Prevalence, Incidence, and Clinical Characteristics of Thyroid Eye Disease in Japan.
Although thyroid eye disease (TED) can impact social and psychological well-being, the epidemiological evidence of TED is lacking in Japan. Nationwide claims databases provided by JMDC Inc. and Medical Data Vision Co., Ltd. and national population statistics are used. Three TED definitions ranging from a strict definition only including a TED diagnosis to a broad definition including a TED diagnosis and considering ocular symptoms are considered. The proportion of patients by severity and disease activity are estimated based on definitions that would allow identification of those patients within the claims data. The incidence rate per 100 000 person-years ranged from 7.3 to 11.1 for the strict and broad TED definitions, respectively. For fiscal year 2020 (April 2020 to March 2021) the prevalence rate ranged between 24.65 (strict TED) and 37.58 (broad TED) per 100 000 persons. These correspond to 25 383 and 38 697 patients for the strict and broad TED definitions, respectively. Regardless of the definition used, a predominance of female patients was observed, and the highest burden of the disease was seen in the age group of 35 to 59. Mild and inactive forms of TED were predominant (about 85% and 74%, respectively). The incidence and prevalence of TED in Japan were 7.3 to 11.1 per 100 000 person-years and 24.65 to 37.58 per 100 000 persons, respectively. The robust results of this database study add valuable real-world evidence on the incidence and prevalence of TED in Japan.


Prevalence of asthma in Galway city school children.
To determine the prevalence of asthma in the past 12 months in nine year old Galway school children, a questionnaire on respiratory symptoms was distributed to children for completion by parents and returned to the school. We issued 896 questionnaires and 832 (426 boys and 406 girls) were returned completed. The overall response was 93%. The prevalence of wheeze in the past 12 months was 16.1%. A history of wheeze was more common in boys than in Girls. (19.7% Vs 12.3%). Overall, 67% of those reporting wheeze also reported a history of diagnosed asthma and 74% had used a bronchodilator. 60% reported a history of exercise induced wheezing and 67% had nocturnal cough. 28% were taking prophylactic medication. The current prevalence of asthma in Galway city school children is high. There is an increased willingness to diagnose and treat asthma in this community.


Cerberus-like is a secreted factor with neutralizing activity expressed in the anterior primitive endoderm of the mouse gastrula.
We report the isolation of mouse cerberus-like (cer-l), a gene encoding a novel secreted protein that is specifically expressed in the anterior visceral endoderm during early gastrulation. Expression in the primitive endoderm starts before the appearance of the primitive streak and lasts until the head-fold stage. In later stages, a second region of expression is found in newly formed somites. Mouse cer-l shares some sequence similarity with Xenopus cerberus (Xcer). In Xenopus assays cer-l, like Xcer, mRNA acts as a potent neuralizing factor that induces forebrain markers and endoderm, but is unable to induce ectopic head-like structures as Xcer does. In addition to cer-l, anterior visceral endoderm was found to express the transcription factors Lim1, goosecoid and HNF-3beta that are also present in trunk organizer cells. A model of how head and trunk development might be regulated is discussed. Given its neuralizing activity, the secreted protein Cer-l is a candidate for mediating inductive activities of anterior visceral endoderm.


Rehabilitation of Posterior Maxilla with Obturator Supported by Zygomatic Implants.
Prosthetic rehabilitation of atrophic maxilla and large maxillary defects can be done successfully by zygomatic implant-supported prosthesis. Zygomatic implants are an avant-garde to complex and invasive-free vascularised osteocutaneous flaps, distraction osteogenesis, and the solution to flap failures. A treated case of tuberculous osteomyelitis, with a class II (Aramany's classification) maxillary defect, reported to oral maxillofacial department, Government Dental College (RUHS-CODS). The defect in this group was unilateral, retaining the anterior teeth. The patient was previously rehabilitated with a removable maxillary obturator. Inadequate retention affected essential functions like speaking, mastication, swallowing, esthetics, and so on due to lack of sufficient supporting tissues. A fixed prosthetic rehabilitation of posterior maxillary defect was done with obturator supported with two single-piece zygomatic implants. At 1-year follow-up, the patient was comfortable with the prosthesis, and no further complaints were recorded.


Physics-constrained, low-dimensional models for magnetohydrodynamics: First-principles and data-driven approaches.
Plasmas are highly nonlinear and multiscale, motivating a hierarchy of models to understand and describe their behavior. However, there is a scarcity of plasma models of lower fidelity than magnetohydrodynamics (MHD), although these reduced models hold promise for understanding key physical mechanisms, efficient computation, and real-time optimization and control. Galerkin models, obtained by projection of the MHD equations onto a truncated modal basis, and data-driven models, obtained by modern machine learning and system identification, can furnish this gap in the lower levels of the model hierarchy. This work develops a reduced-order modeling framework for compressible plasmas, leveraging decades of progress in projection-based and data-driven modeling of fluids. We begin by formalizing projection-based model reduction for nonlinear MHD systems. To avoid separate modal decompositions for the magnetic, velocity, and pressure fields, we introduce an energy inner product to synthesize all of the fields into a dimensionally consistent, reduced-order basis. Next, we obtain an analytic model by Galerkin projection of the Hall-MHD equations onto these modes. We illustrate how global conservation laws constrain the model parameters, revealing symmetries that can be enforced in data-driven models, directly connecting these models to the underlying physics. We demonstrate the effectiveness of this approach on data from high-fidelity numerical simulations of a three-dimensional spheromak experiment. This manuscript builds a bridge to the extensive Galerkin literature in fluid mechanics and facilitates future principled development of projection-based and data-driven models for plasmas.


Second-messenger control of catecholamine release from PC12 cells. Role of muscarinic receptors and nerve-growth-factor-induced cell differentiation.
The role of various intracellular signals and of their possible interactions in the control of neurotransmitter release was investigated in PC12 cells. To this purpose, agents that affect primarily the cytosolic concentration of Ca2+, [Ca2+]i (ionomycin, high K+), agents that affect cyclic AMP concentrations (forskolin; the adenosine analogue phenylisopropyladenosine; clonidine) and activators of protein kinase C (phorbol esters) were applied alone or in combination to either growing chromaffin-like PC12-cells, or to neuron-like PC12+ cells differentiated by treatment with NGF (nerve growth factor). In addition, the release effects of muscarinic-receptor stimulation (which causes increase in [Ca2+]i, activation of protein kinase C and decrease in cyclic AMP) were investigated. Two techniques were employed to measure catecholamine release: static incubation of [3H]dopamine-loaded cells, and perfusion incubation of unlabelled cells coupled to highly sensitive electrochemical detection of released catecholamines. The results obtained demonstrate that: (1) release from PC12 cells can be elicited by both raising [Ca2+]i and activating protein kinases (protein kinase C and, although to a much smaller extent, cyclic AMP-dependent protein kinase); and (2) these various control pathways interact extensively. Activation of muscarinic receptors by carbachol induced appreciable release responses, which appeared to be due to a synergistic interplay between [Ca2+]i and protein kinase C activation. The muscarinic-induced release responses tended to become inactivated rapidly, possibly by feedback desensitization of the receptor mediated by protein kinase C. Muscarinic inactivation was prevented (or reversed) by agents that increase, and accelerated by agents that decrease, cyclic AMP. Agents that stimulate release primarily through the Ca2+ pathway (ionomycin and high K+) were found to be equipotent in both PC12- and PC12+ cells, whereas the protein kinase C activator 12-O-tetradecanoyl-phorbol 13-acetate was approx. 10-fold less potent in PC12+ cells, when administered either alone or in combination with ionomycin. In contrast, the cell binding of phorbol esters was not greatly modified by NGF treatment. Thus control of neurotransmitter release from PC12 cells is changed by differentiation, with a diminished role of the mechanism mediated by protein kinase C.


Particle effects on heart-rate regulation in senescent mice.
Because epidemiology studies consistently identify the elderly at risk for air pollution-related morbidity and mortality, we developed a model of senescent-dependent susceptibility based on indices of physiological aging. In the current study, we hypothesized that heart-rate regulation during particulate matter (PM) exposure differs with senescence-dependent susceptibility owing to variation in autonomic nervous control. Heart rate (HR) and heart-rate variability (HRV) parameters were measured from 162 samples of 2-min electrocardiograph (ECG) recordings in age-matched healthy (n = 5) and terminally senescent (n = 3) AKR mice during 3-h exposures to filtered-air (FA, day 1) and carbon black (CB, day 4; <200 microg/m(3)). On day 1, HR was significantly (p <.01) depressed during FA in terminally senescent mice. By day 4, HR was further slowed significantly (p <.01) due to the effects of CB exposure for 3 days. The combined effects of terminal senescence and CB exposure acted to depress HR to an average (+/-SEM) 445 +/- 40 bpm, or approximately 80 bpm lower compared to healthy HR responses. The change in rMSSD, an HRV parameter corresponding to relative influences of parasympathetic tone on HR, was significantly (p <.01) greater on day 1 and day 4 in terminally senescent mice compared to healthy mice. In contrast, the LF/HF ratio, an HRV parameter derived from spectral analysis indicating relative changes in cardiac sympathetic tone, was significantly (p <.01) depressed in terminally senescent mice on day 1. By day 4, significant increases in LF/HF were evident in healthy mice during CB exposure, suggesting that HR regulation was associated with an increase in sympathetic tone. Alternatively, terminally senescent mice appeared to modulate a lower HR without change in LF/HF ratio during CB exposure, suggesting an absence of sympathetic tone. In conclusion, older healthy mice increase cardiac sympathetic tone during PM exposure while terminally senescent mice show a greater PM-induced parasympathetic tone in regulating HR. The significance of the current results suggest that PM-induced HR regulatory changes may ultimately depend on the degree of physiological aging.


poirot, a new regulatory gene of Drosophila oskar acts at the level of the short Oskar protein isoform.
Embryonic germ cell formation and abdomen development in Drosophila requires localisation and site specific translation of oskar mRNA in the posterior part of the oocyte. Targeting of oskar function to the posterior pole of the oocyte needs a large set of proteins and RNAs, encoded by posterior group genes. Consequently, mutations in the posterior group genes can result in embryos without abdomens and/or germ cells. During a systematic hobo-mediated mutant isolation screen, we identified poirot, a novel posterior group gene, owing to its germ cell-less phenotype. We show that the lack of poirot activity dramatically decreases OSK protein levels, without affecting the oskar mRNA distribution. In poirot mutant oocytes, delocalised OSK protein is observed, indicating that wild-type poirot has a role in the anchoring process of the OSK protein at the posterior pole. Furthermore, we demonstrate that poirot acts in an isoform-specific manner, only the short OSK isoform is affected, while the long OSK isoform remains at wild-type levels in poirot mutants.


Bright-Exciton Fine-Structure Splittings in Single Perovskite Nanocrystals.
Here we show that, in single perovskite CsPbI_{3} nanocrystals synthesized from a colloidal approach, a bright-exciton fine-structure splitting as large as hundreds of μeV can be resolved with two orthogonally and linearly polarized photoluminescence peaks. This doublet could switch to a single peak when a single CsPbI_{3} nanocrystal is photocharged to eliminate the electron-hole exchange interaction. The above findings have prepared an efficient platform suitable for probing exciton and spin dynamics of semiconductor nanostructures at the visible-wavelength range, from which a variety of practical applications such as in entangled photon-pair source and quantum information processing can be envisioned.


[Root colonization and nodulation of Sinorhizobium fredii HN01DL in Glycine max rhizosphere].
Rhizobox-soil microcosms studies on the colonization, dispersal and nodulation of Sinorhizobium fredii HN01DL marked with luxAB gene in Glycine max rhizosphere showed that the colonization dynamics and the density of HN01DL in non-sterilized rhizobox-soil microcosms were different from those in sterilized rhizobox-soil microcosms. The colonization density of the former reached the maximum (8.65 log cfu.g-1 root) 12 days after the coated seeds planted, and that of the latter decreased rapidly at the early stage and achieved the maximum (6.88 log cfu.g-1 root) 15 days afterwards. Furthermore, the colonization density of HN01DL reached the maximum (7.05 log cfu.g-1 root) in section A (0-4 cm) of root system 5 days after seeds planted, decreased slowly and kept a relative stable level until 19 days, and began to rise up again 33 days afterwards. The strain could also disperse to the place of 16 cm from seed to root tip by 46 days after seed planted. HN01DL maintained a constantly higher colonization density level in section A of root system, formed the largest number of luminescent nodules (total 16.3, dominantly located in main root of section A), and had the highest luminescent percentage (68.8%). The luminescent nodule percentage decreased gradually along section A to E of root system, and no luminescent nodule was detected in section E of root system.


Collaborative modelling-based shelter planning analysis: a case study of the Nagata Elementary School Community in Kobe City, Japan.
This study, based on a questionnaire survey and workshops, and with a focus on the impact of an earthquake on the Nagata Elementary School Community in Kobe City, Japan, develops a collaborative model to assess the allocation of residents to shelters. The current official allocation plan is compared with three alternative allocations developed within the framework of this model. The collaborative model identifies accessibility, amenity, capacity, connectivity, continuity, security, and stability as the basic, necessary criteria for shelter planning. The three alternative allocations are very similar to the local residents' own choice of shelters, but they are quite different from the current official allocation plan, which is supposed to be followed but has achieved relatively low satisfaction among households. The proposed collaborative approach provides an effective tool to assess the officially determined allocation plan by taking into account the viewpoints of local residents, and the results are useful for enhancing community evacuation planning.


The oral multitarget tumour growth inhibitor, ZK 304709, inhibits growth of pancreatic neuroendocrine tumours in an orthotopic mouse model.
Current systemic therapies for neuroendocrine tumours (NETs) do not provide sufficient control of tumour growth. However, efficient evaluation of novel drugs is hindered by the lack of a suitable preclinical animal model. Here an orthotopic mouse model of pancreatic NET is established and used to study the action of ZK 304709, a first in class, oral multitarget tumour growth inhibitor. ZK 304709 is an inhibitor of cyclin-dependent kinases (Cdks) 1, 2, 4, 7 and 9, vascular endothelial growth factor receptor-type kinases (VEGF-RTKs) 1-3 and platelet-derived growth factor receptor-type kinase beta (PDGF-RTKss). BON and QGP-1 human NET cells were used to study proliferation, survival and cell cycle distribution in vitro. For induction of orthotopic NETs, BON cells were injected into the pancreas of NMRI(nu/nu) mice. Primary tumour growth and metastatic spread were recorded after 9 weeks, and apoptosis, microvessel density and lymphatic vessel density were determined. ZK 304709 dose-dependently suppressed proliferation and colony formation of NET cells. Direct effects on NET cells were consistent with Cdk inhibition and involved G(2) cell cycle arrest and apoptosis induction, which was associated with reduced expression of MCL1 (myeloid cell leukaemia sequence 1), survivin and hypoxia-inducible factor 1alpha (HIF1alpha). Apoptosis similarly occurred in vivo in ZK 304709-treated orthotopic BON tumours, resulting in a 80% reduction of primary tumour growth. In contrast, treatment with lanreotide or 5-fluorouracil and streptozotocin failed to inhibit tumour gowth. ZK 304709 also reduced tumour microvessel density, implicating antiangiogenic mechanisms. BON orthotopic tumours provide an informative model for preclinical drug evaluation in NETs. In this model, ZK 304709 achieved efficacious tumour growth control via induction of apoptosis and inhibition of tumour-induced angiogenesis.


[LAL (Limulus Amoebocyte Lysate) test as applied to the safety evaluation of biological preparations].
In the paper some problems concerning of pyrogen testing were described. The risk of reactions after administration parenteral preparations contaminated pyrogenic substances give the cause for searching sensitive, repeated methods of their designation. The paper is review of the adaptation Limulus Amoebocyte Lysate (LAL) test for the estimation of endotoxin in biological preparations. The paper overview, chemical structure of endotoxin the characteristic of Limulus polyphemus, principle basis of the LAL test and general remarks of application. The LAL test according to the opinion of many authors is more sensitive in comparing with the pyrogen rabbit test.


Competitive regulation of nucleolin expression by HuR and miR-494.
The RNA-binding protein (RBP) nucleolin promotes the expression of several proliferative proteins. Nucleolin levels are high in cancer cells, but the mechanisms that control nucleolin expression are unknown. Here, we show that nucleolin abundance is controlled posttranscriptionally via factors that associate with its 3' untranslated region (3'UTR). The RBP HuR was found to interact with the nucleolin (NCL) 3'UTR and specifically promoted nucleolin translation without affecting nucleolin mRNA levels. In human cervical carcinoma HeLa cells, analysis of a traceable NCL 3'UTR bearing MS2 RNA hairpins revealed that NCL RNA was mobilized to processing bodies (PBs) after silencing HuR, suggesting that the repression of nucleolin translation may occur in PBs. Immunoprecipitation of MS2-tagged NCL 3'UTR was used to screen for endogenous repressors of nucleolin synthesis. This search identified miR-494 as a microRNA that potently inhibited nucleolin expression, enhanced NCL mRNA association with argonaute-containing complexes, and induced NCL RNA transport to PBs. Importantly, miR-494 and HuR functionally competed for modulation of nucleolin expression. Moreover, the promotion of cell growth previously attributed to HuR was due in part to the HuR-elicited increase in nucleolin expression. Our collective findings indicate that nucleolin expression is positively regulated by HuR and negatively regulated via competition with miR-494.


Longitudinal changes in antipsychotic dose in patients treated with long-acting injectable second-generation antipsychotics.
Only a few studies have investigated changes in the dose of long-acting injectable second-generation antipsychotics (LAI-SGAs) over the long term in the maintenance treatment of schizophrenia. In this retrospective cohort study, we examined longitudinal changes in antipsychotic dose over a 3-year period in patients with schizophrenia who had been taking LAI-SGAs for at least 1 year. We compared the total daily chlorpromazine equivalent dose of antipsychotics at 12, 24 and 36 months with the baseline dose at 3 months after initiation of LAI-SGAs. We also performed multiple regression analysis to explore factors associated with change in total daily dose 12 months after treatment initiation. A total of 154 patients fulfilled the inclusion criteria. There was no significant difference in total daily antipsychotic dose between 3 months and 12, 24 or 36 months after treatment initiation. Total daily dose was increased in 43 (27.9%), 31 (34.8%) and 22 patients (36.7%) at 12, 24 and 36 months, respectively. Age and total antipsychotic dose at 3 months were significantly negatively associated with change in total daily dose. Antipsychotic dose was basically unchanged during long-term treatment in patients treated with LAI-SGAs in the maintenance phase, although there was an increase in some patients.


Plasma biomarkers of depressive symptoms in older adults.
The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) τ and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (~80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches.


Serial electrophysiologic studies in patients with chronic bundle branch block.
Serial His bundle recordings were obtained during 1:1 atrioventricular (AV) conduction in 90 patients with chronic bundle branch block over a mean interval of 30 months. Atrioventricular conduction time (AH) increased greater than or equal to 10 msec in 25 (28%) and infranodal conduction time (HV) increased greater than or equal to 8 msec in 29 (32%), but only 10 patients had parallel increases in AH and HV intervals. Increases in conduction times were independent of age, time interval between studies, cause of heart disease or initial AH or HV intervals. Women were significantly more likely than men to show an increased HV interval and spontaneous trifascicular block. Spontaneous progression to second- or third-degree AV block occurred at the AV node in seven patients and below the node in 12 patients. The initial AH interval was prolonged in five of seven patients (71%) with AV nodal block and had increased further in only two at restudy. The initial HV interval was abnormal in eight of 12 patients (67%) who progressed to infranodal block and was prolonged further in eight at restudy. We conclude that in patients with chronic bundle branch block, (1) approximately 33% show progressive AV conduction system disease and AV nodal and infranodal disease progress independently; (2) progression of infranodal disease is more common in women; (3) AV nodal disease progress independently; (2) progression of infranodal disease is more common in women; (3) AV nodal disease is a common cause of AV block and can occur without further prolongation of the AH interval once a critical level of disease is attained, whereas infranodal block is usually accompanied by progressive lengthening of the HV interval; and (4) progression of AV conduction disease is not readily predictable from clinical and electrophysiologic variables.


Impact of seamless compression garments on limb functionality, comfort and quality of life.
Lymphoedema is a chronic disease affecting the patients' quality of life (QoL) especially with regard to mobility and daily activities. Lymphoedema cannot be cured but symptoms can effectively be improved by a comprehensive approach and the continuous use of compression therapy. An appropriate fitted compression garment is essential for compliance and thus a prerequisite for successful lymphoedema management. Compression garments with bulky seams are not only uncomfortable they also can lead to severe pressure marks or even reduce the mobility and function of the affected limb, which may negatively impact the already reduced QoL of lymphoedema patients. A prospective multicentre observational study was conducted to compare compression garments without and with a seam for hands and toes in 143 patients with lymphoedema. Product performance, lymphoedema symptoms, functionality of hands/toes, QoL and patient satisfaction were documented for the previously worn compression garment as well as for the 3D flat knitted JOBST® Elvarex Plus compression garment without a seam. The JOBST Elvarex Plus glove was perceived very positively by patients, who rated the mobility of the fingers, the adaptability to the shape of the hand/fingers, the fit of cuffs/welts, and the tactile sense of the fingers to be significantly better compared to the previous glove. Also pressure marks between fingers/toes and pressure marks due to cuffs/welts were significantly less frequent when wearing JOBST Elvarex Plus. Also pain, sensation of heaviness, swelling, tightness and dryness of skin were significantly improved when wearing JOBST Elvarex Plus gloves. Furthermore, 80% of the patients rated the wearing comfort of JOBST Elvarex Plus to be better than their previous garments with a seam. Regarding functionality, patients were significantly less limited in their daily activities when wearing JOBST Elvarex Plus garments. Finally, when wearing JOBST Elvarex Plus gloves and toe caps, patients rated the negative effect of their lymphoedema on their QoL to be significantly lower. In conclusion, the application of anatomically adapted compression garments without a seam led to improving patient's reported lymphoedema symptoms, increased patient's satisfaction with the compression garment and supported a better QoL.


Effects of gripping volume in the mechanical strengths of orthodontic mini-implant.
The objective of study was to investigate the correlation between the mechanical strengths [insertion torque (IT); resonance frequency (RF); and horizontal pullout strength (HPS)] and gripping volume (GV) of mini-implants. Thirty mini-implants of three types (Type A: 2 mm × 10 mm, cylindrical, titanium alloy; Type B: 2 mm × 10 mm, tapered, stainless steel; and Type C: 2 mm × 11 mm, cylindrical, titanium alloy) were inserted 7 mm into artificial bones. One-way analysis of variance and Spearman's test were applied to assess intergroup comparisons and intragroup correlations. The null hypothesis was that no statistically significant correlations exist between the GV and mechanical strengths (IT, RF, and HPS). In the IT test, Type C (14.2 Ncm) had significantly (p=0.016) greater values than did Type A (12.4 Ncm). In the RF analysis, no significant difference was observed among the three types of mini-implants. In the HPS test, Type C (388.9 Ncm) was significantly larger than both Type B (294.5 Ncm) and Type A (286 Ncm). In the GV measurement, Type C (14.4 mm3) was significantly larger than Type B (11.4 mm3) and Type A (9.2 mm3). Type A and Type B exhibited no significant correlations among the tests. Therefore, the null hypothesis was accepted. Although no significant correlation was noted between the GV and mechanical strengths (IT, RF, and HPS), we observed a trend that the mechanical strengths (IT, RF, and HPS) of the mini-implants corresponded to the order and values of GV (Type C > Type B > Type A).


[Use of medication and associated factors: a population-based study in Campinas, São Paulo State, Brazil].
This article analyzes prevalence rates in the use of medication according to demographic, socioeconomic, and health-related behavioral variables through a population-based cross-sectional study of individuals 18 years and older (n=941) in Campinas, São Paulo State, Brazil. The study used multistage sampling, both stratified and cluster. Chi-square test was performed, and adjusted prevalence ratios were estimated by gender and age, both with 95% confidence intervals. A Poisson multiple regression model was developed, and the following factors were associated with use of medication: female gender, age 40 and over, reported illness in the previous two weeks, and number of chronic diseases. The most widely consumed drugs were for the cardiovascular and nervous systems, besides herbal remedies. Prevalence of medication in Campinas was lower than in most studies. Local health surveys could help identify drug use patterns and guarantee more appropriate interventions for pharmaceutical care policy.


BHRF1, a viral homologue of the Bcl-2 oncogene, is conserved at both the sequence and functional level in different Epstein-Barr virus isolates.
BHRF 1, a component of the restricted early antigen (EA) complex of the Epstein-Barr virus (EBV) lytic cycle, encodes a 17 kDa putative transmembrane protein with both sequence and functional homology to the Bcl-2 proto-oncogene. To determine whether there was any sequence variation over the BHRF1 open reading frame (ORF), 15 EBV isolates from different geographical regions and from both healthy donors and patients with EBV-associated diseases were sequenced. A small number of base changes which resulted in amino acid substitutions in the BHRF1 protein were found relative to the prototype B95.8 EBV sequence and these were predominantly clustered near the amino terminus of the BHRF1 protein outside conserved domains identified in the Bcl-2 homologues. In transient transfection assays none of the mutations in the BHRF1 ORF from eight different EBV isolates had a significant effect on BHRF1 protein localization compared to the B95.8 BHRF1 protein. However, transient expression of the adenovirus 12 19K protein or Bcl-2 resulted in localization patterns distinct from that observed with BHRF1 protein. Whilst all eight EBV isolates and E1B-19K gave comparable levels of protection to the DNA-damaging agent cis-platin, Bcl-2 did not afford significant protection. Thus, despite several amino acid changes in the BHRF1 ORF of some of the EBV isolates studied, the ability of the protein to protect against cis-platin induced apoptosis is conserved. The highly conserved nature of BHRF1 amongst different EBV isolates at both the sequence and functional level supports the proposed important role of BHRF1 in delaying cell death, thereby maximizing the production of progeny virus and facilitating the establishment of virus persistence.


Biochemical markers and skeletal metastases.
Bisphosphonate therapy for the treatment of skeletal complications from osteolytic metastases has become standard care in patients with cancer who have metastatic bone disease. The ability to assess patient response to bisphosphonate therapy has been helped by the availability of immunoassays that can measure bone collagen breakdown products that are increased in the blood and urine of patients with osteolytic metastases. Measurements of the carboxy and amino terminal telopeptides in blood and urine particularly have been helpful as adjunct methods to facilitate the treatment of patients with skeletal metastases. These biochemical bone markers have been shown to correlate with the extent of skeletal involvement and seem to provide a means of monitoring the dose and scheduling of bisphosphonate therapy of patients with cancer who have bony metastases.


American Academy of Pediatrics. Policy statement--child fatality review.
Injury remains the leading cause of pediatric mortality and requires public health approaches to reduce preventable deaths. Child fatality review teams, first established to review suspicious child deaths involving abuse or neglect, have expanded toward a public health model of prevention of child fatality through systematic review of child deaths from birth through adolescence. Approximately half of all states report reviewing child deaths from all causes, and the process of fatality review has identified effective local and state prevention strategies for reducing child deaths. This expanded approach can be a powerful tool in understanding the epidemiology and preventability of child death locally, regionally, and nationally; improving accuracy of vital statistics data; and identifying public health and legislative strategies for reducing preventable child fatalities. The American Academy of Pediatrics supports the development of federal and state legislation to enhance the child fatality review process and recommends that pediatricians become involved in local and state child death reviews.


Familiarity for associations? A test of the domain dichotomy theory.
Episodic recognition memory is mediated by functionally separable retrieval processes, notably familiarity (a general sense of prior exposure) and recollection (the retrieval of contextual details), whose relative engagement depends partly on the nature of the information being retrieved. Currently, the specific contribution of familiarity to associative recognition memory (where retrieval of the relationships between pairs of stimuli is required) is not clearly understood. In this study, we tested domain dichotomy theory, which predicts that familiarity should contribute more to associative memory when stimuli are similar (within-domain) than when they are distinct (between-domain). Participants studied stimulus pairs, and at test, discriminated intact from rearranged pairs. Stimuli were either within-domain (name-name or image-image pairs) or between-domain (name-image pairs). Across experiments we used 2 different behavioral measures of familiarity based on receiver operating characteristic curves and a modified remember-know procedure. Both experiments provided evidence that familiarity can contribute to associative recognition; however, familiarity was stronger for between-domain pairs, in direct contrast to the domain dichotomy prediction.


A systematic review of the use of computers in the management of hypertension.
To assess the effect of computers and computer-based clinical decision support systems on the management of hypertension. Systematic review of randomised controlled trials. Ambulatory hypertension clinics, community-based health centres, and general practices. 11,962 patients enrolled in seven trials retrieved from a systematic search (electronic databases, contact with authors, reference lists; no restriction on language). Individual trials report on a diverse population of patients (newly diagnosed or established hypertensive patients), interventions (computers used for case finding, recall and registration, feedback on quality of blood pressure control and prescribing information), and outcomes (administration, physician performance and blood pressure control). Four of five trials reported an improvement in patient administration using a computer. Two of three trials reported an improvement in physician performance using a computer. Two of six trials. reported an improvement in blood pressure control in patients using a computer. However, positive findings in two trials should be regarded cautiously because of the potential effects of cluster randomisation. It seems that computers have a favourable effect on the uptake and follow up of patients in hypertension management. The effect of computers on physician knowledge, recording of information, and blood pressure control in patients is less conclusive and further studies are required.


Lung growth and development in anencephaly and hydranencephaly.
Significant qualitative and quantitative differences were observed in the lungs of 4 of 6 infants with anencephaly and hydranencephaly. In 3 of 4 of them, the findings were explicable on the basis of the presence of associated congenital anomalies, and in the fourth there was polyhydramnios. The infants with normal lungs did not have associated congenital abnormalities. The absence of the pituitary did not correlate with the degree of development of the lungs. Studies of lung growth in anencephaly and hydranencephaly must clearly note the presence of associated anomalies because anencephaly/hydranencephaly per se may not cause pulmonary hypoplasia in the majority of cases. The most satisfactory assessment in evaluation of lung growth and development was obtained by combining morphologic findings with more than one morphometric parameter. Radial count estimation alone was found to be a poor predictor of lung maturity (morphologic age) in hypoplastic lungs. Radial count and fixed lung volume together provide a better assessment of lung growth and development than does the ratio of lung weight to body weight, which is of use only if severely depressed. The terms immaturity and hypoplasia of the lungs are not necessarily synonymous.


Review article: Improving the hospital clinical handover between paramedics and emergency department staff in the deteriorating patient.
Clinical communication and recognising and responding to a deteriorating patient are key current patient safety issues in healthcare. The aim of this literature review is to identify themes associated with aspects of the hospital clinical handover between paramedics and ED staff that can be improved, with a specific focus on the transfer of care of a deteriorating patient. Extensive searches of scholarly literature were conducted using the main medical and nursing electronic databases, including Cumulative Index to Nursing and Allied Health Literature, Medline and PubMed, during 2011 and again in July 2012. Seventeen peer-reviewed English-language original quantitative and qualitative studies from 2001 to 2012 were selected and critically appraised using an evaluation tool based on published instruments. Relevant themes identified were: professional relationships, respect and barriers to communication; multiple or repeated handovers; identification of staff in the ED; significance of vital signs; need for a structured handover tool; documentation and other communication methods and education and training to improve handovers. The issues raised in the literature included the need to: produce more complete and concise handovers, create respectful and effective communication, and identify staff in the ED. A structured handover tool such as ISBAR (a mnemonic covering Introduction, Situation, Background, Assessment and Recommendations) would appear to provide a solution to many of these issues. The recording of vital signs and transfer of these data might be improved with better observation systems incorporating early warning strategies. More effective teamwork could be achieved with further clinical communications training.


Successful development of microsatellite markers in a challenging species: the horizontal borer Austroplatypus incompertus (Coleoptera: Curculionidae).
The analysis of microsatellite loci has allowed significant advances in evolutionary biology and pest management. However, until very recently, the potential benefits have been compromised by the high costs of developing these neutral markers. High-throughput sequencing provides a solution to this problem. We describe the development of 13 microsatellite markers for the eusocial ambrosia beetle, Austroplatypus incompertus, a significant pest of forests in southeast Australia. The frequency of microsatellite repeats in the genome of A. incompertus was determined to be low, and previous attempts at microsatellite isolation using a traditional genomic library were problematic. Here, we utilised two protocols, microsatellite-enriched genomic library construction and high-throughput 454 sequencing and characterised 13 loci which were polymorphic among 32 individuals. Numbers of alleles per locus ranged from 2 to 17, and observed and expected heterozygosities from 0.344 to 0.767 and from 0.507 to 0.860, respectively. These microsatellites have the resolution required to analyse fine-scale colony and population genetic structure. Our work demonstrates the utility of next-generation 454 sequencing as a method for rapid and cost-effective acquisition of microsatellites where other techniques have failed, or for taxa where marker development has historically been both complicated and expensive.


Higher-order spike triggered analysis of neural oscillators.
For the purpose of elucidating the neural coding process based on the neural excitability mechanism, researchers have recently investigated the relationship between neural dynamics and the spike triggered stimulus ensemble (STE). Ermentrout et al. analytically derived the relational equation between the phase response curve (PRC) and the spike triggered average (STA). The STA is the first cumulant of the STE. However, in order to understand the neural function as the encoder more explicitly, it is necessary to elucidate the relationship between the PRC and higher-order cumulants of the STE. In this paper, we give a general formulation to relate the PRC and the nth moment of the STE. By using this formulation, we derive a relational equation between the PRC and the spike triggered covariance (STC), which is the covariance of the STE. We show the effectiveness of the relational equation through numerical simulations and use the equation to identify the feature space of the rat hippocampal CA1 pyramidal neurons from their PRCs. Our result suggests that the hippocampal CA1 pyramidal neurons oscillating in the theta frequency range are commonly sensitive to inputs composed of theta and gamma frequency components.


Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor.
We have assessed the ability of bispecific fusion proteins to improve adenovirus-mediated transfer of therapeutic and marker transgenes. We constructed an expression vector that can be easily modified to synthesize a variety of fusion proteins for retargeting adenoviral gene therapy vectors to cell surface markers, which are differentially expressed between normal and cancer cells. Adenoviral transduction can be improved in a number of tumour cell lines which overexpress EGFR (epidermal growth factor receptor) or uPAR (urokinase-type plasminogen activator receptor), but which have only low levels of endogenous hCAR (human coxsackie B and adenovirus receptor) expression. Up to 40-fold improvement in beta-galactosidase transgene expression was seen using an EGFR retargeting protein, and up to 16-fold using a second fusion protein targeting uPAR. In vitro, our uPAR retargeting fusion protein improved the sensitivity to adenoviral herpes simplex virus thymidine kinase/ganciclovir by an order of magnitude, whereas in vivo, our EGFR retargeting protein is able to significantly delay tumour growth in rodent animal models in a dose-dependent manner. The 'cassette' design of our fusion protein constructs offers a flexible method for the straightforward synthesis of multiple adenoviral retargeting proteins, directed against a variety of tumour-associated antigens, for use in clinical trials.


Comparing verbal autopsy cause of death findings as determined by physician coding and probabilistic modelling: a public health analysis of 54 000 deaths in Africa and Asia.
Coverage of civil registration and vital statistics varies globally, with most deaths in Africa and Asia remaining either unregistered or registered without cause of death. One important constraint has been a lack of fit-for-purpose tools for registering deaths and assigning causes in situations where no doctor is involved. Verbal autopsy (interviewing care-givers and witnesses to deaths and interpreting their information into causes of death) is the only available solution. Automated interpretation of verbal autopsy data into cause of death information is essential for rapid, consistent and affordable processing. Verbal autopsy archives covering 54 182 deaths from five African and Asian countries were sourced on the basis of their geographical, epidemiological and methodological diversity, with existing physician-coded causes of death attributed. These data were unified into the WHO 2012 verbal autopsy standard format, and processed using the InterVA-4 model. Cause-specific mortality fractions from InterVA-4 and physician codes were calculated for each of 60 WHO 2012 cause categories, by age group, sex and source. Results from the two approaches were assessed for concordance and ratios of fractions by cause category. As an alternative metric, the Wilcoxon matched-pairs signed ranks test with two one-sided tests for stochastic equivalence was used. The overall concordance correlation coefficient between InterVA-4 and physician codes was 0.83 (95% CI 0.75 to 0.91) and this increased to 0.97 (95% CI 0.96 to 0.99) when HIV/AIDS and pulmonary TB deaths were combined into a single category. Over half (53%) of the cause category ratios between InterVA-4 and physician codes by source were not significantly different from unity at the 99% level, increasing to 62% by age group. Wilcoxon tests for stochastic equivalence also demonstrated equivalence. These findings show strong concordance between InterVA-4 and physician-coded findings over this large and diverse data set. Although these analyses cannot prove that either approach constitutes absolute truth, there was high public health equivalence between the findings. Given the urgent need for adequate cause of death data from settings where deaths currently pass unregistered, and since the WHO 2012 verbal autopsy standard and InterVA-4 tools represent relatively simple, cheap and available methods for determining cause of death on a large scale, they should be used as current tools of choice to fill gaps in cause of death data.


Interactions between bacterial surface and nanoparticles govern the performance of "chemical nose" biosensors.
Rapid and portable diagnosis of pathogenic bacteria can save lives lost from infectious diseases. Biosensors based on a "chemical nose" approach are attracting interest because they are versatile but the governing interactions between bacteria and the biosensors are poorly understood. Here, we use a "chemical nose" biosensor based on gold nanoparticles to explore the role of extracellular polymeric substances in bacteria-nanoparticle interactions. We employ simulations using Maxwell-Garnett theory to show how the type and extent of aggregation of nanoparticles influence their colorimetric response to bacteria. Using eight different species of Gram-positive and Gram-negative bacteria, we demonstrate that this "chemical nose" can detect and identify bacteria over two orders of magnitude of concentration (89% accuracy). Additionally, the "chemical nose" differentiates between binary and tertiary mixtures of the three most common hospital-isolated pathogens: Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa (100% accuracy). We demonstrate that the complex interactions between nanoparticles and bacterial surface determine the colorimetric response of gold nanoparticles and thus, govern the performance of "chemical nose" biosensors.


A Novel Method for Prediction of Raised Intracranial Pressure Through Automated ONSD and ETD Ratio Measurement From Ocular Ultrasound.
The paper presents a novel framework for the prediction of the raised Intracranial Pressure (ICP) from ocular ultrasound images of traumatic patients through automated measurement of Optic Nerve Sheath Diameter (ONSD) and Eyeball Transverse Diameter (ETD). The measurement of ONSD using an ocular ultrasound scan is non-invasive and correlates with the raised ICP. However, the existing studies suggested that the ONSD value alone is insufficient to indicate the ICP condition. Since the ONSD and ETD values may vary among patients belonging to different ethnicity/origins, there is a need for developing an independent global biomarker for predicting raised ICP condition. The proposed work develops an automated framework for the prediction of raised ICP by developing algorithms for the automated measurement of ONSD and ETD values. It is established that the ONSD and ETD ratio (OER) is a potential biomarker for ICP prediction independent of ethnicity and origin. The OER threshold value is determined by performing statistical analysis on the data of 57 trauma patients obtained from the AIIMS, New Delhi. The automated OER is computed and compared with the conventionally measured ICP by determining suitable correlation coefficients. It is found that there is a significant correlation of OER with ICP (r = .81, p ≤ .01), whereas the correlation of ONSD alone with ICP is relatively less (r = .69, p = .004). These correlation values indicate that OER is a better parameter for the prediction of ICP. Further, the threshold value of OER is found to be 0.21 for predicting raised ICP conditions in this study. Scatter plot and Heat map analysis of OER and corresponding ICP reveal that patients with OER ≥ 0.21, have ICP in the range of 17 to 35 mm Hg. In the data available for this research work, OER ranges from 0.17 to 0.35.


Structure of the bifunctional aminoglycoside-resistance enzyme AAC(6')-Ie-APH(2'')-Ia revealed by crystallographic and small-angle X-ray scattering analysis.
Broad-spectrum resistance to aminoglycoside antibiotics in clinically important Gram-positive staphylococcal and enterococcal pathogens is primarily conferred by the bifunctional enzyme AAC(6')-Ie-APH(2'')-Ia. This enzyme possesses an N-terminal coenzyme A-dependent acetyltransferase domain [AAC(6')-Ie] and a C-terminal GTP-dependent phosphotransferase domain [APH(2'')-Ia], and together they produce resistance to almost all known aminoglycosides in clinical use. Despite considerable effort over the last two or more decades, structural details of AAC(6')-Ie-APH(2'')-Ia have remained elusive. In a recent breakthrough, the structure of the isolated C-terminal APH(2'')-Ia enzyme was determined as the binary Mg2GDP complex. Here, the high-resolution structure of the N-terminal AAC(6')-Ie enzyme is reported as a ternary kanamycin/coenzyme A abortive complex. The structure of the full-length bifunctional enzyme has subsequently been elucidated based upon small-angle X-ray scattering data using the two crystallographic models. The AAC(6')-Ie enzyme is joined to APH(2'')-Ia by a short, predominantly rigid linker at the N-terminal end of a long α-helix. This α-helix is in turn intrinsically associated with the N-terminus of APH(2'')-Ia. This structural arrangement supports earlier observations that the presence of the intact α-helix is essential to the activity of both functionalities of the full-length AAC(6')-Ie-APH(2'')-Ia enzyme.


Application of N-Terminal Labeling Methods Provide Novel Insights into Endoproteolysis of the Prion Protein in Vivo.
Alternative α- and β-cleavage events in the cellular prion protein (PrPC) central region generate fragments with distinct biochemical features that affect prion disease pathogenesis, but the assignment of precise cleavage positions has proven challenging. Exploiting mouse transgenic models expressing wild-type (WT) PrPC and an octarepeat region mutant allele (S3) with increased β-fragmentation, cleavage sites were defined using LC-MS/MS in conjunction with N-terminal enzymatic labeling and chemical in-gel acetylation. Our studies profile the net proteolytic repertoire of the adult brain, as deduced from defining hundreds of proteolytic events in other proteins, and position individual cleavage events in PrPC α- and β-target areas imputed from earlier, lower resolution methods; these latter analyses established site heterogeneity, with six cleavage sites positioned in the β-cleavage region of WT PrPC and nine positions for S3 PrPC. Regarding α-cleavage, aside from reported N-termini at His110 and Val111, we identified a total of five shorter fragments in the brain of both mice lines. We infer that aminopeptidase activity in the brain could contribute to the ragged N-termini observed around PrPC's α- and β-cleavage sites, with this work providing a point of departure for further in vivo studies of brain proteases.


High rate of detection of ultrasound signs of prostatitis in patients with HPV-DNA persistence on semen: role of ultrasound in HPV-related male accessory gland infection.
Papillomavirus (HPV) often occurs in the semen of patients with male accessory gland infection (MAGI). Ultrasound (US) evaluation has been suggested as a promising diagnostic tool for patients with HPV-related MAGI. No data on the spontaneous clearance of HPV-DNA have been reported so far in HPV-related MAGI. The primary aim of the study was to assess the percentage of early HPV-DNA spontaneous clearance in patients with prostatitis. The secondary aim was to evaluate the frequency of spontaneous clearance of HPV-DNA among patients with prostatitis associated with the presence or absence of US abnormalities. Patients with inflammatory MAGI and at least one suspicious criterion for HPV infection underwent semen HPV-DNA detection and prostate US. The presence of HPV-DNA was further investigated after a 6-month-long follow-up. Eighty patients satisfied the inclusion criteria and were recruited in the study. 69% of patients (55/80) showed HPV-DNA persistence in the semen. Among them, 82% (45/55) was positive for US signs of prostatitis, while they occurred only in 12% (3/25) of those patients with no sign of HPV-DNA persistence (p < 0.001). All patients with persistent high-risk HPV genotype (n = 30) showed at least two US signs of prostatitis. In 73% of patients (22/30), E6 and E7 mRNAs were detected. US signs of prostatitis more frequently occurred in patients with evidence of HPV-DNA persistence on semen, especially in those with high-risk genotypes. This highlights the importance of US in the framework of HPV-related MAGI.


A Review on Electroporation-Based Intracellular Delivery.
Intracellular delivery is a critical step in biological discoveries and has been widely utilized in biomedical research. A variety of molecular tools have been developed for cell-based gene therapies, including FDA approved CAR-T immunotherapy, iPSC, cell reprogramming and gene editing. Despite the inspiring results of these applications, intracellular delivery of foreign molecules including nucleic acids and proteins remains challenging. Efficient yet non-invasive delivery of biomolecules in a high-throughput manner has thus long fascinates the scientific community. As one of the most popular non-viral technologies for cell transfection, electroporation has gone through enormous development with the assist of nanotechnology and microfabrication. Emergence of miniatured electroporation system brought up many merits over the weakness of traditional electroporation system, including precise dose control and high cell viability. These new generation of electroporation systems are of considerable importance to expand the biological applications of intracellular delivery, bypassing the potential safety issue of viral vectors. In this review, we will go over the recent progresses in the electroporation-based intracellular delivery and several potential applications of cutting-edge research on the miniatured electroporation, including gene therapy, cellular reprogramming and intracellular probe.


Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial.
Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. This study assessed whether immediate preoperative treatment could result in reduced perioperative red blood cell (RBC) transfusions and improved outcome. In this single-centre, randomised, double-blind, parallel-group controlled study, patients undergoing elective cardiac surgery with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled. Participants were randomly assigned (1:1) with the use of a computer-generated range minimisation (allocation probability 0·8) to receive either placebo or combination treatment consisting of a slow infusion of 20 mg/kg ferric carboxymaltose, 40 000 U subcutaneous erythropoietin alpha, 1 mg subcutaneous vitamin B12, and 5 mg oral folic acid or placebo on the day before surgery. Primary outcome was the number of RBC transfusions during the first 7 days. This trial is registered with ClinicalTrials.gov, number NCT02031289. Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. The combination treatment significantly reduced RBC transfusions from a median of one unit in the placebo group (IQR 0-3) to zero units in the treatment group (0-2, during the first 7 days (odds ratio 0·70 [95% CI 0·50-0·98] for each threshold of number of RBC transfusions, p=0·036) and until postoperative day 90 (p=0·018). Despite fewer RBC units transfused, patients in the treatment group had a higher haemoglobin concentration, higher reticulocyte count, and a higher reticulocyte haemoglobin content during the first 7 days (p≤0·001). Combined allogeneic transfusions were less in the treatment group (0 [IQR 0-2]) versus the placebo group (1 [0-3]) during the first 7 days (p=0·038) and until postoperative day 90 (p=0·019). 73 (30%) serious adverse events were reported in the treatment group group versus 79 (33%) in the placebo group. An ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery. Vifor Pharma and Swiss Foundation for Anaesthesia Research.


Endoscopic third ventriculostomy for treatment of adult hydrocephalus: long-term follow-up of 163 patients.
OBJECTIVE The efficacy of endoscopic third ventriculostomy (ETV) for the treatment of pediatric hydrocephalus has been extensively reported in the literature. However, ETV-related long-term outcome data are lacking for the adult hydrocephalus population. The objective of the present study was to assess the role of ETV as a primary or secondary treatment for hydrocephalus in adults. METHODS The authors performed a retrospective chart review of all adult patients (age ≥ 18 years) with symptomatic hydrocephalus treated with ETV in Calgary, Canada, over a span of 20 years (1994-2014). Patients were dichotomized into a primary or secondary ETV cohort based on whether ETV was the initial treatment modality for the hydrocephalus or if other CSF diversion procedures had been previously attempted respectively. Primary outcomes were subjective patient-reported clinical improvement within 12 weeks of surgery and the need for any CSF diversion procedures after the initial ETV during the span of the study. Categorical and actuarial data analysis was done to compare the outcomes of the primary versus secondary ETV cohorts. RESULTS A total of 163 adult patients with symptomatic hydrocephalus treated with ETV were identified and followed over an average of 98.6 months (range 0.1-230.4 months). All patients presented with signs of intracranial hypertension or other neurological symptoms. The primary ETV group consisted of 112 patients, and the secondary ETV consisted of 51 patients who presented with failed ventriculoperitoneal (VP) shunts. After the initial ETV procedure, clinical improvement was reported more frequently by patients in the primary cohort (87%) relative to those in the secondary ETV cohort (65%, p = 0.001). Additionally, patients in the primary ETV group required fewer reoperations (p < 0.001), with cumulative ETV survival time favoring this primary ETV cohort over the course of the follow-up period (p < 0.001). Fifteen patients required repeat ETV, with all but one experiencing successful relief of symptoms. Patients in the secondary ETV cohort also had a higher incidence of complications, with one occurring in 8 patients (16%) compared with 2 in the primary ETV group (2%; p = 0.010), although most complications were minor. CONCLUSIONS ETV is an effective long-term treatment for selected adult patients with hydrocephalus. The overall ETV success rate when it was the primary treatment modality for adult hydrocephalus was approximately 87%, and 99% of patients experience symptomatic improvement after 2 ETVs. Patients in whom VP shunt surgery fails prior to an ETV have a 22% relative risk of ETV failure and an almost eightfold complication rate, although mostly minor, when compared with patients who undergo a primary ETV. Most ETV failures occur within the first 7 months of surgery in patients treated with primary ETV, but the time to failure is more prolonged in patients who present with failed previous shunts.


Surgery for cholangiocarcinoma: the role of liver transplantation.
Liver transplantation alone for unresectable hilar cholangiocarcinoma (CCA) is fraught with frequent recurrence and poor long-term survival. The Mayo Clinic developed a novel therapeutic protocol combining neoadjuvant chemoradiation and orthotopic liver transplantation (OLT) in 1993 to treat patients with unresectable hilar CCA or CCA arising in the setting of PSC. We recently reviewed our experience over the past 14 years with the specific aim to evaluate the long-term outcomes of CCA patients treated according to our study protocol. We analyzed data from all patients enrolled in the Mayo Clinic liver transplant protocol since 1993. Statistical data analysis of recurrence and survival rates was performed using the Kaplan-Meier method. 148 patients were enrolled in the protocol. Of 90 patients who completed neoadjuvant therapy and subsequent OLT, 71 are alive and 19 have died--only 8 due to recurrent CCA. Nineteen patients are awaiting OLT and 39 were removed from the protocol owing to disease progression or death. Overall, 1-, 3-, and 5-year patient survival was 82%, 63%, and 55%, respectively; 1-, 3-, and 5-year survival after OLT was 90%, 80%, and 71%. Neoadjuvant chemoradiation and OLT achieves significantly lower recurrence and higher long-term survival rates than resection, OLT alone, or medical treatment in hilar CCA. Additional experience at independent transplant centers is necessary to confirm these encouraging results, address the role of neoadjuvant therapy and liver transplantation versus conventional resection, determine appropriate inclusion/exclusion criteria, and define the risk of disease progression while awaiting transplantation.


Stringent control of ribonucleic acid synthesis in Bacillus subtilis treated with granaticin.
The antibiotic granaticin interferes in Bacillus subtilis with the charging process of tRNALeu causing both the arrest of protein synthesis and bacteriostasis [A. Ogilvie, K. Wiebauer & W. Kersten (1975) Biochem. J. 152, 511-515]. A concomitant inhibition of RNA synthesis is observed. This inhibition was studied with mutant strains of B. subtilis. 2. Granaticin inhibits protein and RNA synthesis in stringently controlled B. subtilis (rel+) to about the same extent. In a relaxed mutant strain (rel-) of B. subtilis, protein synthesis is also inhibited, but the accumulation of RNA continues after the addition of the drug. 3. Chloramphenicol, which is known to abolish the stringent control mechanism, added simultaneously with granaticin, allows the synthesis of RNA to proceed in the stringent strain. 4. Guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) accumulate in granaticin-treated stringently controlled B. subtilis but not in the rel- mutant. 5. It is concluded that the inhibition of RNA synthesis granaticin can adequately be explained as a stringent response caused by the interference by the drug with leucyl-tRNA synthetase.


Fifteen-Year Mortality and Cardiac, Thrombotic, and Bleeding Events in Survivors of ST-Elevation Myocardial Infarction.
Although short-term mortality in ST-elevation myocardial infarction (STEMI) has improved, data is limited regarding very long-term mortality and concomitant clinical events in STEMI survivors who undergo primary percutaneous coronary intervention (p-PCI). This study aimed to evaluate these parameters at 15 years and to determine the predictors of 15-year mortality in these patients. The study endpoints were all-cause mortality and cardiac mortality at 15 years. Independent predictors of all-cause mortality were also analyzed. Furthermore, each thrombotic and bleeding event was evaluated. Between January 2004 and December 2006, 260 STEMI survivors who underwent p-PCI (median follow-up period: 3970 days) were evaluated from the Ogaki Municipal hospital registry. The rates of all-cause mortality (cardiac mortality) at 5, 10, and 15 years were 12.1% (4.9%), 23.4% (9.5%), and 34.9% (12.4%), respectively. The cumulative incidences of recurrent myocardial infarction, target vessel revascularization, ischemic stroke, hemorrhagic bleeding, and gastric bleeding at 15 years were 11.3%, 43.6%, 14.3%, 6.9%, and 10.9%, respectively. Cox regression analysis showed that age ≥ 75 years [adjusted hazard ratio (aHR), 7.074, p < 0.001], chronic kidney disease (aHR, 2.320, p = 0.001), left ventricular ejection fraction <40% (aHR, 2.930, p = 0.001), Killip class ≥II at admission (aHR, 2.639, p = 0.003), untreated chronic total occlusion (aHR, 2.090, p = 0.042), and final TIMI grade ≤ 2 (aHR, 1.736, p = 0.048) were independent predictors of all-cause mortality. This study demonstrated that all-cause and cardiac mortality at 15 years were 34.9% and 12.4%, respectively, in all-comers STEMI survivors after p-PCI, indicating that STEMI survivors might have a benign prognosis.


Fine-mapping QTL for mastitis resistance on BTA9 in three Nordic red cattle breeds.
A QTL affecting clinical mastitis and/or somatic cell score (SCS) has been reported previously on chromosome 9 from studies in 16 families from the Swedish Red and White (SRB), Finnish Ayrshire (FA) and Danish Red (DR) breeds. In order to refine the QTL location, 67 markers were genotyped over the whole chromosome in the 16 original families and 18 additional half-sib families. This enabled linkage disequilibrium information to be used in the analysis. Data were analysed by an approach that combines information from linkage and linkage disequilibrium, which allowed the QTL affecting clinical mastitis to be mapped to a small interval (<1 cM) between the markers BM4208 and INRA084. This QTL showed a pleiotropic effect on SCS in the DR and SRB breeds. Haplotypes associated with variations in mastitis resistance were identified. The haplotypes were predictive in the general population and can be used in marker-assisted selection. Pleiotropic effects of the mastitis QTL were studied for three milk production traits and eight udder conformation traits. This QTL was also associated with yield traits in DR but not in FA or SRB. No QTL were found for udder conformation traits on chromosome 9.


Testing the interaction between analytical modules: an example with Roundup Ready soybean line GTS 40-3-2.
The modular approach to analysis of genetically modified organisms (GMOs) relies on the independence of the modules combined (i.e. DNA extraction and GM quantification). The validity of this assumption has to be proved on the basis of specific performance criteria. An experiment was conducted using, as a reference, the validated quantitative real-time polymerase chain reaction (PCR) module for detection of glyphosate-tolerant Roundup Ready(R) GM soybean (RRS). Different DNA extraction modules (CTAB, Wizard and Dellaporta), were used to extract DNA from different food/feed matrices (feed, biscuit and certified reference material [CRM 1%]) containing the target of the real-time PCR module used for validation. Purity and structural integrity (absence of inhibition) were used as basic criteria that a DNA extraction module must satisfy in order to provide suitable template DNA for quantitative real-time (RT) PCR-based GMO analysis. When performance criteria were applied (removal of non-compliant DNA extracts), the independence of GMO quantification from the extraction method and matrix was statistically proved, except in the case of Wizard applied to biscuit. A fuzzy logic-based procedure also confirmed the relatively poor performance of the Wizard/biscuit combination. For RRS, this study recognises that modularity can be generally accepted, with the limitation of avoiding combining highly processed material (i.e. biscuit) with a magnetic-beads system (i.e. Wizard).


Transcriptional activation triggers deposition and removal of the histone variant H3.3.
DNA in eukaryotic cells is packaged into nucleosomes, the structural unit of chromatin. Both DNA and bulk histones are extremely long-lived, because old DNA strands and histones are retained when chromatin duplicates. In contrast, we find that the Drosophila HSP70 genes rapidly lose histone H3 and acquire variant H3.3 histones as they are induced. Histone replacement does not occur at artificial HSP70 promoter arrays, demonstrating that transcription is required for H3.3 deposition. The H3.3 histone is enriched in all active chromatin and throughout large transcription units, implying that deposition occurs during transcription elongation. Strikingly, we observed that the stability of chromatin-bound H3.3 differs between loci: H3.3 turns over at continually active rDNA genes, but becomes stable at induced HSP70 genes that have shut down. We conclude that H3.3 deposition is coupled to transcription, and continues while a gene is active. Repeated histone replacement suggests a mechanism to both maintain the structure of chromatin and access to DNA at active genes.


Preeclampsia: Linking Placental Ischemia with Maternal Endothelial and Vascular Dysfunction.
Preeclampsia (PE), a hypertensive disorder, occurs in 3% to 8% of pregnancies in the United States and affects over 200,000 women and newborns per year. The United States has seen a 25% increase in the incidence of PE, largely owing to increases in risk factors, including obesity and cardiovascular disease. Although the etiology of PE is not clear, it is believed that impaired spiral artery remodeling of the placenta reduces perfusion, leading to placental ischemia. Subsequently, the ischemic placenta releases antiangiogenic and pro-inflammatory factors, such as cytokines, reactive oxygen species, and the angiotensin II type 1 receptor autoantibody (AT1-AA), among others, into the maternal circulation. These factors cause widespread endothelial activation, upregulation of the endothelin system, and vasoconstriction. In turn, these changes affect the function of multiple organ systems including the kidneys, brain, liver, and heart. Despite extensive research into the pathophysiology of PE, the only treatment option remains early delivery of the baby and importantly, the placenta. While premature delivery is effective in ameliorating immediate risk to the mother, mounting evidence suggests that PE increases risk of cardiovascular disease later in life for both mother and baby. Notably, these women are at increased risk of hypertension, heart disease, and stroke, while offspring are at risk of obesity, hypertension, and neurological disease, among other complications, later in life. This article aims to discuss the current understanding of the diagnosis and pathophysiology of PE, as well as associated organ damage, maternal and fetal outcomes, and potential therapeutic avenues. © 2021 American Physiological Society. Compr Physiol 11:1315-1349, 2021.


Buccal Fat Pad Augmentation for Facial Rejuvenation.
The buccal space, with its fat pad, is a valuable, overlooked target in facial rejuvenation procedures. The authors identified a specific group of patients who have normal or prominent malar projection in the presence of atrophy of the buccal fat pad, with or without prominent gonial angles. Eight of 24 prospectively studied patients (Biomedical Research Institute of America) who had fat grafts and face lifts received an average of 2.7 ml of fat transferred into the buccal space. Immediate visual correction of the buccal depression was noted. No overcorrection was carried out. None of the eight patients suffered an adverse event from transoral buccal space fat grafting. Persistent facial volume in this area has been noted up to 24 months after treatment. In patients with buccal fat pad atrophy, fat grafting into the buccal space can be safely performed through an intraoral approach.


Quantitative in vivo biomarkers of oxidative damage and their application to the diagnosis and management of Alzheimer's disease.
Dementia from Alzheimer's disease (AD) represents a significant and growing public health burden and presents a clear therapeutic imperative. Key to success in this undertaking will be biomarkers for the objective assessment of disease progression and response to therapeutics. Oxidative damage is one facet of AD pathogenesis for which there are experimentally validated quantitative in vivo biomarkers, the F2-isoprostanes (IsoPs). While plasma- or urine-based assays are desirable, consistent and reproducible cross-sectional data for increased F2-IsoPs in AD and mild cognitive impairment have been obtained only for CSF. In addition, measurement of CSF F2-IsoPs can increase the accuracy of laboratory-based classification of geriatric dementias, and have been used to assess objectively the response to anti-oxidant interventions in AD.


Icebergs as unique Lagrangian ecosystems in polar seas.
Global warming and its disproportionate impact on polar regions have led to increased iceberg populations. Southern Ocean studies in the northwest Weddell Sea have verified substantial delivery of terrestrial material accompanied by increased primary production and faunal abundance associated with free-drifting icebergs. It is hypothesized that input and utilization of macro- and micronutrients are promoted by conditions unique to free-drifting icebergs, leading to increased production, grazing, and export of organic carbon. In Arctic regions, increased freshwater input from meltwater acts to stratify and stabilize the upper water column. As has been observed in the Southern Ocean, Arctic-region icebergs should drive turbulent upwelling and reduce stratification, potentially leading to increased nitrate delivery to the local ecosystem. Increasing populations of icebergs in polar regions can potentially be important in mediating the drawdown and sequestration of CO(2) and can thus impact the oceanic carbon cycle.


Trabecular bone recovers from mechanical unloading primarily by restoring its mechanical function rather than its morphology.
Upon returning to normal ambulatory activities, the recovery of trabecular bone lost during unloading is limited. Here, using a mouse population that displayed a large range of skeletal susceptibility to unloading and reambulation, we tested the impact of changes in trabecular bone morphology during unloading and reambulation on its simulated mechanical properties. Female adult mice from a double cross of BALB/cByJ and C3H/HeJ strains (n=352) underwent 3wk of hindlimb unloading followed by 3wk of reambulation. Normally ambulating mice served as controls (n=30). As quantified longitudinally by in vivo μCT, unloading led to an average loss of 43% of trabecular bone volume fraction (BV/TV) in the distal femur. Finite element models of the μCT tomographies showed that deterioration of the trabecular structure raised trabecular peak Von-Mises (PVM) stresses on average by 27%, indicating a significant increase in the risk of mechanical failure compared to baseline. Further, skewness of the Von-Mises stress distributions (SVM) increased by 104% with unloading, indicating that the trabecular structure became inefficient in resisting the applied load. During reambulation, bone of experimental mice recovered on average only 10% of its lost BV/TV. Even though the addition of trabecular tissue was small during reambulation, PVM and SVM as indicators of risk of mechanical failure decreased by 56% and 57%, respectively. Large individual differences in the response of trabecular bone, together with a large sample size, facilitated stratification of experimental mice based on the level of recovery. As a fraction of all mice, 66% of the population showed some degree of recovery in BV/TV while in 89% and 87% of all mice, PVM and SVM decreased during reambulation, respectively. At the end of the reambulation phase, only 8% of the population recovered half of the unloading induced losses in BV/TV while 50% and 49% of the population recovered half of the unloading induced deterioration in PVM and SVM, respectively. The association between morphological and mechanical variables was strong at baseline but progressively decreased during the unloading and reambulation cycles. The preferential recovery of trabecular micromechanical properties over bone volume fraction emphasizes that mechanical demand during reambulation does not, at least initially, seek to restore bone's morphology but its mechanical integrity.


Ethnic Differences in Geriatric Conditions and Diabetes Complications Among Older, Insured Adults With Diabetes: The Diabetes and Aging Study.
The aim of this study was to evaluate ethnic differences in burden of prevalent geriatric conditions and diabetic complications among older, insured adults with diabetes. An observational study was conducted among 115,538 diabetes patients, aged ≥60, in an integrated health care system with uniform access to care. Compared with Whites, Asians and Filipinos were more likely to be underweight but had substantively lower prevalence of falls, urinary incontinence, polypharmacy, depression, and chronic pain, and were least likely of all groups to have at least one geriatric condition. African Americans had significantly lower prevalence of incontinence and falls, but higher prevalence of dementia; Latinos had a lower prevalence of falls. Except for end-stage renal disease (ESRD), Whites tended to have the highest rates of prevalent diabetic complications. Among these insured older adults, ethnic health patterns varied substantially; differences were frequently small and rates were often better among select minority groups, suggesting progress toward the Healthy People 2020 objective to reduce health disparities.


Gotfried percutaneous compression plating compared with sliding hip screw fixation of intertrochanteric hip fractures: a prospective randomized study.
The use of a Gotfried percutaneous compression plate provides a minimally invasive technique for the fixation of intertrochanteric proximal femoral fractures. The purpose of this study was to determine if the percutaneous compression plate provided advantages compared with the sliding hip screw for treatment of A1 and A2 AO/OTA intertrochanteric proximal femoral fractures. An institutional review board-approved, prospective, randomized, single-blinded study was conducted at a level-I trauma center between July 2004 and September 2007. All patients who met the study criteria and provided informed consent were randomized to treatment with a sliding hip screw or percutaneous compression plate. Of the sixty-six patients who consented to participate, thirty-three were randomized to be treated with a sliding hip screw and thirty-three, with a percutaneous compression plate. Data evaluated included surgical time, incision length, blood loss, need for blood transfusion, and postoperative functional status. Follow-up included clinical findings, radiographs until healing was confirmed, functional and pain assessment scores, and the Short Form-36. The median follow-up period for surviving patients was thirty-six months. Sixty-six patients, forty-seven women and nineteen men, with a mean age of seventy-seven years were entered into the study. The treatment groups were similar with respect to study variables (p > 0.05). Operative times (forty-eight vs. seventy-eight minutes), incision length (56 vs. 82 mm), and blood loss (41 vs. 101 mL) significantly favored the percutaneous compression plate group (p < 0.001). The groups were similar immediately postoperatively; however, by discharge, fewer patients with a percutaneous compression plate required walking aids (40% vs. 59%). This trend continued throughout the study but was not significant. Pain with activity was lower throughout the study for the percutaneous compression plate group, but the difference was significant only at the three-month interval. Previously published reports showing shorter operative times and less blood loss with the percutaneous compression plate were reaffirmed. Compared with the sliding hip screw, the percutaneous compression plate resulted in a larger percentage of patients who were able to walk independently, consistently lower levels of pain with activity, and improved quality of life according to multiple scales of the Short Form-36, but the differences were not significant. Significant differences favoring the percutaneous compression plate were found with regard to operating times, incision length, and blood loss.


GABAergic terminals are required for postsynaptic clustering of dystrophin but not of GABA(A) receptors and gephyrin.
In rat hippocampal cultures, we show by multilabeling immunocytochemistry that pyramidal cells, which receive little or no GABAergic input, mistarget alpha2-GABA(A) receptors and gephyrin to glutamatergic terminals. This mismatch does not occur in neurons innervated by numerous GABAergic terminals. A similar phenomenon has been reported for isolated autaptic hippocampal neurons (Rao et al., 2000). GABAergic synapses typically form multiple release sites apposed to GABA(A) receptor and gephyrin clusters. Remarkably, dystrophin, a protein highly abundant in skeletal muscle membranes, is extensively colocalized with alpha2-GABA(A) receptors exclusively opposite GABAergic terminals. In addition, selective apposition of syntrophin and beta-dystroglycan to GABAergic presynaptic terminals suggests that the entire dystrophin-associated protein complex (DPC) clusters at GABAergic synapses. In contrast to gephyrin and GABA(A) receptors, DPC proteins are not mistargeted to glutamatergic synapses, indicating independent clustering mechanisms. This was confirmed in hippocampal neurons cultured from GABA(A) receptor gamma2 subunit-deficient mice. Clustering of GABA(A) receptor and gephyrin in these neurons was strongly impaired, whereas clustering of dystrophin and associated proteins was unaffected by the absence of the gamma2 subunit. Our results indicate that accumulation of dystrophin and DPC proteins at GABAergic synapses occurs independently of postsynaptic GABA(A) receptors and gephyrin. We suggest that selective signaling from GABAergic terminals contributes to postsynaptic clustering of dystrophin.


The yield of tuberculosis screening of undocumented migrants from the Horn of Africa based on chest radiography.
Since 2006 more than 60,000 migrants arrived in Israel from the Horn of Africa (HoA: Sudan, Eritrea, Ethiopia). They were detained in prison and screened for tuberculosis (TB) by means of an interview and chest X-ray (CXR). To evaluate the yield of this screening process. This cross-sectional study evaluated the validity of CXR in a random sample of 1087 of the 5335 HoA migrants (20.4%) who arrived in 2009, and assessed its related costs. Sixty-two migrants (5.7%) had CXRs with TB-suspicious findings, and 11 of them were finally diagnosed with TB (17.7% of all TB-suspicious CXRs). TB point-prevalence was 1000 cases per 100,000 migrants (1.0%). As no additional TB cases were diagnosed on arrival, CXR sensitivity, specificity and positive predictive value were 100%, 96.1% and 17.7%, respectively. The interview did not contribute to the detection of migrants with TB. Direct costs related to the detection of single TB cases in prison was 17,970 shekels (US$ 4585), lower than the treating cost of 28,745 shekels ($7335). During 2008-2010, 88 HoA migrants who had been screened at the prison after crossing the border were later diagnosed with TB in the community. The average annual TB incidence was 132 cases/100,000 migrants. We traced 56 (63.6%) of the CXRs that were performed during detention. Of those, 41 (73.2%) were unremarkable, 8 (14.2%) were TB suspicious and 7 (12.5%) had non-TB-related abnormalities. CXR-based screening is a valid and cost-saving tool for screening HoA migrants for TB; the interview has significant limitations.


CAPS and syntaxin dock dense core vesicles to the plasma membrane in neurons.
Docking to the plasma membrane prepares vesicles for rapid release. Here, we describe a mechanism for dense core vesicle docking in neurons. In Caenorhabditis elegans motor neurons, dense core vesicles dock at the plasma membrane but are excluded from active zones at synapses. We have found that the calcium-activated protein for secretion (CAPS) protein is required for dense core vesicle docking but not synaptic vesicle docking. In contrast, we see that UNC-13, a docking factor for synaptic vesicles, is not essential for dense core vesicle docking. Both the CAPS and UNC-13 docking pathways converge on syntaxin, a component of the SNARE (soluble N-ethyl-maleimide-sensitive fusion protein attachment receptor) complex. Overexpression of open syntaxin can bypass the requirement for CAPS in dense core vesicle docking. Thus, CAPS likely promotes the open state of syntaxin, which then docks dense core vesicles. CAPS function in dense core vesicle docking parallels UNC-13 in synaptic vesicle docking, which suggests that these related proteins act similarly to promote docking of independent vesicle populations.


Recording of auditory brainstem response at high stimulation rates using randomized stimulation and averaging.
The recording of auditory brainstem response (ABR) at high stimulation rates is of great interest in audiology. It allows a more accurate diagnosis of certain pathologies at an early stage and the study of different mechanisms of adaptation. This paper proposes a methodology, which we will refer to as randomized stimulation and averaging (RSA) that allows the recording of ABR at high stimulation rates using jittered stimuli. The proposed method has been compared with quasi-periodic sequence deconvolution (QSD) and conventional (CONV) stimulation methodologies. Experimental results show that RSA provides a quality in ABR recordings similar to that of QSD and CONV. Compared with CONV, RSA presents the advantage of being able to record ABR at rates higher than 100 Hz. Compared with QSD, the formulation of RSA is simpler and allows more flexibility on the design of the pseudorandom sequence. The feasibility of the RSA methodology is validated by an analysis of the morphology, amplitudes, and latencies of the most important waves in ABR recorded at high stimulation rates from eight normal hearing subjects.


Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients.
An interim analysis of an all-patient postmarketing surveillance programme in Japan to investigate the safety of tocilizumab for the treatment of rheumatoid arthritis (RA) in the real world. This analysis included 3881 patients. Patients received 8 mg/kg of tocilizumab every 4 weeks, and were observed for 28 weeks. Data on baseline characteristics and adverse events (AE) were collected. Total and serious AE were reported as 167 and 27 events/100 patient-years, respectively. The most frequent AE and serious AE were infections. Logistic regression analysis identified the following risk factors for the development of serious infection: concurrent or medical history of respiratory disorders; prednisolone dose at baseline ≥5 mg/day; and age ≥65 years. Twenty-five patients died, and the standardised mortality ratio, with the Japanese general population in 2008 as reference, was 1.66, similar to the results from the Japanese cohort study for RA patients. Tocilizumab is acceptably safe in the real clinical setting. Tocilizumab needs to be used with consideration of the benefit-risk balance to avoid serious infections in elderly patients and those on high doses of corticosteroids or with a concurrent or medical history of respiratory disorders.


Subjective and objective sleep disturbance and longitudinal risk of depression in a cohort of older women.
To investigate the longitudinal relationship between subjective and objective sleep disturbance and depressive symptoms. Longitudinal. Three US clinical centers. Nine hundred fifty-two community-dwelling older women (70 y or older). At baseline, subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and objective sleep measures were assessed with wrist actigraphy. Depressive symptoms were assessed with the Geriatric Depression Scale (GDS) at baseline and approximately 5 y later. The analysis was restricted to women with few (GDS 0-2) depressive symptoms at baseline. There was an independent association between greater PSQI score (per standard deviation increase, indicating worse subjective sleep quality) at baseline and greater odds of worsening depressive symptoms (≥ 2-point increase in GDS) (Multivariate Odds Ratio [MOR] 1.19, confidence interval [CI] 1.01-1.40, P = 0.036). Higher scores specifically on the sleep quality (MOR 1.41, CI 1.13-1.77, P < 0.003) and sleep latency (MOR 1.21, CI 1.03-1.41, P = 0.018) PSQI subscales were also associated with greater odds for worsening depressive symptoms. Objective assessments revealed an association between baseline prolonged wake after sleep onset (WASO ≥ 60 min) and worsening depressive symptoms at follow-up (MOR 1.36, CI 1.01-1.84, P = 0.046). There were no associations between other objectively assessed sleep measures and worsening depressive symptoms. In older women with few or no depressive symptoms at baseline, those with more subjectively reported sleep disturbance and more objectively assessed fragmentation of sleep at baseline had greater odds of worsening depressive symptoms 5 y later. Future studies investigating this relationship in more detail are indicated. Maglione JE, Ancoli-Israel S, Peters KW, Paudel ML, Yaffe K, Ensrud KE, Stone KL, Study of Osteoporotic Fractures Research Group. Subjective and objective sleep disturbance and longitudinal risk of depression in a cohort of older women.


Amplification of early drought responses caused by volatile cues emitted from neighboring plants.
Plants have developed sophisticated mechanisms to survive in dynamic environments. Plants can communicate via volatile organic compounds (VOCs) to warn neighboring plants of threats. In most cases, VOCs act as positive regulators of plant defense. However, the communication and role of volatiles in response to drought stress are poorly understood. Here, we showed that tea plants release numerous VOCs. Among them, methyl salicylate (MeSA), benzyl alcohol, and phenethyl alcohol markedly increased under drought stress. Interestingly, further experiments revealed that drought-induced MeSA lowered the abscisic acid (ABA) content in neighboring plants by reducing 9-cis-epoxycarotenoid dioxygenase (NCED) gene expression, resulting in inhibition of stomatal closure and ultimately decreasing early drought tolerance in neighboring plants. Exogenous application of ABA reduced the wilting of tea plants caused by MeSA exposure. Exposure of Nicotiana benthamiana to MeSA also led to severe wilting, indicating that the ability of drought-induced MeSA to reduce early drought tolerance in neighboring plants may be conserved in other plant species. Taken together, these results provide evidence that drought-induced volatiles can reduce early drought tolerance in neighboring plants and lay a novel theoretical foundation for optimizing plant density and spacing.


A recursive nonstationary MAP displacement vector field estimation algorithm.
A recursive model-based algorithm for obtaining the maximum a posteriori (MAP) estimate of the displacement vector field (DVF) from successive image frames of an image sequence is presented. To model the DVF, we develop a nonstationary vector field model called the vector coupled Gauss-Markov (VCGM) model. The VCGM model consists of two levels: an upper level, which is made up of several submodels with various characteristics, and a lower level or line process, which governs the transitions between the submodels. A detailed line process is proposed. The VCGM model is well suited for estimating the DVF since the resulting estimates preserve the boundaries between the differently moving areas in an image sequence. A Kalman type estimator results, followed by a decision criterion for choosing the appropriate line process. Several experiments demonstrate the superior performance of the proposed algorithm with respect to prediction error, interpolation error, and robustness to noise.


Physicochemical properties and biological effects of quaternary ammonium methacrylates in an experimental adhesive resin for bonding orthodontic brackets.
Fixed orthodontic appliances may lead to biofilm accumulation around them that may increase caries risk. This study aimed to evaluate the influence of quaternary ammonium methacrylates (QAMs) on the physicochemical properties, cytotoxicity, and antibacterial activity of adhesive resins for orthodontic purposes. A base resin was prepared with a comonomer blend and photoinitiator/co-initiator system. Two different QAMs were added to the base adhesive: dimethylaminododecyl methacrylate at 5 wt.% (DMADDM) or dimethylaminohexadecyl methacrylate (DMAHDM) at 10 wt.%. The base adhesive, without QAMs, (GC) and the commercial Transbond™ XT Primer 3M (GT) were used as control. The resins were tested immediately and after six months of aging in the water regarding the antibacterial activity and shear bond strength (SBS). The antibacterial activity was tested against Streptococcus mutans via metabolic activity assay (MTT test). The groups were also tested for the degree of conversion (DC) and cytotoxicity against keratinocytes. The resins containing QAM showed antibacterial activity compared to the commercial material by immediately reducing the metabolic activity by about 60%. However, the antibacterial activity decreased after aging (p<0.05). None of the groups presented any differences for SBS (p>0.05) and DC (p>0.05). The incorporation of DMADDM and DMAHDM significantly reduced the keratinocyte viability compared to the GT and GC groups (p<0.05). Both adhesives with QAMs showed a significant reduction in bacterial metabolic activity, but this effect decreased after water aging. Lower cell viability was observed for the group with the longer alkyl chain-QAM, without significant differences for the bonding ability and degree of conversion. The addition of QAMs in adhesives may affect the keratinocytes viability, and the aging effects maybe decrease the bacterial activity of QAM-doped materials.


Human perceptual learning by mental imagery.
Perceptual learning is learning to perceive. For example, a radiologist is able to easily identify anomalies in medical images only after extended training. Theoretical and psychophysical studies [1-12] suggest that such improvements of performance are accomplished by neural synaptic changes driven by the repetitive presentation of stimuli. Here, we demonstrate that an equally reliable improvement can also occur in the absence of physical stimulation. Imagining the crucial part of a bisection stimulus was sufficient for successful perceptual learning. Hence, the neural processes underlying perceptual learning, which are usually assumed to be primarily dependent on stimulus processing, can be equally based on mentally generated signals.


The Effect of Different Metabolic Syndrome: Definitions on the Relationship Between Metabolic Syndrome and LUTS in Men With Benign Prostatic Enlargement.
Because various criteria are used to define metabolic syndrome (MetS), this study examines the most relevant definition for patients with benign prostatic enlargement (BPE). Most studies regarding the link between MetS and BPE/lower urinary tract symptoms (LUTS) have used the National Cholesterol Education Program Adult Treatment Panel III criteria for diagnosis, while a few have used criteria from the International Diabetes Federation and/or American Heart Association. Patients with LUTS due to BPE are classified as having MetS or not by the aforementioned three definitions. Prostate volume, International Prostate Symptom Score, storage and voiding subscores, maximum urinary flow rate, and the postvoid urine of patients with and without MetS were compared separately in the three different groups. Surgical and medical treatment prevalence was also compared between three groups. No matter which definition was used, the International Prostate Symptom Score, the storage and voiding symptom scores, prostate volume, prostate-specific antigen, and postvoid urine were significantly higher in the patients with MetS. The maximum urinary flow rate was similar between patients with and without MetS, according to all three different definitions. There was no significant difference in the aforementioned parameter between patients with MetS diagnosed with the three different definitions. Irrespective of which definition was used, the surgical treatment rate was not significantly different in patients diagnosed with than without MetS, or between the patients with MetS diagnosed with the three different definitions. The authors suggest that it does not matter which of the aforementioned three definitions is used during the evaluation of MetS in men with BPE/LUTS.