Role of arginine residues on the S4 segment of the Bacillus halodurans Na+ channel in voltage-sensing.
The one-domain voltage-gated sodium channel of Bacillus halodurans (NaChBac) is composed of six transmembrane segments (S1-S6) comprising a pore-forming region flanked by segments S5 and S6 and a voltage-sensing element composed of segment S4. To investigate the role of the S4 segment in NaChBac channel activation, we used the cysteine mutagenesis approach where the positive charges of single and multiple arginine (R) residues of the S4 segment were replaced by the neutrally charged amino acid cysteine (C). To determine whether it was the arginine residue itself or its positive charge that was involved in channel activation, arginine to lysine (R to K) mutations were constructed. Wild-type (WT) and mutant NaChBac channels were expressed in tsA201 cells and Na+ currents were recorded using the whole-cell configuration of the patch-clamp technique. The current/voltage (I-V) and conductance/voltage (G-V) relationships steady-state inactivation (h(infinity)) and recovery from inactivation were evaluated to determine the effects of the S4 mutations on the biophysical properties of the NaChBac channel. R to C on the S4 segment resulted in a slowing of both activation and inactivation kinetics. Charge neutralization of arginine residues mostly resulted in a shift toward more positive potentials of G-V and h(infinity) curves. The G-V curve shifts were associated with a decrease in slope, which may reflect a decrease in the gating charge involved in channel activation. Single neutralization of R114, R117, or R120 by C resulted in a very slow recovery from inactivation. Double neutralization of R111 and R129 confirmed the role of R111 in activation and suggested that R129 is most probably not part of the voltage sensor. Most of the R to K mutants retained WT-like current kinetics but exhibited an intermediate G-V curve, a steady-state inactivation shifted to more hyperpolarized potentials, and intermediate time constants of recovery from inactivation. This indicates that R, at several positions, plays an important role in channel activation. The data are consistent with the notion that the S4 is most probably the voltage sensor of the NaChBac channel and that both positive charges and the nature of the arginine residues are essential for channel activation.


Enhancing early literacy skills for preschool children: bringing a professional development model to scale.
A quasi-experimental, statewide intervention targeting preschool teachers' enhancement of children's language and early literacy was evaluated. Across 2 years and 20 Head Start sites, 750 teachers participated (500 target, 250 control), with 370 classrooms randomly selected to conduct pre- and posttest assessments (10 randomly selected children per class). The inability to randomize children to classrooms was addressed by examining children's performance for teachers who were control teachers in Year 1 and target teachers in Year 2. We also compared teachers with 2 years of training with teachers with 1 year of training and with control teachers. Greater gains were found for children in target classrooms than for those in control classrooms for all skills, but particularly for language skills, in Year 2, and this varied by program site. The presence of a research-based early literacy curriculum, higher levels of teacher education, and full-day versus half-day programs were significant moderators of intervention effectiveness. The challenges of implementing a statewide initiative across programs that varied in their readiness to implement a cognitively rich experience for preschool children are discussed.


Metal concentrations in the serum and hair of patients with titanium alloy spinal implants.
A retrospective study of serum and hair metal concentrations in patients with titanium alloy spinal implants was performed. To determine the incidence and possible causes of abnormal metal concentrations. Several studies have demonstrated that metal debris are present in the tissues surrounding titanium alloy spinal implants. However, few studies suggest that metals dissolve, circulate in the body fluid, and accumulate in remote organs. Titanium, aluminum, and vanadium concentrations in serum and hair were measured after surgery in 46 patients with titanium alloy spinal implants (12 patients in the implant failure group and 34 patients in the no implant failure group) and 20 patients without spinal implants (control group). All the subjects were examined again 1 year after the first examination or implant removal. Of the 46 patients with titanium alloy spinal implants, 16 patients (34.8%) exhibited abnormal serum metal concentrations and 11 patients (23.9%) exhibited abnormal hair metal concentrations. In the control group, three patients (15%) exhibited only abnormal serum and metal aluminum concentrations at the first examination. In both of the two patients who exhibited abnormal serum titanium concentrations and then had their spinal implants removed, the serum and hair titanium levels decreased to beneath the reference value limit in 1 year after the removal. Comparison of the implant failure and no implant failure groups showed no significant differences in the incidence of abnormal serum concentrations of titanium, aluminum, or both metals. Therefore, serum metal concentrations did not seem to be a useful indicator of hardware loosening or implant failure. Approximately one third of patients with titanium alloy spinal implants exhibited abnormal serum or hair metal concentrations at a mean time of mean 5.1 years after surgery. Titanium or aluminum may travel to distant organs after dissolution of metals from the spinal implants.


Evaluation of On- and Off-Line Bioluminescence Tomography System for Focal Irradiation Guidance.
In response to the limitations of computed tomography (CT) and cone-beam CT (CBCT) in irradiation guidance, especially for soft-tissue targets without the use of contrast agents, our group developed a solution that implemented bioluminescence tomography (BLT) as the image-guidance modality for preclinical radiation research. However, adding such a system to existing small animal irradiators is no small task. A potential solution is to utilize an off-line BLT system in close proximity to the irradiator, with stable and effective animal transport between the two systems. In this study, we investigated the localization accuracy of an off-line BLT system when used for the small animal radiation research platform (SARRP) and compared the results with those of an on-line system. The CBCT was equipped on both the off-line BLT system and the SARRP, with a distance of 5 m between them. To evaluate the setup error during animal transport between the two systems, the mice underwent CBCT imaging on the SARRP and were then transported to the off-line system for a second CBCT imaging session. The normalized intensity difference of the two images and the corresponding histogram and correlation were computed to evaluate if the transport process perturbed animal positioning. Strong correlation (correlation coefficients >0.95) between the SARRP and the off-line mouse CBCT was observed. The offset of the implanted light source center can be maintained within 0.2 mm during transport. To compare the target localization accuracy using the on-line SARRP BLT and the off-line system, a self-illuminated bioluminescent source was implanted in the abdomen of anesthetized mice. In addition to the application for dose calculation, CBCT imaging was also employed to generate the mesh grid of the imaged mouse for BLT reconstruction. Two scenarios were devised and compared, which involved localization of the luminescence source based on either: 1. on-line SARRP bioluminescence image and CBCT; or 2. off-line bioluminescence image and SARRP CBCT. The first scenario is assumed to have the least setup error, because no animal transport was involved. The second scenario examines if an off-line BLT system, with the mesh generated from the SARRP CBCT, can be used to guide SARRP irradiation when there is minimal target contrast in CBCT. Stability during animal transport between the two systems was maintained. The center of mass (CoM) of the light source reconstructed by the off-line BLT had an offset of 1.0 ± 0.4 mm from the true CoM derived from the SARRP CBCT. These results are comparable to the offset of 1.0 ± 0.2 mm using on-line BLT. With CBCT information provided by the SARRP and effective animal immobilization during transport, these findings support the utilization of an off-line BLT-guided system, in close proximity to the SARRP, for accurate soft-tissue target localization. In addition, a dedicated standalone BLT system for our partner site at the University of Pennsylvania was introduced in this study.


Results from a community-based trial testing a community health worker asthma intervention in Puerto Rican youth in Chicago.
Abstract Objective: Puerto Rican children suffer disproportionately from asthma. Project CURA tested the efficacy of a community health worker (CHW) intervention to improve use of inhaled corticosteroids (ICS) and reduce home asthma triggers in Puerto Rican youth in Chicago. This study employed a behavioral randomized controlled trial design with a community-based participatory research approach. Medications and technique were visually assessed; adherence was determined using dose counters. Home triggers were assessed via self-report, visual inspection and salivary cotinine. All participants received education on core asthma topics and self-management skills. Participants in the CHW arm were offered home education by the CHW in four visits over four months. The attention control arm received four newsletters covering the same topics. While most of the participants had uncontrolled persistent asthma, <50% had ICS at baseline. In the CHW arms, 67% of participants received the full four-visit intervention. In the Elementary school cohort (n=51), the CHW arm had lower odds of having an ICS (OR=0.2; p=0.02) at 12-months; no differences were seen in other outcomes between arms at any time point. The only significant treatment arm difference in the high school cohort (n=50) was in inhaler technique where the CHW arm performed 18.0% more steps correct at five months (p<0.01) and 14.2% more steps correct at 12 months (p<0.01). While this CHW intervention did not increase the number of participants with ICS or reduce home asthma triggers, important lessons were learned including challenges to CHW intervention fidelity and the need for CHWs to partner with clinical providers.


Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG.
Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an (18)F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG). Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with (18)F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [(125)I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values. [(18)F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [(18)F]FPOIBG at 2h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [(125)I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The (125)I-labeled congener of FPOIBG gave similar results. On the other hand, [(18)F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [(125)I]MIBG. IC50 values for FPOIBG were higher than those obtained for MIBG and FPOBBG. Unlike the case with [(18)F]FPOBBG, the heart uptake [(18)F]FPOIBG in normal mice was significantly lower than that of MIBG. Although [(18)F]FPOIBG does not appear to warrant further consideration as an (18)F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing. An (18)F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although (18)F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.


[Discourses about health risk behaviour and the moralization of the everyday life].
The text analyses critically the polarity between discourses about healthy life styles and the sedentariness in the context of new technologies for health information research and dissemination. We argue that the techno-scientific rationality has grown an 'economy of trues' which, on the perspective of conducting to safe life styles, has prescribed a normative ideal of self discipline which tends to generate distress and consumerism of artifacts of burning calories. In the hegemonic production of systems of truth, sedentariness has been seen as a kind of unhealthy behavior that is ranked as moral failure. Emphasis is given about the multiple discourses embracing life styles and risk, taken as biopolitics devices imbricated in the communication processes in health, which has to be lightened up for their ethics and politics implications. The spectacularization of life styles associated to the consumption and the production of narratives that have badly influenced our culture, making bigger the distance of a socially possible notion of health. We discussed the regulatory essence of such a symbolic reference in the construction of knowledge systems that have been (re)defined what is to be healthy, normal and unhealthy.


A retrospective case-control study of the use of hormone-related supplements and association with breast cancer.
Hormone-related supplements (HRS), many of which contain phytoestrogens, are widely used to manage menopausal symptoms, yet their relationship with breast cancer risk has generally not been evaluated. We evaluated whether use of HRS was associated with breast cancer risk, using a population-based case-control study in 3 counties of the Philadelphia metropolitan area consisting of 949 breast cancer cases and 1,524 controls. Use of HRS varied significantly by race, with African American women being more likely than European American women to use any herbal preparation (19.2% vs. 14.7%, p=0.003) as well as specific preparations including black cohosh (5.4% vs. 2.0%, p=0.003), ginseng (12.5% vs. 7.9%, p<0.001) and red clover (4.7% vs. 0.6%, p<0.001). Use of black cohosh had a significant breast cancer protective effect (adjusted odds ratio 0.39, 95% CI: 0.22-0.70). This association was similar among women who reported use of either black cohosh or Remifemin (an herbal preparation derived from black cohosh; adjusted odds ratio 0.47, 95% CI: 0.27-0.82). The literature reports that black cohosh may be effective in treating menopausal symptoms, and has antiestrogenic, antiproliferative and antioxidant properties. Additional confirmatory studies are required to determine whether black cohosh could be used to prevent breast cancer.


Phosphodiesterase 4B negatively regulates endotoxin-activated interleukin-1 receptor antagonist responses in macrophages.
Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability. Studies with PDE4-deficient macrophages revealed that the IL-1Ra upregulation elicited by LPS alone is PKA-independent, whereas the rolipram-enhanced response was mediated by inhibition of only PDE4B, one of the three PDE4 isoforms expressed in macrophages, and it requires PKA but not Epac activity. However, both pathways activate CREB to induce IL-1Ra expression. PDE4B ablation also promoted STAT3 phosphorylation (Tyr705) to LPS stimulation, but this STAT3 activation is not entirely responsible for the IL-1Ra upregulation in PDE4B-deficient macrophages. In a model of LPS-induced sepsis, only PDE4B-deficient mice displayed an increased circulating IL-1Ra, suggesting a protective role of PDE4B inactivation in vivo. These findings demonstrate that PDE4B negatively modulates anti-inflammatory cytokine expression in innate immune cells, and selectively targeting PDE4B should retain the therapeutic benefits of nonselective PDE4 inhibitors.


Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)-defined morbidity and mortality associated with pediatric ventricular assist device support at a single US center: the Stanford experience.
The use of ventricular assist devices (VADs) to bridge pediatric patients to heart transplantation has increased dramatically over the last 15 years. In this report, we present the largest US single-center report of pediatric VAD use to date. We present detailed descriptions of morbidity and mortality associated with VAD support, using standard Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria for pediatrics to facilitate the comparison of these results to other studies. We retrospectively identified 25 patients younger than 18 years with 27 episodes of mechanical circulatory support using VADs as bridge to heart transplantation from January 1998 to December 2007. Survival to transplant for the entire cohort was 74%. The most common major morbidities, as defined by INTERMACS criteria for a pediatric population, were respiratory failure, major localized infections, major bleeding events, hepatic dysfunction, and right heart failure. Major neurological events occurred in 48% of the study population. The median time to the first occurrence of an adverse event was less than 14 days for respiratory failure, right heart failure, major localized infection, and major bleeding. Patients who died before transplantation had significantly more adverse events per day of support than did those who were successfully transplanted. Episodes of major bleeding, tamponade, acute renal failure, respiratory failure, and right heart failure were all associated with increased risk of mortality. INTERMACS criteria can be successfully used to analyze pediatric VAD outcomes. These data serve as a baseline for future studies of VAD support in children and indicate good survival rates but considerable morbidity.


Measuring and improving quality of care in an academic medical center.
The Donabedian definition of quality—structure, process, and outcome—provides a useful framework. A relentless focus on measuring process adherence and outcome is critical. Systemic improvements usually require teams to plan and to implement them. The lean or Toyota production system for process improvement is one useful method of organizing work, although different approaches are often necessary at the physician, practice unit, and statewide level. Challenges include scalability of the change (ie, rolling them out across the institution or system), tailoring the information technology tools, and building systems for sustainability.


Increased expression of the 43-kD protein disrupts acetylcholine receptor clustering in myotubes.
The 43-kD protein is a peripheral membrane protein that is in approximately 1:1 stoichiometry with the acetylcholine receptor (AChR) in vertebrate muscle cells and colocalizes with it in the postsynaptic membrane. To investigate the role of the 43-kD protein in AChR clustering, we have isolated C2 muscle cell lines in which some cells overexpress the 43-kD protein. We find that myotubes with increased levels of the 43-kD protein have small AChR clusters and that those with the highest levels of expression have a drastically reduced number of clusters. Our results suggest that the 1:1 stoichiometry of AChR and 43-kD protein found in muscle cells is important for AChR cluster formation.


Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy.
Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts. Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes. Defective MCP-1 signaling inhibits the development of ischemic fibrotic cardiomyopathy in mice. The profibrotic actions of MCP-1 are associated with decreased macrophage recruitment and may not involve direct effects on cardiac fibroblasts.


Contour superresolved imaging of static ground targets using satellite platform.
We propose a method for increasing the contour resolution of static ground targets and to overcome the diffraction limit of an optical system installed on top of a satellite. The resolution improvement is obtained by using a sequence of low-resolution images taken from different angles realized by the movement of the satellite platform. The superresolving process is obtained by the generation of relative movement between the inspected object and the a priori known high-resolution background. The relative movement is caused because the images are taken from different angles. The captured set of low-resolution images are decoded by the a priori known high-resolution background obtained from a set of reference images taken only once by a high-resolution camera. The proposed concept is demonstrated via Matlab simulation and laboratory experiments.


Hyperacute cerebral aneurysm rerupture during CT angiography.
The object of this study was to identify the clinical features and outcomes of a subgroup of patients with aneurysmal subarachnoid hemorrhage (SAH) who had active contrast extravasation from a ruptured aneurysm during initial cerebral CT angiography (CTA). The authors performed a retrospective study of spontaneous SAH cases involving patients treated at their institute. They identified 9 cases in which active contrast extravasation was evident on the initial CT angiogram. Another 12 similar cases were also identified in a literature review and data was gathered from these cases to evaluate the outcomes. Analysis of all 21 cases revealed that the overall outcomes in cases characterized by active aneurysmal bleeding during CTA were poor. Seventy-six percent of patients had unfavorable results. Patients who showed poor neurological status at presentation died no matter what kind of treatment they received. In contrast, patients who presented with good neurological status initially had a chance of favorable outcome. Among the patients with good initial neurological status, most demonstrated rapid deterioration of their condition during the CTA examination; only those who received immediate and effective decompressive surgery and aneurysm obliteration had good results. Active aneurysmal rebleeding during CTA is an uncommon but devastating event. Though the mortality of this distinct group of patients remains high, a clinical subgroup may benefit from immediate surgery. Patients with good initial neurological status who show rapid neurological deterioration may still have a favorable outcome if they undergo timely and successful decompressive surgery and proper aneurysm obliteration. Patients who present with poor neurological status do badly, and there is no effective treatment for such patients.


Electrophysiological mapping for the implantation of deep brain stimulators for Parkinson's disease and tremor.
The vast majority of centers use electrophysiological mapping techniques to finalize target selection during the implantation of deep brain stimulation (DBS) leads for the treatment of Parkinson's disease and tremor. This review discusses the techniques used for physiological mapping and addresses the questions of how various mapping strategies modify target selection and outcome following subthalamic nucleus (STN), globus pallidus internus (GPi), and ventralis intermedius (Vim) deep brain stimulation. Mapping strategies vary greatly across centers, but can be broadly categorized into those that use microelectrode or semimicroelectrode techniques to optimize position prior to implantation and macrostimulation through a macroelectrode or the DBS lead, and those that rely solely on macrostimulation and its threshold for clinical effects (benefits and side effects). Microelectrode criteria for implantation into the STN or GPi include length of the nucleus recorded, presence of movement-responsive neurons, and/or distance from the borders with adjacent structures. However, the threshold for the production of clinical benefits relative to side effects is, in most centers, the final, and sometimes only, determinant of DBS electrode position. Macrostimulation techniques for mapping, the utility of microelectrode mapping is reflected in its modification of electrode position in 17% to 87% of patients undergoing STN DBS, with average target adjustments of 1 to 4 mm. Nevertheless, with the absence of class I data, and in consideration of the large number of variables that impact clinical outcome, it is not possible to conclude that one technique is superior to the other in so far as motor Unified Parkinson's Disease Rating Scale outcome is concerned. Moreover, mapping technique is only one out of many variables that determine the outcome. The increase in surgical risk of intracranial hemorrhage correlated to the number of microelectrode trajectories must be considered against the risk of suboptimal benefits related to omission of this technique.


Bisphosphonate treatment delays stress fracture remodeling in the rat ulna.
Because bisphosphonates (BPs) are potent inhibitors of bone resorption, we hypothesized that they would retard direct remodeling of stress fractures. The aim of this study was to determine the effect of risedronate on direct remodeling and woven bone callus formation following stress fracture formation in the rat ulna. In 135 adult female Wistar rats, cyclic loading of the ulna created stress fractures. Rats were treated daily with oral saline, or risedronate at 0.1 or 1.0 mg/kg. From each bone, histomorphometry was performed on sections stained with toluidine blue at a standard level along the fracture. The high dose of risedronate caused a significant decrease in the percentage of repaired stress fracture and bone resorption along the stress fracture line at 6 and 10 weeks after loading (p < 0.05). At this dose, intracortical resorption was significantly reduced at 10 weeks after loading and intracortical new bone area was significantly reduced at 6 and 10 weeks. Woven bone formation and consolidation phases of stress fracture repair were not affected by low or high doses of risedronate. In conclusion, high dose bisphosphonate treatment impaired healing of a large stress fracture line by reducing the volume of bone resorbed and replaced during remodeling. We also confirmed that periosteal callus formation was not adversely affected by risedronate treatment.


Rapid Variations in Atmospheric Methane Concentration During the Past 110,000 Years
A methane record from the GISP2 ice core reveals that millennial-scale variations in atmospheric methane concentration characterized much of the past 110,00 years. As previously observed in a shorter record from central Greenland, abrupt concentration shifts of about 50 to 300 parts per billion by volume were coeval with most of the interstadial warming events (better known as Dansgaard-Oeschger events) recorded in the GISP2 ice core throughout the last glacial period. The magnitude of the rapid concentration shifts varied on a longer time scale in a manner consistent with variations in Northern Hemisphere summer insolation, which suggests that insolation may have modulated the effects of interstadial climate change on the terrestrial biosphere.


Identification of an imidazoline binding protein: creatine kinase and an imidazoline-2 binding site.
Drugs that bind to imidazoline binding proteins have major physiological actions. To date, three subtypes of such proteins, I(1), I(2) and I(3), have been proposed, although characterisations of these binding proteins are lacking. I(2) binding sites are found throughout the brain, particularly dense in the arcuate nucleus of the hypothalamus. Selective I(2) ligands demonstrate antidepressant-like activity and the identity of the proteins that respond to such ligands remained unknown until now. Here we report the isolation of a approximately 45 kDa imidazoline binding protein from rabbit and rat brain using a high affinity ligand for the I(2) subtype, 2-BFI, to generate an affinity column. Following protein sequencing of the isolated approximately 45 kDa imidazoline binding protein, we identified it to be brain creatine kinase (B-CK). B-CK shows high binding capacity to selective I(2) ligands; [(3)H]-2-BFI (5 nM) specifically bound to B-CK (2330+/-815 fmol mg protein(-1)). We predicted an I(2) binding pocket near the active site of B-CK using molecular modelling. Furthermore, B-CK activity was inhibited by a selective I(2) irreversible ligand, where 20 microM BU99006 reduced the enzyme activity by 16%, confirming the interaction between B-CK and the I(2) ligand. In summary, we have identified B-CK to be the approximately 45 kDa imidazoline binding protein and we have demonstrated the existence of an I(2) binding site within this enzyme. The importance of B-CK in regulating neuronal activity and neurotransmitter release may well explain the various actions of I(2) ligands in brain and the alterations in densities of I(2) binding sites in psychiatric disorders.


Morphogenesis of the papillary lesions of the breast: phenotypic observation.
Papillary lesions of the breast are a heterogeneous group of diseases characterised by the presence epithelial proliferation supported by fibrovascular stalks. Normal breast tissue does not show papillary morphology and the mechanisms underlying papillary morphogenesis in breast tumours remain poorly understood. Current clinical evidence indicates an indolent behaviour of malignant papillary breast tumours. Herein, we present some phenotypic features that may explain the development of papillary morphology of breast lesions. Active papillary morphogenesis, which appears to reflect a unique mechanism involving interaction between epithelial and mesenchymal elements, is best appreciated in intraductal papilloma and papillary carcinoma. Morphological evidence suggests papillary morphogenesis during oncogenesis is a dynamic process with variable degrees of papillary differentiation among the same lesion and between primary and metastatic tumours. Secondary papillary-like architecture of non-papillary breast lesions exists. Further studies of the molecular mechanisms underlying papillary morphogenesis in the breast and its association with a better outcome are warranted.


Baseline Hemodynamics and Response to Contrast Media During Diagnostic Cardiac Catheterization Predict Adverse Events in Heart Failure Patients.
Contrast media administered during cardiac catheterization can affect hemodynamic variables. However, little is documented about the effects of contrast on hemodynamics in heart failure patients or the prognostic value of baseline and changes in hemodynamics for predicting subsequent adverse events. In this prospective study of 150 heart failure patients, we measured hemodynamics at baseline and after administration of iodixanol or iopamidol contrast. One-year Kaplan-Meier estimates of adverse event-free survival (death, heart failure hospitalization, and rehospitalization) were generated, grouping patients by baseline measures of pulmonary capillary wedge pressure (PCWP) and cardiac index (CI), and by changes in those measures after contrast administration. We used Cox proportional hazards modeling to assess sequentially adding baseline PCWP and change in CI to 5 validated risk models (Seattle Heart Failure Score, ESCAPE [Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness], CHARM [Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity], CORONA [Controlled Rosuvastatin Multinational Trial in Heart Failure], and MAGGIC [Meta-Analysis Global Group in Chronic Heart Failure]). Median contrast volume was 109 mL. Both contrast media caused similarly small but statistically significant changes in most hemodynamic variables. There were 39 adverse events (26.0%). Adverse event rates increased using the composite metric of baseline PCWP and change in CI (P<0.01); elevated baseline PCWP and decreased CI after contrast correlated with the poorest prognosis. Adding both baseline PCWP and change in CI to the 5 risk models universally improved their predictive value (P≤0.02). In heart failure patients, the administration of contrast causes small but significant changes in hemodynamics. Calculating baseline PCWP with change in CI after contrast predicts adverse events and increases the predictive value of existing models. Patients with elevated baseline PCWP and decreased CI after contrast merit greatest concern.


[Prevalence of obesity among Chilean women in childbearing ages].
Women in childbearing ages (WCBA) represent a strategic intervention group to reverse the global trend of increasing obesity. To conduct a review of studies reporting obesity prevalence in WCBA in Chile in the last 25 years. To describe obesity prevalence, we used three approaches, namely qualitative review of studies describing obesity prevalence in WCBA and a comparative study of the prevalence of obesity, overweight, abdominal and morbid obesity in WCBA from 2003 and 2009-10 National Health Surveys (ENS). Finally, nutrition status trends of pregnant women in the period 1987-2013 were plotted. According to ENS, obesity prevalence exceeded 20% and excess weight 50%, both in 2003 and 2009-10 surveys. We found seven population studies, being difficult to compare them due to the heterogeneity of obesity definitions, design, and populations. Population studies showed that the prevalence of obesity increases along with age. The higher prevalence of obesity in WCBA aged 20 to 43 years was found in the city of San Carlos in 2007 (35.5%). The lowest was found in female university students, ranging from 0% to 5.9%. Obesity in pregnant women increased from 12.9% to 32.2% in the period 1987-2004 and from 20.3% to 26.3% in the period 2005-2013. There is a high and increasing prevalence of obesity among women in childbearing age, whether pregnant or not-pregnant.


Phylogenetic incongruence among oncogenic genital alpha human papillomaviruses.
The human papillomaviruses (HPVs) have long been thought to follow a monophyletic pattern of evolution with little if any evidence for recombination between genomes. On the basis of this model, both oncogenicity and tissue tropism appear to have evolved once. Still, no systematic statistical analyses have shown whether monophyly is the rule across all HPV open reading frames (ORFs). We conducted a taxonomic analysis of 59 mucosal/genital HPVs using whole-genome and sliding-window similarity measures; maximum-parsimony, neighbor-joining, and Bayesian phylogenetic analyses; and localized incongruence length difference (LILD) analyses. The algorithm for the LILD analyses localized incongruence by calculating the tree length differences between constrained and unconstrained nodes in a total-evidence tree across all HPV ORFs. The process allows statistical evaluation of every ORF/node pair in the total-evidence tree. The most significant incongruence was observed at the putative high-risk (i.e., cancer-associated) node, the common oncogenic ancestor for alpha HPV species 9 (e.g., HPV type 16 [HPV16]), 11, 7 (e.g., HPV18), 5, and 6. Although these groups share early-gene homology, including high degrees of similarity among E6 and E7, groups 9 and 11 diverge from groups 7, 5, and 6 with respect to L2 and L1. The HPV species groups primarily associated with cervical and anogenital cancers appear to follow two distinct evolutionary paths, one conferred by the early genes and another by the late genes. The incongruence in the genital HPV phylogeny could have occurred from an early recombination event, an ecological niche change, and/or asymmetric genome convergence driven by intense selection. These data indicate that the phylogeny of the oncogenic HPVs is complex and that their evolution may not be monophyletic across all genes.


Neurochemical Changes Associated with Stress-Induced Sleep Disturbance in Rats: In Vivo and In Vitro Measurements.
The goal of this study was to quantitatively assess the changes in the cerebral neurochemical profile and to identify those factors that contribute to the alteration of endogenous biomolecules when rats are subjected to stress-induced sleep disturbance. We exposed Sprague-Dawley rats (controls: n = 9; stress-induced sleep perturbation rats: n = 11) to a psychological stressor (cage exchange method) to achieve stress-induced sleep perturbation. In vivo magnetic resonance imaging assessments were carried out using a high-resolution 9.4 T system. For in vivo neurochemical analysis, a single voxel was localized in the right dorsal hippocampal region, and in vivo spectra were quantified for 17 cerebral neurochemical signals. Rats were sacrificed upon completion of the magnetic resonance spectroscopy protocol, and whole-brain tissue was harvested from twenty subjects. The dopamine and serotonin signals were obtained by performing in vitro liquid chromatography-tandem mass spectrometry on the harvested tissue. In the right dorsal hippocampal region, the gamma-aminobutyric-acid (GABA) and glutamine (Gln) concentrations were significantly higher in the sleep-perturbed rats than in the sham controls. The ratios of Gln/Glu (glutamate), Gln/tCr (total-creatine), and GABA/Glu were also significantly higher in the sleep-perturbed group, while serotonin concentrations were significantly lower in the sleep-perturbed rats. Pearson correlation results among individual rat data indicate that concentrations of dopamine (DA) and serotonin (5-HT) were significantly higher in SSP rats. A larger correlation coefficient was also observed for the SSP rats. Analysis of the correlation between the in vivo and in vitro signals indicated that the concentrations of Gln, 5-HT, and DA exhibited a significant negative correlation in the SSP rat data but not in that of control rats. The authors propose that the altered and correlated GABA, Gln, 5-HT, and DA concentrations/ratios could be considered key markers of neurological function in animal models of stress-induced sleep perturbation.


Outcomes and processes of care related to preoperative medical consultation.
Preoperative consultations by internal medicine physicians facilitate documentation of comorbid disease, optimization of medical conditions, risk stratification, and initiation of interventions intended to reduce risk. Nonetheless, the impact of these consultations, which may be performed by general internists or specialists, on outcomes is unclear. We used population-based administrative databases to conduct a cohort study of patients 40 years or older who underwent major elective noncardiac surgery in Ontario, Canada, between 1994 and 2004. Propensity scores were used to assemble a matched-pairs cohort that reduced differences between patients who did and did not undergo preoperative consultation by general internists or specialists. The association of consultation with mortality and hospital stay was determined within this matched cohort. As a sensitivity analysis, we evaluated the association of consultation with an outcome for which no difference would be expected: postoperative wound infection. Of 269,866 patients in the cohort, 38.8% (n=104,695) underwent consultation. Within the matched cohort (n=191,852), consultation was associated with increased 30-day mortality (relative risk [RR], 1.16; 95% confidence interval [CI], 1.07-1.25; number needed to harm, 516), 1-year mortality (1.08; 1.04-1.12; number needed to harm, 227), mean hospital stay (difference, 0.67 days; 0.59-0.76), preoperative testing, and preoperative pharmacologic interventions. Notably, consultation was not associated with any difference in postoperative wound infections (RR, 0.98; 95% CI, 0.95-1.02). These findings were stable across subgroups as well as sensitivity analyses that tested for unmeasured confounding. Medical consultation before major elective noncardiac surgery is associated with increased mortality and hospital stay, as well as increases in preoperative pharmacologic interventions and testing. These findings highlight the need to better understand mechanisms by which consultation influences outcomes and to identify efficacious interventions to decrease perioperative risk.


Na(+)-dependent transporters mediate HCO(3)(-) salvage across the luminal membrane of the main pancreatic duct.
To study the roles of Na(+)-dependent H(+) transporters, we characterized H(+) efflux mechanisms in the pancreatic duct in wild-type, NHE2(-/-), and NHE3(-/-) mice. The pancreatic duct expresses NHE1 in the basolateral membrane, and NHE2 and NHE3 in the luminal membrane, but does not contain NHE4 or NHE5. Basolateral Na(+)-dependent H(+) efflux in the microperfused duct was inhibited by 1.5 microM of the amiloride analogue HOE 694, consistent with expression of NHE1, whereas the luminal activity required 50 microM HOE 694 for effective inhibition, suggesting that the efflux might be mediated by NHE2. However, disruption of NHE2 had no effect on luminal transport, while disruption of the NHE3 gene reduced luminal Na(+)-dependent H(+) efflux by approximately 45%. Notably, the remaining luminal Na(+)-dependent H(+) efflux in ducts from NHE3(-/-) mice was inhibited by 50 microM HOE 694. Hence, approximately 55% of luminal H(+) efflux (or HCO(3)(-) influx) in the pancreatic duct is mediated by a novel, HOE 694-sensitive, Na(+)-dependent mechanism. H(+) transport by NHE3 and the novel transporter is inhibited by cAMP, albeit to different extents. We propose that multiple Na(+)-dependent mechanisms in the luminal membrane of the pancreatic duct absorb Na(+) and HCO(3)(-) to produce a pancreatic juice that is poor in HCO(3)(-) and rich in Cl(-) during basal secretion. Inhibition of the transporters during stimulated secretion aids in producing the HCO(3)(-)-rich pancreatic juice.


Writing and erasing of temporal cavity solitons by direct phase modulation of the cavity driving field.
Temporal cavity solitons (CSs) are persisting pulses of light that can manifest themselves in continuously driven passive resonators, such as macroscopic fiber ring cavities and monolithic microresonators. Experiments so far have demonstrated two techniques for their excitation, yet both possess drawbacks in the form of system complexity or lack of control over soliton positioning. Here we experimentally demonstrate a new CS writing scheme that alleviates these deficiencies. Specifically, we show that temporal CSs can be excited at arbitrary positions through direct phase modulation of the cavity driving field, and that this technique also allows existing CSs to be selectively erased. Our results constitute the first experimental demonstration of temporal CS excitation via direct phase modulation, as well as their selective erasure (by any means). These advances reduce the complexity of CS excitation and could lead to controlled pulse generation in monolithic microresonators.


Expression of a prokaryotic P-type ATPase in E. coli Plasma Membranes and Purification by Ni2+-affinity chromatography.
In order to characterize the P-type ATPase from Synechocystis 6803 [Geisler (1993) et al. J. Mol. Biol. 234, 1284] and to facilitate its purification, we expressed an N-terminal 6xHis-tagged version of the ATPase in an ATPase deficient E. coli strain. The expressed ATPase was immunodetected as a dominant band of about 97 kDa localized to the E. coli plasma membranes representing about 20-25% of the membrane protein. The purification of the Synecho-cystis 6xHis-ATPase by single-step Ni-affinity chromatography under native and denaturating conditions is described. ATPase activity and the formation of phosphointermediates verify the full function of the enzyme: the ATPase is inhibited by vanadate (IC(50)= 119 &mgr;M) and the formation of phosphorylated enzyme intermediates shown by acidic PAGE depends on calcium, indicating that the Synechocystis P-ATPase functions as a calcium pump.


Acute aflatoxicosis: case report.
The objective of this presentation is to document the salient clinical findings in a case of aflatoxicosis and to review the literature on the same so as to increase the index of suspicion, enhance early diagnosis and improve management. The case was a 17-year-old schoolboy presenting with vomiting, features of infection and gastrointestinal tract symptoms. Examination revealed a very ill looking pale patient with abdominal distension, tenderness and rectal bleeding and easy bruisability. Investigations showed abnormal liver function tests, pancytopenia and elevated serum levels of aflatoxins. Management consisted of supportive care including antibiotics and antifungal therapy, transfusion of red blood cells and fresh frozen plasma. His recovery was uneventful. The literature on human aflatoxicosis shows that the presentation may be acute, subacute and chronic. The degree of emanating clinical events also conforms to status of the aflatoxicosis. Overall, the features are protean and may masquerade many other forms of toxaemias. In conclusion, the diagnosis of aflatoxicosis takes cognisance of geographical location, past events, staple diet and clinical features to exclude other infections. Also required are high index of suspicion and importantly serum levels of aflatoxin. Treatment strategies involved use of antimicrobials and supporting the damaged multi-organs.


Intravenously administered tetra-thiomolybdate and the removal of copper from the liver of copper-loaded sheep.
Eighteen ewes divided into two groups were dosed orally with CuSO4 in order to induce chronic Cu toxicity. Copper dosing was stopped at the first rise of serum acid phosphatase activity in sheep of group 1 and on the first day of haemolysis in sheep of group 2. Tetra-thiomolybdate was administered intravenously to five group 1 sheep (group 1B) and to group 2 from the cessation of Cu dosing. Following thiomolybdate administration, in groups 1B and 2, there was a reduction in the concentration of Cu in the liver and liver fractions, the number and size of electron-dense lysosomes in particulate liver fractions, the volume density and the mean volume of electron-dense lysosomes in hepatocytes and the number of necrotic cells in the liver. Thiomolybdate appeared to remove Cu from the lysosomes and the cytosol of Cu-loaded liver cells. However, neither the total specific activity of acid phosphatase in liver homogenate and liver fractions nor the numerical density of electron-dense lysosomes in hepatocytes decreased significantly. This may be due to the production of new lysosomes in the liver cells. Furthermore, following thiomolybdate administration, Mo concentration in the liver and liver fractions increased indicating that Mo of thiomolybdate was entering liver cells. The percentage distribution of Cu and Mo in the liver fractions was similar. This may suggest that Mo is bound to Cu and that they remain together with each fraction. The decrease in Cu concentration may indicate that the liver retains its ability to excrete copper via bile.


Acute disseminated encephalomyelitis following endonasal resection of a craniopharyngioma: illustrative case.
Acute disseminated encephalomyelitis (ADEM) is a rare, acquired demyelination syndrome that causes cognitive impairment and focal neurological deficits and may be fatal. The potentially reversible disease mainly affects children, often after vaccination or viral infection, but may be seen rarely in adults. A 50-year-old woman presented with loss of visual acuity of the left eye. Magnetic resonance imaging (MRI) revealed an intra- and suprasellar mass, which was removed successfully. On postoperative day 1, MRI showed gross total resection of the lesion and no surgery-related complications. On postoperative day 2, the patient presented with a progressive left-sided hemiparesis, hemineglect, and decline of cognitive performance. MRI showed white matter edema in both hemispheres. Cerebrospinal fluid analysis revealed mixed pleocytosis (355/µL) without further evidence of infection. In synopsis of the findings, ADEM was diagnosed and treated with intravenous immunoglobulins. Shortly thereafter, the patient recovered, and no sensorimotor deficits were detected in the follow-up examination. Pituitary gland pathologies are commonly treated by transsphenoidal surgery, with only minor risks for complications. A case of ADEM after craniopharyngioma resection has not been published before and should be considered in case of progressive neurological deterioration with multiple white matter lesions.


Asymmetric transmission of terahertz waves using polar dielectrics.
Asymmetric wave transmission is a Lorentz reciprocal phenomenon, which can appear in the structures with broken symmetry. It may enable high forward-to-backward transmittance contrast, while transmission for one of the two opposite incidence directions is blocked. In this paper, it is demonstrated that ultrawideband, high-contrast asymmetric wave transmission can be obtained at terahertz frequencies in the topologically simple, i.e., one- or two-layer nonsymmetric gratings, which are entirely or partially made of a polar dielectric working in the ultralow-ε regime inspired by phonon-photon coupling. A variety of polar dielectrics with different characteristics can be used that gives one a big freedom concerning design. Simple criteria for estimating possible usefulness of a certain polar dielectric are suggested. Contrasts exceeding 80dB can be easily achieved without a special parameter adjustment. Stacking a high-ε corrugated layer with a noncorrugated layer made of a polar dielectric, one can enhance transmission in the unidirectional regime. At large and intermediate angles of incidence, a better performance can be obtained owing to the common effect of nonsymmetric diffractions and directional selectivity, which is connected with the dispersion of the ultralow-ε material. At normal incidence, strong asymmetry in transmission may occur in the studied structures as a purely diffraction effect.


The Saccharomyces cerevisiae TAN1 gene is required for N4-acetylcytidine formation in tRNA.
The biogenesis of transfer RNA is a process that requires many different factors. In this study, we describe a genetic screen aimed to identify gene products participating in this process. By screening for mutations lethal in combination with a sup61-T47:2C allele, coding for a mutant form of, the nonessential TAN1 gene was identified. We show that the TAN1 gene product is required for formation of the modified nucleoside N(4)-acetylcytidine (ac(4)C) in tRNA. In Saccharomyces cerevisiae, ac(4)C is present at position 12 in tRNAs specific for leucine and serine as well as in 18S ribosomal RNA. Analysis of RNA isolated from a tan1-null mutant revealed that ac(4)C was absent in tRNA, but not rRNA. Although no tRNA acetyltransferase activity by a GST-Tan1 fusion protein was detected, a gel-shift assay revealed that Tan1p binds tRNA, suggesting a direct role in synthesis of ac(4)C(12). The absence of the TAN1 gene in the sup61-T47:2C mutant caused a decreased level of mature, indicating that ac(4)C(12) and/or Tan1p is important for tRNA stability.


Valorization of Proteins from Co- and By-Products from the Fish and Meat Industry.
Large volumes of protein-rich residual raw materials, such as heads, bones, carcasses, blood, skin, viscera, hooves and feathers, are created as a result of processing of animals from fisheries, aquaculture, livestock and poultry sectors. These residuals contain proteins and other essential nutrients with potentially bioactive properties, eligible for recycling and upgrading for higher-value products, e.g. for human, pet food and feed purposes. Here, we aim to cover all the important aspects of achieving optimal utilization of proteins in such residual raw materials, identifying those eligible for human consumption as co-products and for feed applications as by-products. Strict legislation regulates the utilization of various animal-based co- and by-products, representing a major hurdle if not addressed properly. Thorough understanding and optimization of all parts of the production chain, including conservation and processing, are important prerequisites for successful upgrading and industrial implementation of such products. This review includes industrially applied technologies such as freezing/cooling, acid preservation, salting, rendering and protein hydrolysis. In this regard, it is important to achieve stable production and quality through all the steps in the manufacturing chain, preferably supported by at- or online quality control points in the actual processing step. If aiming for the human market, knowledge of consumer trends and awareness are important for production and successful introduction of new products and ingredients.


Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.
Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to interferon (IFN)-beta production. Here we disrupted the gene encoding a Toll/IL-1 receptor (TIR) domain-containing adaptor, TRIF. TRIF-deficient mice were defective in both TLR3- and TLR4-mediated expression of IFN-beta and activation of IRF-3. Furthermore, inflammatory cytokine production in response to the TLR4 ligand, but not to other TLR ligands, was severely impaired in TRIF-deficient macrophages. Mice deficient in both MyD88 and TRIF showed complete loss of nuclear factor kappa B activation in response to TLR4 stimulation. These findings demonstrate that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.


IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression.
Diffuse gliomas are poorly immunogenic, fatal brain tumors. The basis for insufficient antitumor immunity in diffuse gliomas is unknown. Gain-of-function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. We analyzed the database of The Cancer Genome Atlas for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligand expression levels and NK cell-mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza-2'deoxycytodine (decitabine) as a potential NK cell sensitizing agent in IDH mutant cells. IDH mutant glioma stemlike cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes are resistant to NK cell-mediated lysis. Decitabine increases NKG2D ligand expression and restores NK-mediated lysis of IDH mutant cells in an NKG2D-dependent manner. IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULBP3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas.


Optical fingerprint recognition based on local minutiae structure coding.
A parallel volume holographic optical fingerprint recognition system robust to fingerprint translation, rotation and nonlinear distortion is proposed. The optical fingerprint recognition measures the similarity by using the optical filters of multiplexed holograms recorded in the holographic media. A fingerprint is encoded into multiple template data pages based on the local minutiae structure coding method after it is adapted for the optical data channel. An improved filter recording time schedule and a post-filtering calibration technology are combined to suppress the calculating error from the large variations in data page filling ratio. Experimental results tested on FVC2002 DB1 and a forensic database comprising 270,216 fingerprints demonstrate the robustness and feasibility of the system.


Control of backbone chemistry and chirality boost oligonucleotide splice switching activity.
Although recent regulatory approval of splice-switching oligonucleotides (SSOs) for the treatment of neuromuscular disease such as Duchenne muscular dystrophy has been an advance for the splice-switching field, current SSO chemistries have shown limited clinical benefit due to poor pharmacology. To overcome limitations of existing technologies, we engineered chimeric stereopure oligonucleotides with phosphorothioate (PS) and phosphoryl guanidine-containing (PN) backbones. We demonstrate that these chimeric stereopure oligonucleotides have markedly improved pharmacology and efficacy compared with PS-modified oligonucleotides, preventing premature death and improving median survival from 49 days to at least 280 days in a dystrophic mouse model with an aggressive phenotype. These data demonstrate that chemical optimization alone can profoundly impact oligonucleotide pharmacology and highlight the potential for continued innovation around the oligonucleotide backbone. More specifically, we conclude that chimeric stereopure oligonucleotides are a promising splice-switching modality with potential for the treatment of neuromuscular and other genetic diseases impacting difficult to reach tissues such as the skeletal muscle and heart.


Effects of broken affordance on visual extinction.
Previous studies have shown that visual extinction can be reduced if two objects are positioned to "afford" an action. Here we tested if this affordance effect was disrupted by "breaking" the affordance, i.e., if one of the objects actively used in the action had a broken handle. We assessed the effects of broken affordance on recovery from extinction in eight patients with right hemisphere lesions and left-sided extinction. Patients viewed object pairs that were or were not commonly used together and that were positioned for left- or right-hand actions. In the unrelated pair conditions, either two tools or two objects were presented. In line with previous research (e.g., Riddoch et al., 2006), extinction was reduced when action-related object pairs and when unrelated tool pairs were presented compared to unrelated object pairs. There was no significant difference in recovery rate between action-related (object-tool) and unrelated tool pairs. In addition, performance with action-related objects decreased when the tool appeared on the ipsilesional side compared to when it was on the contralesional side, but only when the tool handle was intact. There were minimal effects of breaking the handle of an object rather than a tool, and there was no effect of breaking the handle on either tools or objects on single item trials. The data suggest that breaking the handle of a tool lessens the degree to which it captures attention, with this attentional capture being strongest when the tool appears on the ipsilesional side. The capture of attention by the ipsilesional item then reduces the chance of detecting the contralesional stimulus. This attentional capture effect is mediated by the affordance to the intact tool.


Prevalence of bipolar disorder in multiple sclerosis: a systematic review and meta-analysis.
Multiple sclerosis (MS) is a chronic disabling, demyelinating disease of the central nervous system and is often associated with psychiatric comorbidities. Some studies suggest increased prevalence of bipolar disorder (BD) in MS. To conduct a systematic review and meta-analysis assessing the prevalence of BD in adults with MS. We registered this review with PROSPERO and searched electronic databases (Ovid MEDLINE, Central, Embase, PsycINFO and Scopus) for eligible studies from earliest inception to October 2020. Prevalence data of BD in adult patients with MS were extracted. Meta-analysis was conducted using random-effects model. Of the 802 articles that were screened, 23 studies enrolling a total of 68 796 patients were included in the systematic review and meta-analysis. The pooled prevalence rate of BD in patients with MS was 2.95% (95% CI 2.12% to 4.09%) with higher prevalence in the Americas versus Europe. The lifetime prevalence of BD was 8.4% in patients with MS. Subgroup analysis showed a higher prevalence of BD in MS in females (7.03%) than in males (5.64%), which did not reach statistical significance (p=0.53). This meta-analysis suggests a high lifetime prevalence of BD in patients with MS. Patients with MS should be routinely screened for BD. Further assessment of bipolar comorbidity in MS through prospective studies may help in developing effective management strategies and may improve treatment outcomes in patients with MS.


MRI Volumetric Quantification in Persons with a History of Traumatic Brain Injury and Cognitive Impairment.
While traumatic brain injury (TBI) is recognized as a risk factor for dementia, there is lack of clinical tools to identify brain changes that may confer such vulnerability. Brain MRI volumetric quantification can sensitively identify brain atrophy. To characterize regional brain volume loss in persons with TBI presenting with cognitive impairment. IRB approved review of medical records in patients with cognitive decline focused on those who had documented TBI histories and brain MRI scans after TBI (n = 40, 67.7±14.5 years) with volumetric quantification by applying an FDA cleared software program. TBI documentation included head trauma mechanism. Brain volumes were compared to a normative database to determine the extent of atrophy. Correlations between these regions and global tests of cognition (MMSE in n = 17, MoCA in n = 27, n = 14 in both) were performed. Multiple regions demonstrated volume loss in TBI, particularly ventral diencephalon, putamen, and pallidum with smaller magnitude of atrophy in temporal lobes and brainstem. Lobar structures showed strongest correlations between atrophy and lower scores on MMSE and MoCA. The hippocampus, while correlated to tests of cognitive function, was the least atrophic region as a function of TBI history. Persons with TBI history exhibit show regional brain atrophy. Several of these areas, such as thalamus and temporal lobes, also correlate with cognitive function. Alzheimer's disease atrophy was less likely given relative sparing of the hippocampi. Volumetric quantification of brain MRI in TBI warrants further investigation to further determine its clinical potential in TBI and differentiating causes of cognitive impairment.


Telemedicine: an important aid to perform high-quality endoscopic retrograde cholangiopancreatography in low-volume centers.
The aim of this study was to investigate whether telemedicine can help to ensure high-quality endoscopic retrograde cholangiopancreatography (ERCP) in patients living in rural areas. The study was conducted by investigators from two centers: the Karolinska University Hospital, a high-volume center which provided the teleguided support, and the Visby District Hospital, a low-volume center. From September 2010 to August 2011, 26 ERCP procedures performed at a district hospital were teleguided by an experienced endoscopist at the Karolinska University Hospital. To ensure patient data protection, all communication went through a network (Sjunet) that was separate from the Internet and open only to accredited users. The indications for ERCP were common bile duct stones (n = 12), malignant strictures (n = 12), and benign biliary strictures (n = 2). In 15 cases, this was the patient's first ERCP procedure. The common bile duct was successfully cannulated in all 26 teleguided procedures. The local endoscopist scored the teleguided support as crucial for the successful outcome in 8 /26 cases, as an important factor in 8, and as being of less importance in the remaining 10. In the eight cases where the teleguided support was judged to be crucial, six subsequent percutaneous transhepatic cholangiography procedures and two repeat ERCPs were avoided. The overall cannulation rate at the district hospital improved from 85 % to 99 % after teleguided support was introduced. No procedure-related complications occurred. Distant guidance of advanced ERCP procedures in a low-volume center, through teleguided support from a high-volume center, has the potential to improve the quality of care, as reflected in high cannulation rates and the ability to complete the scheduled interventions.


Genomic structure and evolution of the mating type locus in the green seaweed Ulva partita.
The evolution of sex chromosomes and mating loci in organisms with UV systems of sex/mating type determination in haploid phases via genes on UV chromosomes is not well understood. We report the structure of the mating type (MT) locus and its evolutionary history in the green seaweed Ulva partita, which is a multicellular organism with an isomorphic haploid-diploid life cycle and mating type determination in the haploid phase. Comprehensive comparison of a total of 12.0 and 16.6 Gb of genomic next-generation sequencing data for mt- and mt+ strains identified highly rearranged MT loci of 1.0 and 1.5 Mb in size and containing 46 and 67 genes, respectively, including 23 gametologs. Molecular evolutionary analyses suggested that the MT loci diverged over a prolonged period in the individual mating types after their establishment in an ancestor. A gene encoding an RWP-RK domain-containing protein was found in the mt- MT locus but was not an ortholog of the chlorophycean mating type determination gene MID. Taken together, our results suggest that the genomic structure and its evolutionary history in the U. partita MT locus are similar to those on other UV chromosomes and that the MT locus genes are quite different from those of Chlorophyceae.


The attitudes of surgeons concerning preoperative smoking cessation: a questionnaire study*.
The purpose of this study was to evaluate the attitudes and behavior of surgeons regarding preoperative smoking cessation. A total of 109 anonymous questionnaires were distributed to non-vascular surgeons in our hospital, inquiring about their smoking attitudes, their smoking cessation advice practices, whether they appreciated the benefits of preoperative smoking cessation, and their knowledge of smoking cessation methods. Eighty questionnaires (from 51 resident doctors and 29 academic staff) were returned (response rate: 73.40%). Of the surgeons, 17.50% were current smokers. Although 40% of the surgeons surveyed believed that preoperative smoking cessation reduces postoperative complications, 31.2% of the surgeons (25/63) had given smoking cessation advice at least to 1 patient in the last month. Most of the resident doctors (39.2%) advised smoking cessation within a month; prior to surgery however, the academic staff (27.6%) advised cessation immediately before the operation (p=0.038). There was a significant difference between academic sfaff and resident doctors concerning the method to increase a patient's chance of quitting (p=0.045), even among current smokers (p=0.049). The surgeons who participated in the questionnaire were aware that smoking cessation improves outcome, but most of them did not appreciate that providing brief advice, referring to cessation services, or prescribing nicotine replacement therapy (NRT) may be of benefit in helping patients to quit. It is necessary to educate surgeons about the scale of the benefit and the efficacy of smoking cessation interventions or to set up systematic frameworks to offer smoking cessation advice to preoperative patients who smoke.


Evolution of elaborate parental care: phenotypic and genetic correlations between parent and offspring traits.
The evolution of elaborate forms of parental care is an important topic in behavioral ecology, yet the factors shaping the evolution of complex suites of parental and offspring traits are poorly understood. Here, we use a multivariate quantitative genetic approach to study phenotypic and genetic correlations between parental and offspring traits in the burying beetle Nicrophorus vespilloides. To this end, we recorded 2 prenatal traits (clutch size and egg size), 2 postnatal parental behaviors (direct care directed toward larvae and indirect care directed toward resource maintenance), 1 offspring behavior (begging), and 2 measures of breeding success (larval dispersal mass and number of dispersing larvae). Females breeding on larger carcasses provided less direct care but produced larger larvae than females breeding on smaller carcasses. Furthermore, there were positive phenotypic correlations between clutch size, direct, and indirect care. Both egg size and direct care were positively correlated with dispersal mass, whereas clutch size was negatively correlated with dispersal mass. Clutch size and number of dispersed larvae showed genetic variance both in terms of differences between populations of origin and significant heritabilities. However, we found no evidence of genetic variance underlying other parental or offspring traits. Our results suggest that correlations between suites of parental traits are driven by variation in individual quality rather than trade-offs, that some parental traits promote offspring growth while others increase the number of offspring produced, and that parental and offspring traits might respond slowly to selection due to low levels of additive genetic variance.


Urinalysis findings are not predictive of positive urine culture in patients with indwelling stents.
Indwelling stents produce symptoms and urinalysis findings mimicking urinary tract infection (UTI). In this study, we investigated the correlation of urinalysis findings with urine culture in patients with indwelling ureteral stents. All patients with ureteral stents who underwent stent removal in urology clinic from July 2013 to January 2015 and had urine culture available immediately prior to stent removal were included in this study. Urine culture results as well as age, gender, duration of indwelling stent, and reason for stent placement were collected. A total of 122 patients were included in this study. The two most common reasons for ureteral stent placement included urolithiasis (65.6%) and renal transplant (22.1%). Red blood cell (RBC), leukocytes and nitrite were positive in 92.9%, 70.2% and 17.9% of urine samples respectively. Only 17 patients (13.9%) had positive urine culture. Although renal transplant patients had significantly longer duration of stent retention, no statistically significant difference was noted in rate of positive urine culture compared to urolithiasis patients (p = 1.0). Among patients with positive urine culture, 62.5% had resistant bacteria to common antibiotic treatments and two patients had yeast in urine culture (12.5%). The duration of stent retention did not correlate with bacterial resistance. Multivariate analysis failed to show significant correlation of gender, reason for stent, stent duration, RBC and nitrite with positive urine culture. Positive findings on urinalysis in patients with indwelling ureteral stent have poor correlation to positive urine culture and therefore the use of urine culture to diagnose UTI is warranted.


Identification of de novo mutations and rare variants in hypoplastic left heart syndrome.
Hypoplastic left heart syndrome (HLHS) is one of the most severe congenital heart malformations, characterized by underdevelopment of the structures in the left heart-aorta complex. The majority of cases are sporadic. Although multiple genetic loci have been tentatively implicated in HLHS, no gene or pathway seems to be specifically associated with the disease. To elucidate the genetic basis of HLHS, we analyzed 53 well-characterized patients with isolated HLHS using an integrated genomic approach that combined DNA sequencing of five candidate genes (NKX2-5, NOTCH1, HAND1, FOXC2 and FOXL1) and genome-wide screening by high-resolution array comparative genomic hybridization. In 30 patients, we identified two novel de novo mutations in NOTCH1, 23 rare patients inherited gene variants in NOTCH1, FOXC2 and FOXL1, and 33 rare patients mostly inherited copy-number variants. Some of the identified variations coexisted in the same patient. The biological significance of such rare variations is unknown, but our findings strengthen the role of NOTCH pathway in cardiac valve development, indicating that HLHS is, at least in part, a 'valve' disease. This is the first report of de novo mutations associated with isolated HLHS. Moreover, the coexistence of multiple rare variants suggests in some cases a cumulative effect, as shown for other complex disease.


Gamma-linolenic acid dietary supplementation can reverse the aging influence on rat liver microsome delta 6-desaturase activity.
We have recently demonstrated that in rats the process of delta 6-desaturation of linoleic and alpha-linolenic acids slows with aging. One method of counteracting the effect of slowed desaturation of linoleic acid would be to provide the 6-desaturated metabolite, gamma-linolenic acid (18:3(n-6) GLA) directly. We have here investigated the 6-desaturation of both linoleic and alpha-linolenic acids in liver microsomes of young and old rats given GLA in the form of evening primrose oil (EPO) (B diet) in comparison to animals given soy bean oil alone (A diet), monitoring also the fatty acid composition of liver microsomes and relating this to the microviscosity of the membranes. In young rats the different experimental diets did not produce any difference in delta 6-desaturase (D6D) activity on either substrate suggesting that, when D6D activity is at or near its peak, the variations in diet tested are unable to influence it. In the old animals the rate of 6-desaturation of linoleic and particularly of alpha-linolenic acid was significantly greater in the B diet fed animals than in the A diet fed. The effects of the diets on the fatty acid composition of liver microsomes were consistent with the findings with regard to 6-desaturation. Administration of GLA partially corrected the abnormalities of n-6 essential fatty acid (EFA) metabolism by raising the concentration of 20:4(n-6) and other 6-desaturated EFAs. Furthermore, the GLA rich diet also increased the levels of dihomo-gamma-linolenic acid and of 6-desaturated n-3 EFAs in the liver microsomes. The microviscosity of microsomal membranes as indicated by DPH polarization was correlated with the unsaturation index of the same membranes. There was a very strong correlation between the two. In both young and old rats the B diet reduced the microviscosity and increased the unsaturation index. However, the effect was much greater in the old animals.


CSF herpes virus and autoantibody profiles in the evaluation of encephalitis.
To report the frequency of coexisting herpes viruses (herpes simplex virus 1 [HSV-1] or HSV-2, varicella zoster virus, Epstein-Barr virus [EBV], cytomegalovirus, or human herpes virus 6 [HHV-6]) and autoantibodies in patients with encephalitis (herpes or autoimmune) in clinical laboratory service. Three groups were evaluated for herpes viruses and antibodies: group 1-patients whose CSF was positive for a herpes virus by real-time PCR over a period of 6 months; group 2-patients whose CSF was positive for an autoimmune encephalitis-associated antibody over 5 years (e.g., NMDA receptor [NMDA-R] antibody), and the same number of controls without autoimmune/infectious disease; and group 3-incidental autoimmune parainfectious encephalitis cases encountered over 1 year. In group 1, antibodies were detected in 27 of 100 herpes PCR-positive CSF specimens (CSFs), either unclassified neural or nonneural in all but one patient with NMDA-R antibody detected after EBV infection. Antibodies were also detected in 3 of 7 CSFs submitted for repeat PCR testing (unclassified, 2; AMPA receptor, 1). In group 2, herpes viruses were detected in 1 of 77 controls (HHV-6) and 4 of 77 patients with autoimmune encephalitis (EBV, 2; HHV-6, 2); autoantibodies targeted NMDA-R in 3/4 and GABAB-R in 1/4. In group 3, NMDA-R antibody was detected in 7 patients post-HSV-1 encephalitis. Of the remaining 3 patients, 2 had unclassified neural antibodies detected, and one had GABAB-R autoimmunity. Concomitant neoplasms were discovered in 2 patients each from groups 2 and 3. Autoantibodies and herpes virus DNA frequently coexist in encephalitic CSF. Some patients develop parainfectious autoimmunity following viral CNS infection (usually HSV-1 encephalitis). The significance of detecting herpes nucleic acids in others remains unclear.


Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk.
Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes - in subjects carrying simultaneously deviations from the common genotype in more than one gene - were over-represented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations of CYP1A1, GSTM1 and GSTT1 alleles in the development of lung cancer in heavy smokers.


Hospitalization due to horse-related injuries: has anything changed? A 25 year survey.
Horse riding and horse handling are dangerous. There is a lack of knowledge concerning the incidence of hospitalization due to horse-related injuries and types of injuries in Israel. During the last two decades we have observed an increasing incidence of hospitalizations due to horse-related injuries at our medical center as well as the frequent involvement of pediatric patients. To investigate these injuries with respect to type, incidence and modes of prevention. We conducted a retrospective study of medical records for all patients admitted to Assaf Harofeh Medical Center due to horse-related injury between January 1984 and December 2008. A telephone questionnaire was used to complete the data. Eighty-nine subjects (267 injuries) were included in the study. Most of them were not professional horse riders or horse handlers. Helmet use was reported in only 28% of the participants. The number of subjects with horse-related injuries and the percentage of pediatric involvement increased during the study period. Falling from a horse was the most frequent cause of injury (60.67%), followed by being kicked (13.4%). Head and extremities were the most affected areas. On admission, 33.7% had a potential severe injury score. Forty-two participants (47%) had underlying fractures, mostly in the upper extremities. In the pediatric population, 16.2% (vs. 0% adults) rode horses for therapeutic reasons. Seventeen subjects reported having long-term consequences. The findings are similar to those described in other parts of the world. Horseback riding-related injuries are increasing, which emphasizes the need for safety education programs in Israel.


Early evidence of fire in south-western Europe: the Acheulean site of Gruta da Aroeira (Torres Novas, Portugal).
The site of Gruta da Aroeira (Torres Novas, Portugal), with evidence of human occupancy dating to ca. 400 ka (Marine Isotope Stage 11), is one of the very few Middle Pleistocene localities to have provided a fossil hominin cranium associated with Acheulean bifaces in a cave context. The multi-analytic study reported here of the by-products of burning recorded in layer X suggests the presence of anthropogenic fires at the site, among the oldest such evidence in south-western Europe. The burnt material consists of bone, charcoal and, possibly, quartzite cobbles. These finds were made in a small area of the cave and in two separate occupation horizons. Our results add to our still-limited knowledge about the controlled use of fire in the Lower Palaeolithic and contribute to ongoing debates on the behavioural complexity of the Acheulean of Europe.


Effective management of accelerated phase myelofibrosis with low-dose splenic radiotherapy.
The main cause of hepatosplenomegaly in primary (PMF), post polycythemia vera (post-PV MF), and post essential thrombocythemia (post-ET MF) myelofibrosis (MF) is extramedullary hematopoiesis (EMH). Drug-refractory symptomatic splenomegaly in MF is usually managed by splenectomy or involved-field radiotherapy. The latter is most effective in the treatment of MF-associated bone pain and pulmonary hypertension.Our previous experience with hepatosplenic radiotherapy in MF showed efficacy in the majority of treated patients but its utility was limited by the transient nature of its benefit and the occurrence of treatment-related pancytopenia. In an effort to address these issues,we have adopted an induction-maintenance treatment strategy that utilizes lower radiation doses-induction with 100 cGy total in four daily doses of 25 cGy and maintenance with either the same or lower intensity regimen. Herein, we report our most recent experience using this treatment plan in two cases, who in addition to their expected response from the standpoint of splenomegaly, also unexpectedly showed a marked response of their underlying accelerated phase disease,including clearance of circulating blasts and basophilia.


Rosenbluth Separation of the π^{0} Electroproduction Cross Section.
We present deeply virtual π^{0} electroproduction cross-section measurements at x_{B}=0.36 and three different Q^{2} values ranging from 1.5 to 2 GeV^{2}, obtained from Jefferson Lab Hall A experiment E07-007. The Rosenbluth technique is used to separate the longitudinal and transverse responses. Results demonstrate that the cross section is dominated by its transverse component and, thus, is far from the asymptotic limit predicted by perturbative quantum chromodynamics. Nonetheless, an indication of a nonzero longitudinal contribution is provided by the measured interference term σ_{LT}. Results are compared with several models based on the leading-twist approach of generalized parton distributions (GPDs). In particular, a fair agreement is obtained with models in which the scattering amplitude includes convolution terms of chiral-odd (transversity) GPDs of the nucleon with the twist-3 pion distribution amplitude. This experiment, together with previous extensive unseparated measurements, provides strong support to the exciting idea that transversity GPDs can be accessed via neutral pion electroproduction in the high-Q^{2} regime.


Prospective multicenter assessment of risk factors for rod fracture following surgery for adult spinal deformity.
Improved understanding of rod fracture (RF) following adult spinal deformity (ASD) surgery could prove valuable for surgical planning, patient counseling, and implant design. The objective of this study was to prospectively assess the rates of and risk factors for RF following surgery for ASD. This was a prospective, multicenter, consecutive series. Inclusion criteria were ASD, age > 18 years, ≥5 levels posterior instrumented fusion, baseline full-length standing spine radiographs, and either development of RF or full-length standing spine radiographs obtained at least 1 year after surgery that demonstrated lack of RF. ASD was defined as presence of at least one of the following: coronal Cobb angle ≥20°, sagittal vertical axis (SVA) ≥5 cm, pelvic tilt (PT) ≥25°, and thoracic kyphosis ≥60°. Of 287 patients who otherwise met inclusion criteria, 200 (70%) either demonstrated RF or had radiographic imaging obtained at a minimum of 1 year after surgery showing lack of RF. The patients' mean age was 54.8 ± 15.8 years; 81% were women; 10% were smokers; the mean body mass index (BMI) was 27.1 ± 6.5; the mean number of levels fused was 12.0 ± 3.8; and 50 patients (25%) had a pedicle subtraction osteotomy (PSO). The rod material was cobalt chromium (CC) in 53%, stainless steel (SS), in 26%, or titanium alloy (TA) in 21% of cases; the rod diameters were 5.5 mm (in 68% of cases), 6.0 mm (in 13%), or 6.35 mm (in 19%). RF occurred in 18 cases (9.0%) at a mean of 14.7 months (range 3-27 months); patients without RF had a mean follow-up of 19 months (range 12-24 months). Patients with RF were older (62.3 vs 54.1 years, p = 0.036), had greater BMI (30.6 vs 26.7, p = 0.019), had greater baseline sagittal malalignment (SVA 11.8 vs 5.0 cm, p = 0.001; PT 29.1° vs 21.9°, p = 0.016; and pelvic incidence [PI]-lumbar lordosis [LL] mismatch 29.6° vs 12.0°, p = 0.002), and had greater sagittal alignment correction following surgery (SVA reduction by 9.6 vs 2.8 cm, p < 0.001; and PI-LL mismatch reduction by 26.3° vs 10.9°, p = 0.003). RF occurred in 22.0% of patients with PSO (10 of the 11 fractures occurred adjacent to the PSO level), with rates ranging from 10.0% to 31.6% across centers. CC rods were used in 68% of PSO cases, including all with RF. Smoking, levels fused, and rod diameter did not differ significantly between patients with and without RF (p > 0.05). In cases including a PSO, the rate of RF was significantly higher with CC rods than with TA or SS rods (33% vs 0%, p = 0.010). On multivariate analysis, only PSO was associated with RF (p = 0.001, OR 5.76, 95% CI 2.01-15.8). Rod fracture occurred in 9.0% of ASD patients and in 22.0% of PSO patients with a minimum of 1-year follow-up. With further follow-up these rates would likely be even higher. There was a substantial range in the rate of RF with PSO across centers, suggesting potential variations in technique that warrant future investigation. Due to higher rates of RF with PSO, alternative instrumentation strategies should be considered for these cases.


Menstrual cycle phase affects discrimination of infant cuteness.
Recent studies have shown that women are more sensitive than men to subtle cuteness differences in infant faces. It has been suggested that raised levels in estradiol and progesterone may be responsible for this advantage. We compared young women's sensitivity to computer-manipulated baby faces varying in cuteness. Thirty-six women were tested once during ovulation and once during the luteal phase of their menstrual cycle. In a two alternative forced-choice experiment, participants chose the baby which they thought was cuter (Task 1), younger (Task 2), or the baby that they would prefer to babysit (Task 3). Saliva samples to assess levels of estradiol, progesterone and testosterone were collected at each test session. During ovulation, women were more likely to choose the cuter baby than during the luteal phase, in all three tasks. These results suggest that cuteness discrimination may be driven by cyclic hormonal shifts. However none of the measured hormones were related to increased cuteness sensitivity. We speculate that other hormones than the ones measured here might be responsible for the increased sensitivity to subtle cuteness differences during ovulation.


Prevalence of antibodies to hepatitis A, B, C, and E viruses in a healthy population in Leon, Nicaragua.
A cross-sectional survey of the seroprevalence of hepatitis A virus (HAV), B (HBV), C (HCV), and E (HEV) antibodies in a healthy population in Leon, Nicaragua was conducted and associated with demographic data. The overall prevalence of antibodies to HAV was 94.6%, to HBV 6.5% and to HEV between 4.6% and 8.0%, whereas none of 399 tested subjects showed confirmed seropositivity to HCV. A high HAV seropositivity rate (72.7%) was observed even in the lowest age groups tested (2-4 years of age). In contrast, HBV and HEV seropositivity was observed mainly in adults, the seroprevalence in > 40-year-old individuals being 15.4% and 17.6%, respectively. The overall mean hepatitis B surface antigen carrier rate was estimated to be 0.9%, and in individuals more than 20 years of age, 2.0%. The prevalence of anti-HAV as well as anti-HEV was significantly higher in people having their water supply outside rather than inside the house. Furthermore anti-HAV seroprevalence correlated with lack of access to a flush toilet. Hepatitis B virus seropositivity was more frequent in people living in a crowded environment than in those living with few household members. These findings indicate that hepatitis A is a childhood infection in Nicaragua and that the spread of the infection is facilitated by poor socioeconomic conditions. In contrast, HBV infection is relatively infrequent in the country and HCV seems to be very uncommon. Hepatitis E virus infection may occur in all age groups and is apparently associated with water-borne transmission.


The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis.
To determine the expression of interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), and oncostatin M (OSM) and their major cellular sources in the joints of rheumatoid arthritis (RA) patients, as well as the correlation of circulating levels of these IL-6-type cytokines and C-reactive protein (CRP). Messenger RNA (mRNA) and protein levels for IL-6, IL-11, LIF, and OSM were determined by using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Cells isolated from the synovium of RA patients expressed mRNA for IL-6, IL-11, LIF, and OSM at higher levels than did synovial cells from osteoarthritis (OA) patients, and spontaneously released greater quantities of these proteins in culture. Fibroblast cell lines derived from RA synovium were able to produce IL-6, IL-11, and LIF, but not OSM, when stimulated with IL-1 and tumor necrosis factor alpha. OSM was found to be produced spontaneously by synovial tissue macrophages. IL-6, IL-11, LIF, and OSM were present in synovial fluid from the RA patients; levels of IL-6, LIF, and OSM were present in significantly greater quantities in RA patients than in OA patients. However, only IL-6 was significantly elevated in the serum of RA patients and correlated with the serum CRP level, while other IL-6-type cytokines were not detected. IL-6, IL-11, LIF, and OSM are all produced in large amounts at the site of disease activity, but IL-6 derived from synovial fibroblasts may be the major hormone-like mediator that induces the hepatic synthesis of acute-phase proteins in RA.


Interleukin 1 enhances T-dependent immune responses by amplifying the function of dendritic cells.
The function of exogenous murine recombinant IL-1 alpha as a T lymphocyte-activating molecule was examined. IL-1 did not induce IL-2 release or responsiveness in purified T cells regardless of their state of activation: unprimed lymphocytes, freshly sensitized lymphocytes, or memory cells derived from the blasts. Nor did IL-1 synergize with mitogens, or with antigens, to stimulate proliferation. For example the combinations of IL-1 plus Ia+ peritoneal macrophages, or IL-1 plus Con A, were less than 5% as effective in triggering T cell growth as a low dose (1%) of dendritic cells. However, when IL-1 was added at the onset of culture, the response to limiting doses of dendritic cells was increased 3- to 10-fold in several systems: the syngeneic and allogeneic MLR, Con A- and periodate-induced polyclonal mitogenesis, and T-dependent antibody formation against foreign red cells. The amplifying effect of IL-1 could be obtained if the dendritic cells but not the responding lymphocytes were exposed to IL-1 before use as accessory cells. Optimal activation of dendritic cells required a dose of 5 U/ml (50 pM) and 18 h of exposure, and was not due to carryover of IL-1 into the lymphocyte culture. IL-2, IL-3, and cachectin/TNF did not amplify dendritic cell function, while IFN-gamma diminished it. The enhanced function of IL-1-treated dendritic cells was due to an enhanced clustering with helper T lymphocytes in the first day of the MLR response. Therefore IL-1 does not seem to act as an activating factor for most peripheral T lymphocytes. Instead, IL-1 enhances the function of accessory dendritic cells and represents the first molecule that has been shown to enhance the immune response at this critical level.


Closure of the radial forearm donor site using a local hatchet flap: analysis of 45 consecutive cases.
The radial forearm free flap (RFFF) is widely used in reconstructive surgery. Traditional donor-site closure by grafting may be associated with significant aesthetic and functional morbidity. We report our experience with primary closure using a local hatchet flap. In all, 45 consecutive patients who underwent RFFF reconstruction in the head and neck during an 8-year period were retrospectively assessed with regards to their donor-site morbidity. The mean age of the patients was 54, with 23 being female. The mean RFFF area harvested was 37.7 cm; mean width, 7.6 cm (5.5-11 cm); and mean length, 4.7 cm (3.5-6.5 cm). All patients had their donor site closed primarily utilizing a local hatchet flap. At the time of follow-up, there were 33 surviving patients, of which 31 patients were available for assessment. We recommend this technique of primary closure of the RFFF donor site: it is well tolerated by the patient, with good cosmesis and is associated with no discernable functional morbidity.