as (ii) inaccuracies that may have a detrimental effect on the results of statistical tests for temporal trends. Moreover, we observed that the quality assessment of collected data could be further strengthened by combining meteorological normalisation with non-parametric smoothing techniques for seasonal adjustment and detection of sudden shifts in level. Closer examination of apparent trends in tropospheric ozone records from EMEP (European Monitoring and Evaluation Programme) sites in Finland showed that, even if potential raw data errors were taken into account, there was strong evidence of upward trends during winter and early spring.


Bifurcation study of blood flow control in the kidney.
Renal blood flow is maintained within a narrow window by a set of intrinsic autoregulatory mechanisms. Here, a mathematical model of renal hemodynamics control in the rat kidney is used to understand the interactions between two major renal autoregulatory mechanisms: the myogenic response and tubuloglomerular feedback. A bifurcation analysis of the model equations is performed to assess the effects of the delay and sensitivity of the feedback system and the time constants governing the response of vessel diameter and smooth muscle tone. The results of the bifurcation analysis are verified using numerical simulations of the full nonlinear model. Both the analytical and numerical results predict the generation of limit cycle oscillations under certain physiologically relevant conditions, as observed in vivo.


Extrapleural pneumonectomy after induction chemotherapy: perioperative outcome in 251 mesothelioma patients from three high-volume institutions.
Several publications have suggested that induction chemotherapy followed by extrapleural pneumonectomy (EPP) for patients with malignant pleural mesothelioma (MPM) patients is associated with exceedingly high morbidity and mortality, and the role of EPP is controversially debated. The present retrospective study analyzed the perioperative outcome in 251 consecutively treated patients at three high-volume mesothelioma centers. 251 MPM patients completed EPP after platinum-based induction chemotherapy at three institutions for thoracic surgery over more than 10 years. The rates of 30-day and 90-day mortality and of major morbidities (pulmonary embolism, postoperative bleeding, acute respiratory distress syndrome, empyema, bronchopleural fistula (BPF), chylothorax, patch failure) were recorded. Perioperative outcome was correlated to risk factors such as smoking history (pack years), age at operation, body mass index, spirometry results, C-reactive protein, American Society of Anesthesiologists classification, chemotherapy regimen used, blood loss during operation, duration of operation, and characteristics of the tumor (laterality, histologic subtype, pT and pN stage) to find factors predicting 30-day and 90-day mortality or major morbidity. The overall 30-day mortality was 5%. Within 90 days after operation, 8% of the patients died. The rates of 30-day and 90-day mortality were significantly higher in patients with high preoperative C-reactive protein values (p=0.001 and p<0.0005). The spirometry values forced expiratory volume in 1 second and forced vital capacity exhaled (FVCex) were both associated with 30-day and 90-day mortality (p=0.001 and p<0.0005; and p=0.002 and p<0.0005). Major morbidity occurred in 30% of the patients, significantly more often after right-sided EPP (p=0.01) and after longer operations (p<0.0005). Empyema (p<0.0005) and acute respiratory distress syndrome (p=0.02) were associated with longer duration of operation. EPP after induction chemotherapy is a demanding procedure but can be performed with acceptable morbidity and mortality if patients are well selected and treated at dedicated high-volume MPM centers.


The ecdysone receptor (EcR) is a major regulator of tissue development and growth in the marine salmonid ectoparasite, Lepeophtheirus salmonis (Copepoda, Caligidae).
The function of the ecdysone receptor (EcR) during development and molting has been thoroughly investigated in some arthropods such as insects but rarely in crustacean copepods such as the salmon louse Lepeophtheirus salmonis (L. salmonis) (Copepoda, Caligidae). The salmon louse is an ectoparasite on Atlantic salmon that has major economical impact in aquaculture due to the cost of medical treatment methods to remove lice from the fish. Handling of salmon louse infestations is further complicated by development of resistance towards available medicines. Understanding of basic molecular biological processes in the salmon louse is essential to enable development of new tools to control the parasite. In this study, we found L. salmonis EcR (LsEcR) transcript to be present in the neuronal somata of the brain, nuclei of muscle fibres and the immature intestine of the salmon louse. Furthermore, we explored the function of LsEcR during development using RNA interference mediated knock-down and through infection trials. Our results show that knock-down of LsEcR in the salmon louse is associated with hypotrophy of several tissues, delayed development and mortality. In addition, combined knock-down of LsEcR/LsRXR resulted in molting arrest during early larval stages.


Fostering completion of the doctor of philosophy degree through scholarly collegial support.
The doctor of philosophy (PhD) degree in nursing science prepares nurses to be scientists through a rigorous program of scholarship and research. Nurses who complete this degree are recognized globally as researchers who are expected to pursue a career of intellectual inquiry. Today, the internationally small cohort of PhD-prepared nurses contributes empirically to the generation and development of nursing science. There is currently a shortage of doctorally prepared nurses to meet the increased demands for researchers and educators in schools of nursing and experts in patient care. The Institute of Medicine has recommended doubling the number of doctorally prepared nurses by 2020 and has emphasized that nurses achieve higher levels of education and training through an improved educational system that promotes seamless academic progression. However, in the United States, the overall PhD completion rate is only 57%. This article reports on the process undertaken by a collegial support group of students in a PhD in nursing science program who encouraged each other's progress through the dissertation process within a calendar year.


Treatment of cancer-associated hypercalcemia with cisplatin.
Cisplatin (cis-platinum) has been shown to lower cancer-associated humoral hypercalcemia in an animal model and to inhibit bone resorption in vitro. This prospective study was designed to evaluate the efficacy of cisplatin in treating cancer-associated hypercalcemia in humans. Thirteen patients with severe hypercalcemia refractory to rehydration were treated with a 24-hour infusion of cisplatin, 100 mg/m2. Serial measurements of serum calcium and tumor size were made following cisplatin treatment and compared with pretreatment values. Nine patients (69%) achieved normocalcemia after treatment with cisplatin; and mean duration of benefit was 38 days in these patients. No reduction in tumor size was seen. All patients died of progressive cancer. We conclude that cisplatin can control malignant hypercalcemia for relatively long periods, and that its mechanism of action is not due to a reduction in tumor size.


Scalable Workflows and Reproducible Data Analysis for Genomics.
Biological, clinical, and pharmacological research now often involves analyses of genomes, transcriptomes, proteomes, and interactomes, within and between individuals and across species. Due to large volumes, the analysis and integration of data generated by such high-throughput technologies have become computationally intensive, and analysis can no longer happen on a typical desktop computer.In this chapter we show how to describe and execute the same analysis using a number of workflow systems and how these follow different approaches to tackle execution and reproducibility issues. We show how any researcher can create a reusable and reproducible bioinformatics pipeline that can be deployed and run anywhere. We show how to create a scalable, reusable, and shareable workflow using four different workflow engines: the Common Workflow Language (CWL), Guix Workflow Language (GWL), Snakemake, and Nextflow. Each of which can be run in parallel.We show how to bundle a number of tools used in evolutionary biology by using Debian, GNU Guix, and Bioconda software distributions, along with the use of container systems, such as Docker, GNU Guix, and Singularity. Together these distributions represent the overall majority of software packages relevant for biology, including PAML, Muscle, MAFFT, MrBayes, and BLAST. By bundling software in lightweight containers, they can be deployed on a desktop, in the cloud, and, increasingly, on compute clusters.By bundling software through these public software distributions, and by creating reproducible and shareable pipelines using these workflow engines, not only do bioinformaticians have to spend less time reinventing the wheel but also do we get closer to the ideal of making science reproducible. The examples in this chapter allow a quick comparison of different solutions.


Habitat characteristics and eggshell distribution of the salt marsh mosquito, Aedes vigilax, in marshes in subtropical Eastern Australia.
Research at 10 locations in coastal subtropical Queensland, Australia, has shown that salt marshes contained heterogeneous distributions of eggshells of the pest and vector mosquito Aedes vigilax (Skuse) (Diptera:Culicidae). The eggshell distribution was related to specific vegetation assemblages, with a mix of the grass, Sporobolus virginicus (L.) Kunth (Poales: Poaceae), and the beaded glasswort, Sarcocornia quinqueflora (Bunge ex (Ung.-Stern) A.J. Scott (Caryophyllales: Chenopodiaceae), as significantly higher in eggshells than any other vegetation. There were also high numbers in the mix of S. virginicus with the arrowgrass, Triglochin striata Ruiz & Pavón (Alismatales: Juncaginaceae). Both mixed types are found in relatively wetter areas, despite very few eggshells being found generally in the low marsh. Most sites contained S. virginicus and eggshell locations were variable for this species alone. This was probably related to its life form variability in response to salinity and location on the marsh. Location on the marsh was important for eggshell distribution with most eggshells around the edges of pools and depressions, followed by, but to a significantly lesser extent, the marsh surface. Eggshells were fewest in the low marsh. Partition analysis resulted in a tree that simplified and summarised the factors important for eggshell distribution confirming the individual analyses. The potential effects of climate, sea level and other change are also briefly discussed in the context of likely changes to land cover and relative location on the marsh. For example, increased sea level may lead to low marsh conditions extending into higher marsh area with implications for oviposition and numbers of eggshells.


Reconstruction of three-dimensional neourethra using lingual keratinocytes and corporal smooth muscle cells seeded acellular corporal spongiosum.
Tissue engineering technique seems to be the best strategy for treating the urethra disease in the near future. In present study, porcine acellular corpus spongiosum matrices (ACSMs) were combined with autologus corporal smooth muscle cells (CSMCs) and lingual keratinocytes by static-dynamic seeding method to form three-dimensional (3D) "neourethra" tissue for repairing the urethral defection. Six scaffolds with two kinds of cells (Group C), six scaffolds with only lingual keratinocytes (Group B), and six matrices alone (Group A) were used to repair the rabbit urethral defection. Retrograde urethrography and histological analyses were performed to evaluate the results of urethroplasty. In vitro, hematoxylin and eosin staining of seeded ACSM showed multiple epithelial layers and well-distributed CSMCs into the matrix. In vivo, the urethra kept a wide caliber in Group C. Strictures were observed in groups A and B. Histologically, the retrieved urethra in group A showed fibrosis and inflammation during 6 months. Simple epithelial layer regenerated in group B while there was no evidence of CSMCs growing into grafts during study period. Stratified epithelial layer and organized muscle fiber bundles were evident after 6 months in group C. Our study suggested that lingual keratinocytes and CSMCs could be used as a source of seed cells for urethral tissue engineering. Using the dynamic-static seeding method, 3D urethra could be constructed in vivo.


The Risk Of Severe COVID-19 Within Households Of School Employees And School-Age Children.
Across the United States, school districts are grappling with questions of whether and how to reopen and keep open elementary and secondary schools in the 2020-21 academic year. Using household data from before the pandemic (2014-17), we examined how often people who have health conditions placing them at risk for severe coronavirus disease 2019 (COVID-19) were connected to schools, either as employees or by living in the same households as school employees or school-age children. Between 42.0 percent and 51.4 percent of all school employees met the Centers for Disease Control and Prevention's (CDC's) definition of having or potentially having increased risk for severe COVID-19. Among all adults with CDC-defined risk factors for severe COVID-19, between 33.9 million and 44.2 million had direct or within-household connections to schools.


Parents' knowledge, beliefs, acceptance and uptake of the HPV vaccine in members of The Association of Southeast Asian Nations (ASEAN): A systematic review of quantitative and qualitative studies.
Cervical cancer is the second most common malignancy affecting females in Southeast Asia. Human Papillomavirus (HPV) vaccines have been available since 2006. Several Association of Southeast Asian Nations (ASEAN) member countries have since introduced and/or piloted the HPV vaccine with adolescent females. This systematic review was conducted to understand what factors influence parents' acceptance of the HPV vaccine in the region. Seven databases were searched for qualitative and quantitative studies published up to 16 April 2020. Papers were included if they were peer-reviewed, in English, available in full text, and had a focus on parents' knowledge, beliefs, attitudes and acceptance of the HPV vaccine. Findings were integrated to answer the review question using framework analysis based on the Theory of Planned Behaviour. Sixteen publications were included and synthesised under the Theory of Planned Behaviour domains: 1) Knowledge, attitudes and acceptance, 2) subjective norms, and 3) perceived behavioural control. Parents' attitudes to HPV vaccination were positive and acceptance to vaccinate their daughters against HPV was high. The uptake was high when the vaccine was offered for free. Parents' acceptance and uptake of the HPV vaccine in ASEAN member-countries was high when the vaccine was offered for free even though their knowledge of cervical cancer and HPV was poor. Further research is needed to see how uptake and acceptance can be maintain when the vaccine is not offered for free.


Meeting Report From the 2016 11th Biennial Ovarian Cancer Research Symposium: Mechanisms of Initiation and Progression of Ovarian Cancers.
The aim of this study was to review the latest research advances on the mechanisms of initiation and progression of ovarian cancer. At the 11th Biennial Ovarian Cancer Research Symposium, which was held in Seattle, Washington in September 2016, leaders in ovarian cancer research convened to present and discuss current advances and future directions in ovarian cancer research. One session was dedicated to Mechanisms of Initiation and Progression of Ovarian Cancer, and included a keynote presentation from Dr Ronny Drapkin, MD (University of Pennsylvania), and an invited oral presentation from Laising Yen, PhD (Baylor College of Medicine). Nine additional oral presentations were selected from abstract submissions. Thirty-three abstracts were presented in poster format and were grouped into the categories of mechanisms of the genesis of genomic instability, tumor initiation, metastases of ovarian cancers, innate and acquired chemotherapy resistance, tumor progression, tumor-initiating cell and chemotherapy resistance, and immunomodulation. Eradication of ovarian cancers requires clear understanding of molecular mechanisms of ovarian cancer initiation and progression. These mechanisms will not only drive the precision of early detection, but also discovery of new therapies to target precursor lesions and more advanced stage disease.


Tilted MMI crossings based on silicon wire waveguide.
Waveguide crossings employing tilted MMI structures on silicon wire waveguide are proposed and demonstrated. Intersecting angle of the two MMI waveguides is optimized for low crosstalk. The optimization is carried out with input polarizations specified. On the fabricated MMI crossings, crosstalk lower than -38 dB in the C-band was experimentally confirmed. A novel polarization-insensitive crossing based on a diversity circuit was fabricated. Crosstalk lower than -30 dB in the C-band is demonstrated.


Colorectal cancer: Parametric evaluation of morphological, functional and molecular tomographic imaging.
Colorectal cancer (CRC) represents one of the leading causes of tumor-related deaths worldwide. Among the various tools at physicians' disposal for the diagnostic management of the disease, tomographic imaging (e.g., CT, MRI, and hybrid PET imaging) is considered essential. The qualitative and subjective evaluation of tomographic images is the main approach used to obtain valuable clinical information, although this strategy suffers from both intrinsic and operator-dependent limitations. More recently, advanced imaging techniques have been developed with the aim of overcoming these issues. Such techniques, such as diffusion-weighted MRI and perfusion imaging, were designed for the "in vivo" evaluation of specific biological tissue features in order to describe them in terms of quantitative parameters, which could answer questions difficult to address with conventional imaging alone (e.g., questions related to tissue characterization and prognosis). Furthermore, it has been observed that a large amount of numerical and statistical information is buried inside tomographic images, resulting in their invisibility during conventional assessment. This information can be extracted and represented in terms of quantitative parameters through different processes (e.g., texture analysis). Numerous researchers have focused their work on the significance of these quantitative imaging parameters for the management of CRC patients. In this review, we aimed to focus on evidence reported in the academic literature regarding the application of parametric imaging to the diagnosis, staging and prognosis of CRC while discussing future perspectives and present limitations. While the transition from purely anatomical to quantitative tomographic imaging appears achievable for CRC diagnostics, some essential milestones, such as scanning and analysis standardization and the definition of robust cut-off values, must be achieved before quantitative tomographic imaging can be incorporated into daily clinical practice.


Platelet-Derived Microparticles From Obese Individuals: Characterization of Number, Size, Proteomics, and Crosstalk With Cancer and Endothelial Cells.
Rationale: Obesity is a risk factor for atherothrombosis and various cancers. However, the mechanisms are not yet completely clarified. Objectives: We aimed to verify whether the microparticles (MPs) released from thrombin-activated platelets differed in obese and non-obese women for number, size, and proteomics cargo and the capacity to modulate in vitro the expression of (i) genes related to the epithelial to mesenchymal transition (EMT) and the endothelial to mesenchymal transition (EndMT), and (ii) cyclooxygenase (COX)-2 involved in the production of angiogenic and inflammatory mediators. Methods and Results: MPs were obtained from thrombin activated platelets of four obese and their matched non-obese women. MPs were analyzed by cytofluorimeter and protein content by liquid chromatography-mass spectrometry. MPs from obese women were not different in number but showed increased heterogeneity in size. In obese individuals, MPs containing mitochondria (mitoMPs) expressed lower CD41 levels and increased phosphatidylserine associated with enhanced Factor V representing a signature of a prothrombotic state. Proteomics analysis identified 44 proteins downregulated and three upregulated in MPs obtained from obese vs. non-obese women. A reduction in the proteins of the α-granular membrane and those involved in mitophagy and antioxidant defenses-granular membrane was detected in the MPs of obese individuals. MPs released from platelets of obese individuals were more prone to induce the expression of marker genes of EMT and EndMT when incubated with human colorectal cancer cells (HT29) and human cardiac microvascular endothelial cells (HCMEC), respectively. A protein, highly enhanced in obese MPs, was the pro-platelet basic protein with pro-inflammatory and tumorigenic actions. Exclusively MPs from obese women induced COX-2 in HCMEC. Conclusion: Platelet-derived MPs of obese women showed higher heterogeneity in size and contained different levels of proteins relevant to thrombosis and tumorigenesis. MPs from obese individuals presented enhanced capacity to cause changes in the expression of EMT and EndMT marker genes and to induce COX-2. These effects might contribute to the increased risk for the development of thrombosis and multiple malignancies in obesity. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01581801.


Transcripts originating in intron 1 of the HSD11 (11 beta-hydroxysteroid dehydrogenase) gene encode a truncated polypeptide that is enzymatically inactive.
There is evidence for the presence in the kidney of more than one isoform of 11 beta-hydroxysteroid dehydrogenase (11HSD), an enzyme that interconverts cortisol and cortisone (in rodents, corticosterone and 11-dehydrocorticosterone). A specific isoform might arise from transcripts in the kidney that are known to originate in intron 1; translation from these transcripts is predicted to initiate at the codon that in the full-length rat enzyme encodes Met27. Alignment of the full-length rat and human 11HSD sequences with other members of the short chain dehydrogenase family suggests that initiation of translation at Met27 might yield a functional enzyme, since the amino-termini of most of these enzymes occur at equivalent positions. We confirmed that short transcripts are found in the kidney and are detectable at lower levels in the liver and lung. In vitro transcription and translation of short cDNA demonstrated that the AUG encoding Met27 is indeed a functional initiation codon. However, Chinese hamster ovary cells transfected with short cDNA in the pCMV4 vector expressed apparently low levels of the corresponding truncated polypeptide and had no 11HSD activity. Thus, the functional significance of transcripts originating in intron 1 is unclear.


Depression in migrant workers and nationals of Qatar: An exploratory cross-cultural study.
The aim of this study was to compare the prevalence of depressive symptoms among migrants and non-migrants living in Qatar and identify variables associated with depressive symptomology in these groups, including culture of origin, time living in country and perceived quality of life. In addition, we tested if the latter two variables moderated the effect of culture of origin on depressive symptomology in the migrant groups. A telephone survey of a probability-based sample of 2,520 participants was conducted in February 2016. The sample was divided into three groups based on nationality and income: labour migrants (LMs), white-collar migrants (WCMs) and non-migrants or Qatari nationals (QNs). Participants completed the Whooley two-question test for depression. The odds of depression were significantly increased in LMs (OR = 3.31, 95% CI = 2.36-4.65) and WCMs (OR = 1.40, 95% CI = 1.04-1.90) compared with non-migrants. Among LMs, having a problem with current employer in the last 3 months was also associated with depressive symptoms (OR = 2.10, 95% CI = 1.14-3.84). Culture of origin was significantly associated with depressive symptoms including South Asians (OR = 3.12, p < .001), East Asians (OR = 0.52, p = .013) and Westerners (OR = 0.45, p = .044) relative to Arabs. LM status remained strongly associated with depressive symptoms independent of culture of origin (OR = 2.02, p < .001). Perceived quality of life, but not length of stay, appears to be an important variable in explaining differences in symptoms between some cultural groups. Findings from this study highlight the importance of the context of migration and culture of origin as potential determinants of depressive symptomology in the host country.


Evidence of underdiagnosis of myasthenia gravis in older people.
Myasthenia gravis is a potentially serious but treatable muscle disease caused by autoantibodies directed at the acetylcholine receptor (AChR) on the postsynaptic membrane of the neuromuscular junction. There is anecdotal evidence that the diagnosis is sometimes missed in older patients. To examine the incidence and age distribution of positive AChR antibodies in samples referred to diagnostic laboratories in the UK, and the prevalence of positive AChR antibodies in samples from a cohort of older individuals. Positive AChR antibody tests were identified from all UK centres registered for the assay with the European quality assurance scheme (EQAS) during 1997-99, and the age and sex specific incidence was calculated, based on the UK population. The prevalence of AChR antibodies in sera from a sample of 2000 individuals aged > or =60 years was determined. 3183 individuals had positive AChR antibody tests on routine screening during the years 1997 to 1999 in the UK, giving an annual incidence of 1.8/100 000. In both sexes, the age specific incidence rose steeply between the ages of 45 and 74, reaching 9.9/100 000 in men, and then fell, with a sharp decline above the age of 80. In the prevalence study, whereas only one serum from individuals aged 60-74 years was positive for AChR antibodies (0.12%), sera from eight individuals aged > or =75 years were positive (0.7%). Only one had a previous clinical diagnosis of myasthenia gravis but four others had histories of stroke or transient ischaemic attacks. The sharp fall in the incidence of clinically recognised myasthenia gravis in people over 80 years of age in our national AChR antibody incidence study, and the high prevalence of previously unrecognised positive AChR antibodies in those > or =75 years old, suggest that myasthenia gravis may be substantially underdiagnosed in older people.


Role of Immune Cells in the Course of Central Nervous System Injury: Modulation with Natural Products.
Immune cells actively participate to the central nervous system (CNS) injury either damaging or protecting neural tissue with release of various mediators. Residential microglia and monocyte-derived macrophages play a fundamental role within the injured CNS and, here, special emphasis will be placed on M1 and M2 macrophages for their different functional activities. On the other hand, peripheral T regulatory (Treg) cells exert antiinflammatory activities in the diseased host. In this respect, activation of Treg cells by nutraceuticals may represent a novel approach to treat neuroinflammation. Omega-3 fatty acids and polyphenols will be described as substances endowed with antioxidant and anti-inflammatory activities. However, taking into account that Treg cells act in the later phase of CNS injury, favoring immune suppression, manipulation of host immune system with both substances requires caution to avoid undesired side effects.


Positive allosteric modulation of AMPA receptors from efficacy to toxicity: the interspecies exposure-response continuum of the novel potentiator PF-4778574.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulation (i.e., "potentiation") has been proposed to overcome cognitive impairments in schizophrenia, but AMPAR overstimulation can be excitotoxic. Thus, it is critical to define carefully a potentiator's mechanism-based therapeutic index (TI) and to determine confidently its translatability from rodents to higher-order species. Accordingly, the novel AMPAR potentiator N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) was characterized in a series of in vitro assays and single-dose animal studies evaluating AMPAR-mediated activities related to cognition and safety to afford an unbound brain compound concentration (Cb,u)-normalized interspecies exposure-response relationship. Because it is unknown which AMPAR subtype(s) may be selectively potentiated for an optimal TI, PF-4778574 binding affinity and functional potency were determined in rodent tissues expected to express a native mixture of AMPAR subunits and their associated proteins to afford composite pharmacological values. Functional activity was also quantified in recombinant cell lines stably expressing human GluA2 flip or flop homotetramers. Procognitive effects of PF-4778574 were evaluated in both rat electrophysiological and nonhuman primate (nhp) behavioral models of pharmacologically induced N-methyl-d-aspartate receptor hypofunction. Safety studies assessed cerebellum-based AMPAR activation (mouse) and motor coordination disruptions (mouse, dog, and nhp), as well as convulsion (mouse, rat, and dog). The resulting empirically derived exposure-response continuum for PF-4778574 defines a single-dose-based TI of 8- to 16-fold for self-limiting tremor, a readily monitorable clinical adverse event. Importantly, the Cb,u mediating each physiological effect were highly consistent across species, with efficacy and convulsion occurring at just fractions of the in vitro-derived pharmacological values.


2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.
To develop response criteria for juvenile dermatomyositis (DM). We analyzed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique. Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute percent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (P = 0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (P < 0.006). The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute percent change in core set measures, with thresholds for minimal, moderate, and major improvement.


Fertility and women's employment reconsidered: a macro-level time-series analysis for developed countries, 1960-2000.
This paper examines causality and parameter instability in the long-run relationship between fertility and women's employment. This is done by a cross-national comparison of macro-level time-series data from 1960 to 2000 for France, West Germany, Italy, Sweden, the UK, and the USA. By applying vector error correction models (a combination of Granger-causality tests with recent econometric time-series techniques) we find causality in both directions. This finding is consistent with simultaneous movements of both variables brought about by common exogenous factors such as social norms, social institutions, financial incentives, and the availability and acceptability of contraception. We find a negative and significant correlation until about the mid-1970s and an insignificant or weaker negative correlation afterwards. This result is consistent with a recent hypothesis in the demographic literature according to which changes in the institutional context, such as changes in childcare availability and attitudes towards working mothers, might have reduced the incompatibility between child-rearing and the employment of women.