The "Great Lockdown": Inactive workers and mortality by Covid-19.
In response to the Covid-19 outbreak, the Italian Government imposed an economic lockdown on March 22, 2020, and ordered the closing of all non-essential economic activities. This paper estimates the causal effects of this measure on mortality by Covid-19 and on mobility patterns. The identification of the causal effects exploits the variation in the active population across municipalities induced by the economic lockdown. The difference-in-differences empirical design compares outcomes in municipalities above and below the median variation in the share of active population before and after the lockdown within a province, also controlling for municipality-specific dynamics, daily shocks at the provincial level, and municipal unobserved characteristics. Our results show that the intensity of the economic lockdown is associated with a statistically significant reduction in mortality by Covid-19 and, in particular, for age groups between 40 and 64 and older (with larger and more significant effects for individuals above 50). Back of the envelope calculations indicate that 4793 deaths were avoided, in the 26 days between April 5 and April 30, in the 3518 municipalities which experienced a more intense lockdown. Several robustness checks corroborate our empirical findings.


Efficient and accurate Greedy Search Methods for mining functional modules in protein interaction networks.
Most computational algorithms mainly focus on detecting highly connected subgraphs in PPI networks as protein complexes but ignore their inherent organization. Furthermore, many of these algorithms are computationally expensive. However, recent analysis indicates that experimentally detected protein complexes generally contain Core/attachment structures. In this paper, a Greedy Search Method based on Core-Attachment structure (GSM-CA) is proposed. The GSM-CA method detects densely connected regions in large protein-protein interaction networks based on the edge weight and two criteria for determining core nodes and attachment nodes. The GSM-CA method improves the prediction accuracy compared to other similar module detection approaches, however it is computationally expensive. Many module detection approaches are based on the traditional hierarchical methods, which is also computationally inefficient because the hierarchical tree structure produced by these approaches cannot provide adequate information to identify whether a network belongs to a module structure or not. In order to speed up the computational process, the Greedy Search Method based on Fast Clustering (GSM-FC) is proposed in this work. The edge weight based GSM-FC method uses a greedy procedure to traverse all edges just once to separate the network into the suitable set of modules. The proposed methods are applied to the protein interaction network of S. cerevisiae. Experimental results indicate that many significant functional modules are detected, most of which match the known complexes. Results also demonstrate that the GSM-FC algorithm is faster and more accurate as compared to other competing algorithms. Based on the new edge weight definition, the proposed algorithm takes advantages of the greedy search procedure to separate the network into the suitable set of modules. Experimental analysis shows that the identified modules are statistically significant. The algorithm can reduce the computational time significantly while keeping high prediction accuracy.


Characteristics and outcomes of COVID-19 patients with and without asthma from the United States, South Korea, and Europe.
Objective: Large international comparisons describing the clinical characteristics of patients with COVID-19 are limited. The aim of the study was to perform a large-scale descriptive characterization of COVID-19 patients with asthma.Methods: We included nine databases contributing data from January to June 2020 from the US, South Korea (KR), Spain, UK and the Netherlands. We defined two cohorts of COVID-19 patients ('diagnosed' and 'hospitalized') based on COVID-19 disease codes. We followed patients from COVID-19 index date to 30 days or death. We performed descriptive analysis and reported the frequency of characteristics and outcomes in people with asthma defined by codes and prescriptions.Results: The diagnosed and hospitalized cohorts contained 666,933 and 159,552 COVID-19 patients respectively. Exacerbation in people with asthma was recorded in 1.6-8.6% of patients at presentation. Asthma prevalence ranged from 6.2% (95% CI 5.7-6.8) to 18.5% (95% CI 18.2-18.8) in the diagnosed cohort and 5.2% (95% CI 4.0-6.8) to 20.5% (95% CI 18.6-22.6) in the hospitalized cohort. Asthma patients with COVID-19 had high prevalence of comorbidity including hypertension, heart disease, diabetes and obesity. Mortality ranged from 2.1% (95% CI 1.8-2.4) to 16.9% (95% CI 13.8-20.5) and similar or lower compared to COVID-19 patients without asthma. Acute respiratory distress syndrome occurred in 15-30% of hospitalized COVID-19 asthma patients.Conclusion: The prevalence of asthma among COVID-19 patients varies internationally. Asthma patients with COVID-19 have high comorbidity. The prevalence of asthma exacerbation at presentation was low. Whilst mortality was similar among COVID-19 patients with and without asthma, this could be confounded by differences in clinical characteristics. Further research could help identify high-risk asthma patients.[Box: see text]Supplemental data for this article is available online at https://doi.org/10.1080/02770903.2021.2025392 .


The role of spatial attention in the selection of real and illusory objects.
Selective attention may be flexibly directed toward particular locations in the visual field (spatial attention) or to entire object configurations (object-based attention). A key question is whether spatial attention plays a direct role in the selection of objects, perhaps by spreading its facilitatory influence throughout the boundaries of an object. We studied the relationship between spatial and object-based attention in a design in which subjects attended to brief offsets of one corner of a real or illusory square form. Object-selective attention was indexed by differences in event-related potential (ERP) amplitudes and blood oxygen level-dependent (BOLD) activations to unattended corner offsets in conditions in which the objects were intact versus fragmented or absent. This design ensured that object-based attention effects were not an artifact of attention being guided by simple directional cues such as parallel lines, which may have occurred in previous studies. Both space-based and object-based attention were associated with enhanced negative ERPs (N1 component at 140-180 ms) that were colocalized with BOLD activations in lateral occipital cortex (LOC). These results provide physiological evidence that directing spatial attention to one part of an object (whether real or illusory) facilitates the processing of the entire object at the level of the LOC and thus contributes directly to object-based selective attention.


HQG-Net: Unpaired Medical Image Enhancement With High-Quality Guidance.
Unpaired medical image enhancement (UMIE) aims to transform a low-quality (LQ) medical image into a high-quality (HQ) one without relying on paired images for training. While most existing approaches are based on Pix2Pix/CycleGAN and are effective to some extent, they fail to explicitly use HQ information to guide the enhancement process, which can lead to undesired artifacts and structural distortions. In this article, we propose a novel UMIE approach that avoids the above limitation of existing methods by directly encoding HQ cues into the LQ enhancement process in a variational fashion and thus model the UMIE task under the joint distribution between the LQ and HQ domains. Specifically, we extract features from an HQ image and explicitly insert the features, which are expected to encode HQ cues, into the enhancement network to guide the LQ enhancement with the variational normalization module. We train the enhancement network adversarially with a discriminator to ensure the generated HQ image falls into the HQ domain. We further propose a content-aware loss to guide the enhancement process with wavelet-based pixel-level and multiencoder-based feature-level constraints. Additionally, as a key motivation for performing image enhancement is to make the enhanced images serve better for downstream tasks, we propose a bi-level learning scheme to optimize the UMIE task and downstream tasks cooperatively, helping generate HQ images both visually appealing and favorable for downstream tasks. Experiments on three medical datasets verify that our method outperforms existing techniques in terms of both enhancement quality and downstream task performance. The code and the newly collected datasets are publicly available at https://github.com/ChunmingHe/HQG-Net.


Flavopiridol sensitivity of cancer cells isolated from ascites and pleural fluids.
We examined the efficacy of flavopiridol, a cyclin-dependent kinase inhibitor that is undergoing clinical trials, on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers. Metastasized cancer cells were isolated from the pleural fluids (n = 20) or ascites (n = 15) of patients, most of whom were refractory to chemotherapy. These primary cancer cells were used within 2 weeks of isolation without selecting for proliferative capacities. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to characterize the response of these cancer cells to commonly used chemotherapeutic agents, and their response to flavopiridol was compared with rapidly dividing cultured cell lines. The primary cancer cells displayed phenotypes that were different from established cell lines; they had very low replication rates, dividing every 1 to 2 weeks, and underwent replicative senescence within five passages. These primary tumor cells retained their resistance to chemotherapeutic drugs exhibited by the respective patients but did not show cross-resistance to other agents. However, these cancer cells showed sensitivity to flavopiridol with an average LD50 of 50 nmol/L (range, 21.5-69 nmol/L), similar to the LD50 in established cell lines. Because senescent cells also showed similar sensitivity to flavopiridol, it suggests that the mechanism of action is not dependent on the activity of cyclin-dependent kinases that regulate the progression of the cell cycle. Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential of flavopiridol against cancer cells that have developed resistance to conventional chemotherapeutic agents.


Antagonism of cytotoxic T-lymphocyte activation by soluble CD8.
The CD8 co-receptor is important in the differentiation and selection of class I MHC-restricted T cells during thymic development, and in the activation of mature T lymphocytes in response to antigen. Here we show that soluble CD8alphaalpha receptor, despite an extremely low affinity for MHC, inhibits activation of cytotoxic lymphocytes by obstructing CD3 zeta-chain phosphorylation. We propose a model for this effect that involves interference of productive receptor multimerization at the T-cell surface. These results provide new insights into the mechanism of T-cell activation and evidence that CD8 function is exquisitely sensitive to disruption, an effect that might be exploited by molecular therapeutics.


Peer support in type 2 diabetes: a randomised controlled trial in primary care with parallel economic and qualitative analyses: pilot study and protocol.
Diabetes is a chronic illness, which requires the individual to assume responsibility for their own care with the aim of maintaining glucose and blood pressure levels as close to normal as possible. Traditionally self-management training for diabetes has been delivered in a didactic manner. In recent times alternatives to the traditional delivery of diabetes care have been investigated, for example, the concept of peer support which emphasises patient rather than professional domination. This paper describes the pilot study and protocol for a study that aims to evaluate the effectiveness of a peer support intervention for people with type 2 diabetes in a primary care setting. A pilot study was conducted to access the feasibility of a randomized controlled trial of a peer support intervention. We used the MRC Framework for the evaluation of complex interventions. Elements of the intervention were defined and the study protocol was finalized. In this cluster randomised controlled trial twenty general practices are assigned to control and intervention groups. Each practice compiles a diabetes register and randomly selects 21 patients. All practices implement a standardised diabetes care system. In the intervention group all practices recruit three peer supporters. The peer supporters are trained to conduct nine group meetings in their general practice over a period of two years. Each meeting has a structured component. The primary outcomes are blood pressure, total cholesterol, HBA1c and the Diabetes Well-being score. In addition to biophysical, psychosocial, economic and health service utilization data peer supporter activity and qualitative data are collected. Peer support is a complex intervention and evaluating such an intervention presents challenges to researchers. This study will evaluate whether a peer support programme for patients with type 2 diabetes improves biophysical and psychosocial outcomes and whether it is an acceptable, cost effective intervention in the primary care setting. Current Controlled Trials ISRCTN42541690.


Clopidogrel did not inhibit platelet function early after coronary bypass surgery: A prospective randomized trial.
Although the beneficial effect of aspirin prescription after coronary surgery has been established, the efficacy of clopidogrel has never been compared with that of aspirin in the critical early postoperative period. We therefore conducted a prospective, double-blind, randomized controlled trial to compare the efficacies of these antiplatelet regimens. Patients undergoing elective primary coronary artery bypass surgery were invited to participate. After the operation, patients were randomized to receive 100 mg aspirin, 325 mg aspirin, or 75 mg clopidogrel tablets daily for 5 days. Our primary outcome measure was platelet aggregation on day 5, expressed as percentage of baseline. Assessment of platelet aggregation was undertaken with the technique of Born. From September 2002 to July 2003, a total of 54 patients were randomized into the study. There were 2 self-withdrawals and 2 protocol violations, leaving 50 patients for analysis, 34 in the aspirin group and 16 in the clopidogrel arm. Compared with baseline, the mean percentage aggregations with collagen on day 5 were 56% for aspirin and 99% for clopidogrel. The mean difference between the two arms was 42% (95% confidence interval 27%-56%) in favor of aspirin. At the same time point, the effective concentration to inhibit 50% aggregation in the samples from patients randomly assigned to receive clopidogrel were not raised for our entire panel of agonists (changes of -0.04 microg/L for collagen, -0.01 micromol/L for epinephrine, and -0.02 micromol/L for adenosine diphosphate). Clopidogrel, unlike aspirin, did not inhibit platelet aggregation in the first 5 postoperative days and therefore should not be used as a sole antiplatelet agent early after coronary surgery.


Advances in targeted alpha therapy for prostate cancer.
Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.


Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM.
'Checkpoint' controls arrest the cell cycle after DNA damage, allowing repair to take place before mutations can be perpetuated. In multicellular organisms, DNA damage can also induce apoptotic cell death, protecting the organism at the expense of the individual cell. How does a cell 'choose' between cycle arrest and death? Analysis of two human tumour suppressor proteins, p53 and the ATM (ataxia-telangiectasia mutated) gene product, may provide some answers.


Early-Life Intelligence Predicts Midlife Biological Age.
Early-life intelligence has been shown to predict multiple causes of death in populations around the world. This finding suggests that intelligence might influence mortality through its effects on a general process of physiological deterioration (i.e., individual variation in "biological age"). We examined whether intelligence could predict measures of aging at midlife before the onset of most age-related disease. We tested whether intelligence assessed in early childhood, middle childhood, and midlife predicted midlife biological age in members of the Dunedin Study, a population-representative birth cohort. Lower intelligence predicted more advanced biological age at midlife as captured by perceived facial age, a 10-biomarker algorithm based on data from the National Health and Nutrition Examination Survey (NHANES), and Framingham heart age (r = 0.1-0.2). Correlations between intelligence and telomere length were less consistent. The associations between intelligence and biological age were not explained by differences in childhood health or parental socioeconomic status, and intelligence remained a significant predictor of biological age even when intelligence was assessed before Study members began their formal schooling. These results suggest that accelerated aging may serve as one of the factors linking low early-life intelligence to increased rates of morbidity and mortality.


The patients' account of outcome following primary surgery for oral and oropharyngeal cancer using a 'quality of life' questionnaire.
The purpose of this study was to collate all the University of Washington quality of life (UW-QOL) data collected in the Unit since 1995 and to summarize it in a patient-friendly format that can be used when discussing treatment outcomes. The sample of cancer patients consisted of 561 consecutive patients undergoing primary surgery for previously untreated oral and oropharyngeal squamous cell carcinoma presenting to the Regional Maxillofacial Unit Liverpool, between the years 1995 and 2004. Follow-up was on May 2006. Information sheets were constructed based on the UW-QOL, summarizing the patients at around 2 years (median 28 months). The response to each statement in all 12 domains, domains as important, and the general health-related QOL/QOL questions are given. Data has been summarized for six common groups based on the clinical presentation and treatment. The data show big differences by tumour size, free-flap surgery and adjuvant radiotherapy. Information presented in this format is potentially extremely useful when counselling patients and their families regarding the likely outcomes of treatment.


Does sodium nitroprusside kill babies? A systematic review.
To determine whether sodium nitroprusside causes fetal death in pregnancies complicated with hypertension. Medical Literature Analysis and Retrieval System Online (MEDLINE; 1996 to 2003), Excerpta Medica (EMBASE; 1970 to 2003), Web of Science/Institute for Scientific Information (ISI; 1945 to 2003), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS; 1982 to 2003) and the Cochrane Library. The medical subject headings used were "nitroprusside and pregnancy", "hypertension or eclampsia or preeclampsia" and "nitroprusside and pregnancy and hypertensive emergencies". The search was limited to humans and female gender, in all fields, publication types, languages and subsets. Articles were also identified by reviewing the references of articles and textbooks on hypertension and pregnancy. The search located nine studies. The sum of all the publications yielded a total of 22 patients and 24 exposed fetuses (two pairs of twins). There were no randomized clinical trials and no prospective cohorts. All of the studies were observational in nature. At present, there is insufficient evidence for definitive conclusions about any direct association between sodium nitroprusside use and fetal demise.


Visual ageing: unspecific decline of the responses to luminance and colour.
We have investigated whether ageing affects selectively the responses to equiluminant patterns of pure colour contrast. In two groups of subjects (mean ages 29 and 72 yr) contrast thresholds were measured psychophysically for the detection and for the discrimination of the direction of motion of drifting gratings. The gratings were modulated either in pure luminance contrast (and uniform colour), or pure chromatic contrast (red-green equiluminant gratings). In subjects of the same age groups, visual evoked potentials (VEP) were recorded in response to gratings with either pure luminance contrast or pure colour contrast sinusoidally reversed in contrast at various temporal frequencies. It was shown that psychophysical contrast sensitivity for equiluminant patterns deteriorates significantly with age, and VEP latency increases. However, these effects of ageing on the responses to patterns of pure colour contrast are substantially the same as those observed in the same subjects for stimuli with pure luminance contrast. The results suggest that ageing causes a small and unspecific decline of the response of the visual system to luminance and colour contrast.


Electrostatics of DNA-DNA juxtapositions: consequences for type II topoisomerase function.
Type II topoisomerases resolve problematic DNA topologies such as knots, catenanes, and supercoils that arise as a consequence of DNA replication and recombination. Failure to remove problematic DNA topologies prohibits cell division and can result in cell death or genetic mutation. Such catastrophic consequences make topoisomerases an effective target for antibiotics and anticancer agents. Despite their biological and clinical importance, little is understood about how a topoisomerase differentiates DNA topologies in a molecule that is significantly larger than the topoisomerase itself. It has been proposed that type II topoisomerases recognize angle and curvature between two DNA helices characteristic of knotted and catenated DNA to account for the enzyme's preference to unlink instead of link DNA. Here we consider the electrostatic potential of DNA juxtapositions to determine the possibility of juxtapositions occurring through Brownian diffusion. We found that despite the large negative electrostatic potential formed between two juxtaposed DNA helices, a bulk counterion concentration as small as 50 mM provides sufficient electrostatic screening to prohibit significant interaction beyond an interhelical separation of 3 nm in both hooked and free juxtapositions. This suggests that instead of electrostatics, mechanical forces such as those occurring in anaphase, knots, catenanes, or the writhe of supercoiled DNA may be responsible for the formation of DNA juxtapositions.


Treatment-Related Complications of Systemic Therapy and Radiotherapy.
Systemic therapy and radiotherapy can be associated with acute complications that may require emergent care. However, there are limited data characterizing complications and the financial burden of cancer therapy that are treated in emergency departments (EDs) in the United States. To estimate the incidence of treatment-related complications of systemic therapy or radiotherapy, examine factors associated with inpatient admission, and investigate the overall financial burden. A retrospective analysis of the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample was performed. Between January 2006 and December 2015, there was a weighted total of 1.3 billion ED visits; of these, 1.5 million were related to a complication of systemic therapy or radiotherapy for cancer. Data analysis was conducted from February 22 to December 23, 2018. External cause of injury codes, Clinical Classifications Software, International Classification of Diseases, Ninth Revision, Clinical Modification, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), Clinical Modification codes were used to identify patients with complications of systemic therapy or radiotherapy. Patterns in treatment-related complications, patient- and hospital-related factors associated with inpatient admission, and median and total charges for treatment-related complications were the main outcomes. Of the 1.5 million ED visits included in the analysis, 53.2% of patients were female and mean age was 63.3 years. Treatment-related ED visits increased by a rate of 10.8% per year compared with 2.0% for overall ED visits. Among ED visits, 90.9% resulted in inpatient admission to the hospital and 4.9% resulted in death during hospitalization. Neutropenia (136 167 [8.9%]), sepsis (128 171 [8.4%]), and anemia (117 557 [7.7%]) were both the most common and costliest (neutropenia: $5.52 billion; sepsis: $11.21 billion; and anemia: $6.78 billion) complications diagnosed on presentation to EDs; sepsis (odds ratio [OR], 21.00; 95% CI, 14.61-30.20), pneumonia (OR, 9.73; 95% CI, 8.08-11.73), and acute kidney injury (OR, 9.60; 95% CI, 7.77-11.85) were associated with inpatient admission. Costs related to the top 10 most common complications totaled $38 billion and comprised 48% of the total financial burden of the study cohort. Emergency department visits for complications of systemic therapy or radiotherapy increased at a 5.5-fold higher rate over 10 years compared with overall ED visits. Neutropenia, sepsis, and anemia appear to be the most common complications; sepsis, pneumonia, and acute kidney injury appear to be associated with the highest rates of inpatient admission. These complications suggest that significant charges are incurred on ED visits.


Computed tomography and magnetic resonance imaging of the orbit in the diagnosis and treatment of thyroid-associated orbitopathy - experience from practice. A Review.
The purpose is to acquaint readers with the contribution of imaging methods (IMs) of the orbit, specifically computed tomography (CT) and magnetic resonance imaging (MRI), in the diagnosis of thyroid-associated orbitopathy (TAO). Methods: IMs of the orbit are an indispensable accessory in the clinical and laboratory examination of TAO patients. The most frequently used and probably most accessible method is an ultrasound examination of the orbit (US), which, however, has a number of limitations. Other methods are CT and MRI. Based on the published knowledge implemented in our practice and several years of experience with the diagnosis and treatment of TAO patients, we would like to point out the benefits of CT and MRI in the given indications: visualisation of the extraocular muscles, assessment of disease activity, diagnosis of dysthyroid optic neuropathy and differential diagnosis of other pathologies in the orbit. Our recommendation for an ideal MRI protocol for disease activity evaluation is also included. Conclusion: IMs play an irreplaceable role not only in the early diagnosis of TAO, but also in the monitoring of the disease and the response to the applied treatment. When choosing a suitable IM for this diagnosis, a number of factors must always be taken into account; not only availability, cost and burden for the patient, but especially the sensitivity and specificity of the given method for the diagnosis of TAO.


Pain assessment and treatment in children with cognitive impairment: a survey of nurses' and physicians' beliefs.
To gather information about healthcare providers' beliefs regarding pain and its treatment in children with cognitive impairment. A survey consisting of two acute pain vignettes (a child undergoing surgery and a child undergoing an outpatient medical procedure) was completed by 440 nurses and 146 physicians at Arkansas Children's Hospital. Respondents completed one of four different surveys that systematically varied the child's level of cognitive impairment (none, mild, moderate, severe) in both vignettes. Questions addressed expected pain, pain assessment methods, pharmacologic regimens, and nonpharmacologic interventions. In general, provider discipline and level of cognitive impairment did not significantly influence responses about pain experience and treatment. Potent analgesia, regularly scheduled dosing, and nonpainful administration were selected most frequently. Self-report of pain, patient-controlled analgesia, and behavioral interventions requiring higher cognitive skills were selected less frequently for children with more severe cognitive impairment. The presence of cognitive impairment appeared to influence provider decisions regarding the appropriateness of specific pain assessment and treatment methods requiring skills on the part of the child. Overall, healthcare provider views regarding analgesia and sedation were similar for all children, regardless of impairment. Whether these beliefs are consistent with clinical practice is yet to be documented.


Exocytotic fusion pores exhibit semi-stable states.
Rapid-freezing/freeze-fracture electron microscopy and whole-cell capacitance techniques were used to study degranulation in peritoneal mast cells of the rat and the mutant beige mouse. These studies allowed us to create a time-resolved picture for fusion pore formation. After stimulation, a dimple in the plasma membrane formed a small contact area with the secretory granule membrane. Within this zone of apposition no ordered proteinaceous specializations were seen. Electrophysiological technique measured a small fusion pore which widened rapidly to 1 nS. Thereafter, the fusion pore remained at semi-stable conductances between 1 and 20 nS for a wide range of times, between 10 and 15,000 msec. These conductances correspond to pore diameters 25-36 nm. Ultrastructural data confirmed small pores of hourglass morphology, composed of biological membrane coplanar with both the plasma and granular membranes. Later, the fusion pore rapidly increased in conductance, consistent with the observed morphology of omega-figures. The hallmarks of channel-like behavior, instantaneous jumps in pore conductance between defined levels, and sharp peaks in histograms of conductance dwell-time, were not seen. Since the morphology of small pores shows contiguous fracture planes, the electrical data represent pores that contain lipid. These combined morphological and electrophysiological data are consistent with a lipid/protein complex mediating both the initial and later stages of membrane fusion.


Modulation of VEGF production by pH and glucose in retinal Müller cells.
To investigate the influence of pH and glucose concentration, both of which represent significant biochemical variables in tissue ischemia, on the production of VEGF protein by retinal Müller cells and C6 glioma cells, under normoxic and hypoxic conditions. Rat retinal Müller cells and C6 glioma cells grown in tissue culture monolayers were studied. The effect of pH (range 7.0-8.0) and glucose concentration (0.6-25 mmol/L) on VEGF protein production, under both normoxic and hypoxic conditions, were evaluated by ELISA analysis of the conditioned media. Establishment of significant cell hypoxia was verified by measurement of lactate release into the conditioned media. Hypoxia caused a 7.9-fold increase in VEGF production in C6 cells at 24 h, and a 3.4-fold increase in Müller cells after 48 h. Under hypoxic conditions, VEGF protein production was increased further by increasing pH and increasing glucose, and decreased by low pH and low glucose. Varying the glucose concentration or pH of the medium did not result in significant induction of VEGF protein production by either cell type under normoxic conditions. Both glucose and pH significantly affected VEGF production induced by low oxygen. However, neither exerted a measurable stimulatory effect on VEGF production in normoxic conditions. Coexisting hypoxia and acidosis or hypoglycemia, as might occur in severe tissue ischemia, may render glial cells incapable of effectively upregulating VEGF synthesis, while alkalosis or hyperglycemia may augment hypoxia-induced VEGF production.


Generative Feedback Explains Distinct Brain Activity Codes for Seen and Mental Images.
The relationship between mental imagery and vision is a long-standing problem in neuroscience. Currently, it is not known whether differences between the activity evoked during vision and reinstated during imagery reflect different codes for seen and mental images. To address this problem, we modeled mental imagery in the human brain as feedback in a hierarchical generative network. Such networks synthesize images by feeding abstract representations from higher to lower levels of the network hierarchy. When higher processing levels are less sensitive to stimulus variation than lower processing levels, as in the human brain, activity in low-level visual areas should encode variation in mental images with less precision than seen images. To test this prediction, we conducted an fMRI experiment in which subjects imagined and then viewed hundreds of spatially varying naturalistic stimuli. To analyze these data, we developed imagery-encoding models. These models accurately predicted brain responses to imagined stimuli and enabled accurate decoding of their position and content. They also allowed us to compare, for every voxel, tuning to seen and imagined spatial frequencies, as well as the location and size of receptive fields in visual and imagined space. We confirmed our prediction, showing that, in low-level visual areas, imagined spatial frequencies in individual voxels are reduced relative to seen spatial frequencies and that receptive fields in imagined space are larger than in visual space. These findings reveal distinct codes for seen and mental images and link mental imagery to the computational abilities of generative networks.


Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells.
Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases caused by derailment of humoral and cellular immunity. In this study we investigated whether IVIg treatment can modulate regulatory T cells (Tregs ) in humans in vivo. Blood was collected from IVIg-treated patients with immunodeficiency or autoimmune disease who were treated with low-dose (n = 12) or high-dose (n = 15) IVIg before, immediately after and at 7 days after treatment. Percentages and activation status of circulating CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+)) Tregs and of conventional CD4(+) FoxP3(-) T-helper cells (Tconv) were measured. The suppressive capacity of Tregs purified from blood collected at the time-points indicated was determined in an ex-vivo assay. High-dose, but not low-dose, IVIg treatment enhanced the activation status of circulating Tregs , as shown by increased FoxP3 and human leucocyte antigen D-related (HLA-DR) expression, while numbers of circulating Tregs remained unchanged. The enhanced activation was sustained for at least 7 days after infusion, and the suppressive capacity of purified Tregs was increased from 41 to 70% at day 7 after IVIg treatment. The activation status of Tconv was not affected by IVIg. We conclude that high-dose IVIg treatment activates Tregs selectively and enhances their suppressive function in humans in vivo. This effect may be one of the mechanisms by which IVIg restores imbalanced immune homeostasis in patients with autoimmune and systemic inflammatory disorders.


Degraded collagenase deteriorates islet viability.
The utilization of purified enzyme blends consisting of collagenase class I (CI) and II (CII) and neutral protease is an essential step for clinical islet isolation. Previous studies suggested that the use of enzyme lots containing degraded CI reduced islet release from human pancreata. The present study sought to assess the effect of degraded collagenase on islet function in vitro and posttransplantation. Crude collagenase was chromatographically separated into CI, CII, and a mixture of degraded CI and CII isomers. Subsequently, classes were recombined to obtain a CII/CI ratio of 0.5. Rat islets were isolated utilizing neutral protease and 20 units of recombined collagenase containing either intact (Ci) or degraded isomers (Cd). Digestion time was reduced utilizing Cd (P < .001). The highest islet yield and lowest islet fragmentation were obtained with Ci (P < .01). Utilization of Cd corresponded to a reduction in viability and in vitro function (NS). Islet transplantation reversed hyperglycemia in diabetic nude mice, but revealed an absence of weight gain in recipients receiving islets isolated using Cd (P < .01). This study suggested that islet function posttransplantation is affected by degraded collagenase isomers. This finding has to be considered for the purification process of collagenase.


Possible reflex pathway between medial meniscus and semimembranosus muscle: an experimental study in rabbits.
Meniscus is a well innervated tissue with four types of receptors. These receptors are mainly concentrated at the anterior and posterior horns. Although they are intended to be a part in reflex arc, this function has not been thoroughly evaluated. We hypothesized that electrical stimulation of the normal meniscus would elicit electromyographic activity of the hamstring muscle via the reflex arc. Five adult domestic male rabbits were used in this study. Under general anesthesia, knee arthrotomy and thigh dissection were done to expose medial meniscus and semimembranosus muscle. Menisci were stimulated by Teflon-coated bipolar needle electrodes. Needles were placed in the posterior horn of the medial menisci. Two Teflon-coated monopolar needle electrodes were placed in semimembranosus muscle. A four-channel electromyograph was used for recording. Two different potentials were recorded from the target muscle. The first response had a very short distal latency and its amplitude was changing in accordance with the strength of the stimulus, suggesting that this response was being elicited by direct muscle stimulation. The second delayed response with less amplitude also appeared in some traces. The latency and the amplitude of this second response were fairly stable stating that this delayed response was being generated by a reflex pathway and seen in all subjects.


Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B.
The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors has lead to new drug development strategies to produce agents with improved antidepressant efficacy. We report the in vivo characterization of the novel 5-HT(1A/1B) autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B. Ex vivo binding was used to ascertain 5-HT(1A) receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT(1A) and 5-HT(1B) receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B. SB-649915-B (1-10 mg/kg p.o.) produced a dose-related inhibition of 5-HT(1A) receptor radioligand binding and inhibited ex vivo [(3)H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1-10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT(1A) and 5-HT(1B) receptors, respectively. SB-649915-B (0.1-3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs. Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current selective serotonin reuptake inhibitors.


Impact of gastrectomy procedural complexity on surgical outcomes and hospital comparisons.
Most risk adjustment approaches adjust for patient comorbidities and the primary procedure. However, procedures done at the same time as the index case may increase operative risk and merit inclusion in adjustment models for fair hospital comparisons. Our objectives were to evaluate the impact of surgical complexity on postoperative outcomes and hospital comparisons in gastric cancer surgery. Patients who underwent gastric resection for cancer were identified from a large clinical dataset. Procedure complexity was characterized using secondary procedure CPT codes and work relative value units (RVUs). Regression models were developed to evaluate the association between complexity variables and outcomes. The impact of complexity adjustment on model performance and hospital comparisons was examined. Among 3,467 patients who underwent gastrectomy for adenocarcinoma, 2,171 operations were distal and 1,296 total. A secondary procedure was reported for 33% of distal gastrectomies and 59% of total gastrectomies. Six of 10 secondary procedures were associated with adverse outcomes. For example, patients who underwent a synchronous bowel resection had a higher risk of mortality (odds ratio [OR], 2.14; 95% CI, 1.07-4.29) and reoperation (OR, 2.09; 95% CI, 1.26-3.47). Model performance was slightly better for nearly all outcomes with complexity adjustment (mortality c-statistics: standard model, 0.853; secondary procedure model, 0.858; RVU model, 0.855). Hospital ranking did not change substantially after complexity adjustment. Surgical complexity variables are associated with adverse outcomes in gastrectomy, but complexity adjustment does not affect hospital rankings appreciably.


Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures.
Long QT syndrome (LQTS) is characterized by corrected QT interval prolongation leading to torsades de pointes and sudden cardiac death. LQTS type 2 (LQTS2) is caused by mutations in the KCNH2 gene, leading to a reduction of the rapidly activating delayed rectifier K+ current and loss of human ether-à-go-go-related gene (hERG) channel function by different mechanisms. Triggers for life-threatening arrhythmias in LQTS2 are often auditory stimuli. To screen KCNH2 for mutations in patients with LQTS2 on an electrocardiogram and auditory-induced syncope interpreted as seizures and sudden cardiac death, and to analyze their impact on the channel function in vitro. The KCNH2 gene was screened for mutations in the index patients of three families. The novel mutations were reproduced in vitro using site-directed mutagenesis and characterized using the Xenopus oocyte expression system in voltage clamp mode. Novel KCNH2 mutations (Y493F, A429P and del234-241) were identified in the index patients with mostly typical LQTS2 features on their electrocardiograms. The biochemical data revealed a trafficking defect. The biophysical data revealed a loss of function when mutated hERG channels were coexpressed with the wild type. In all families, at least one patient carrying the mutation had a history of seizures after auditory stimuli, which is a major trigger for arrhythmic events in LQTS2. Seizures are likely due to cardiac syncope as a consequence of mutation-induced loss of function of the rapidly activating delayed rectifier K+ current.


Secretory IgA in complex with Lactobacillus rhamnosus potentiates mucosal dendritic cell-mediated Treg cell differentiation via TLR regulatory proteins, RALDH2 and secretion of IL-10 and TGF-β.
The importance of secretory IgA in controlling the microbiota is well known, yet how the antibody affects the perception of the commensals by the local immune system is still poorly defined. We have previously shown that the transport of secretory IgA in complex with bacteria across intestinal microfold cells results in an association with dendritic cells in Peyer's patches. However, the consequences of such an interaction on dendritic cell conditioning have not been elucidated. In this study, we analyzed the impact of the commensal Lactobacillus rhamnosus, alone or associated with secretory IgA, on the responsiveness of dendritic cells freshly recovered from mouse Peyer's patches, mesenteric lymph nodes, and spleen. Lactobacillus rhamnosus-conditioned mucosal dendritic cells are characterized by increased expression of Toll-like receptor regulatory proteins [including single immunoglobulin interleukin-1 receptor-related molecule, suppressor of cytokine signaling 1, and Toll-interacting molecule] and retinaldehyde dehydrogenase 2, low surface expression of co-stimulatory markers, high anti- versus pro-inflammatory cytokine production ratios, and induction of T regulatory cells with suppressive function. Association with secretory IgA enhanced the anti-inflammatory/regulatory Lactobacillus rhamnosus-induced conditioning of mucosal dendritic cells, particularly in Peyer's patches. At the systemic level, activation of splenic dendritic cells exposed to Lactobacillus rhamnosus was partially dampened upon association with secretory IgA. These data suggest that secretory IgA, through coating of commensal bacteria, contributes to the conditioning of mucosal dendritic cells toward tolerogenic profiles essential for the maintenance of intestinal homeostasis.


Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis.
Coccidioidal meningitis is a devastating disease that requires long-term therapy with little hope of cure. A rabbit model of coccidioidal meningitis was used to compare the therapeutic efficacies of fluconazole (FCZ) and itraconazole (ITZ). Hydrocortisone-treated male New Zealand white rabbits were infected intracisternally with 5.0x10(4) to 5.4x10(4) arthroconidia of Coccidioides immitis. Oral treatment with polyethylene glycol 200 (PEG) (n = 9), FCZ (n = 8; 80 mg/kg of body weight/day), or ITZ (n = 8; 80 mg/kg/day) began 5 days after infection and continued for 28 consecutive days. Both FCZ and ITZ reduced the number of CFU of C. immitis organisms in the spinal cord and brain compared with the number in PEG-treated animals (P< or =0.003), but the results for FCZ and ITZ were not different from each other. Histopathologic severity (semiquantitative scoring system by an observer blinded to treatment) was equally reduced in both FCZ and ITZ treatment groups compared with that in controls (P< or =0.0004). Both treatments resulted in lower cerebrospinal fluid (CSF) protein concentrations and leukocyte counts and faster clearing of C. immitis from CSF compared with the results for PEG-treated controls. Neither drug affected CSF glucose levels. Both compounds were effective at reducing neurological and systemic signs and extending survival (P< or =0.014). FCZ was more effective at reducing head and body shakes, posture changes, and incontinence; ITZ was more effective at reducing continuous fever. Mean levels of FCZ and ITZ in the serum and CSF were determined by bioassay; at 17 to 26 h postdosing, levels were 28.1 to 40.0 and 22.4 to 29.9 microg/ml, respectively, for FCZ and 0.77 to 2.51 and 0 microg/ml, respectively, for ITZ. The sera of most animals developed antibody to C. immitis, but azole treatment attenuated antibody development in CSF and its titer. In conclusion, both FCZ and ITZ were efficacious, but neither was curative in a rabbit model of coccidioidal meningitis.


Focus measurement with a simple pattern design.
The increasingly smaller depth of focus of advanced lithographic tools requires that the position of best focus be determined to ensure accuracy and efficiency. We present what we believe is a novel bar in bar that is drawn on a conventional chrome binary mask to translate focal errors into center-to-center shifts of outer and inner bars. An overlay measurement tool can easily measure this shift. A symmetrical center-to-center shift against best focus is created during defocus, and this shift can be well fitted by a second-order polynomial equation. Simply differentiating the fitted equation leads to an accurate and reliable focus value, with a maximum error of less than 0.05 microm. The proposed technique can also be employed to evaluate the tilt, field curvature, and astigmatism of advanced lithographic tools.


Primacy of spatial information in guiding target selection for pursuit and saccades.
Previous studies have examined the facilitative effects of prior spatial information on target selection for saccadic eye movements. More recently, studies have shown that prior spatial information also influences target selection for smooth pursuit. However, direct comparisons of the effects of prior information on target selection for pursuit and saccades have not been made. To this end, we provided different classes of prior information and measured their effects on target selection for pursuit and saccades. In Experiment 1, we assessed the relative effects of spatial cues (indicating the target stimulus' initial location) and color cues (indicating the target stimulus' color) on eye movement latencies. In Experiment 2, we assessed the effects of motion cues (indicating the target stimulus' direction of motion) in addition to spatial cues. For both pursuit and saccades, we found that spatial cues reduced eye movement latencies more than color cues (Experiment 1). Spatial cues also reduced eye movement latencies more than motion cues (Experiment 2), even for pursuit, despite the fact that stimulus motion is essential for the generation of pursuit eye movements. These results indicate that both pursuit and saccades are affected to a greater degree by spatial information than motion or color information. We suggest that the primacy of spatial information for both pursuit and saccades reflects the importance of spatial attention in selecting the stimulus target for both eye movements.


The use of heparin in patients in whom a pulmonary embolism is suspected after total hip arthroplasty.
The morbidity and mortality associated with pulmonary embolism are well known, as is the benefit of the use of heparin in patients who have a pulmonary embolism. However, the patterns of heparin use as well as its undesirable effects, especially in patients who have recently had a total hip arthroplasty, have been less well studied. Thus, concern arises regarding the use of heparin in patients who have no firm evidence of a pulmonary embolism. The purpose of the current study was to track the use of heparin and associated orthopaedic complications in patients in whom a pulmonary embolism was suspected after a total hip arthroplasty. The records of 150 patients in whom a pulmonary embolism had been suspected after a total hip arthroplasty were reviewed retrospectively. The rates of individual complications (such as stroke, infection, and hematoma) and those of groups of complications (such as medical complications, orthopaedic complications, and all complications combined) were recorded and then were stratified according to the treatment (with or without heparin), the presence or absence of pulmonary embolism, and other variables. Thirty-two (47 percent) of sixty-eight patients who were managed with heparin had complications compared with sixteen (20 percent) of eighty-two patients who were not thus managed (p = 0.0006). Specifically, patients who were managed with heparin were more likely to have gastrointestinal bleeding, hematological complications, a loose prosthesis, a hematoma, or an early revision arthroplasty (p<0.05 for all). With the numbers available, the use of heparin was not found to be significantly associated with an increased risk of death, stroke, or infection at the site of the prosthesis. Interestingly, thirty-one (31 percent) of ninety-nine patients who had ventilation-perfusion scans that demonstrated normal findings or findings indicating a low probability of pulmonary embolism were given heparin before the diagnosis of a pulmonary embolism was excluded, and sixteen (52 percent) of these thirty-one had complications. Given this risk profile, we advise against the use of heparin before the diagnosis of pulmonary embolism is established in patients who have had a total hip arthroplasty. This recommendation is supported by algorithms, in widely read medical texts, pertaining to the use of heparin in patients in whom a pulmonary embolism is suspected.


Multiple VH gene segments encode murine antistreptococcal antibodies.
Most mouse strains are able to mount a diverse antibody response against group A streptococcal carbohydrate (GAC). We have previously reported that murine anti-GAC antibodies are for the most part restricted to IgM and IgG3 subclasses. In addition, despite extensive heterogeneity in their isoelectric focusing patterns, greater than 50% of A/J anti-GAC antibodies share a common light chain defined by spectrotypic and idiotypic (VK1GAC) criteria. We have used protein and DNA sequencing strategies to examine the genetic basis of diversity in murine anti-GAC antibodies. In particular, we report that, (a) multiple, closely homologous VH gene segments contribute to the generation of anti-GAC antibodies, (b) a common framework sequence, related to the VK27 subgroup, probably defines VK1GAC, and (c) the A/J anti-GAC VH regions and BALB/c anti-inulin VH sequences are 95% homologous at the protein level and are likely encoded by overlapping VH gene families. Lastly, we discuss the genetic mechanisms that might permit the evolution of multiple, closely homologous germline VH gene segments in the context of highly divergent flanking region sequences.


A Deep Learning Model for Screening Multiple Abnormal Findings in Ophthalmic Ultrasonography (With Video).
The purpose of this study was to construct a deep learning system for rapidly and accurately screening retinal detachment (RD), vitreous detachment (VD), and vitreous hemorrhage (VH) in ophthalmic ultrasound in real time. We used a deep convolutional neural network to develop a deep learning system to screen multiple abnormal findings in ophthalmic ultrasonography with 3580 images for classification and 941 images for segmentation. Sixty-two videos were used as the test dataset in real time. External data containing 598 images were also used for validation. Another 155 images were collected to compare the performance of the model to experts. In addition, a study was conducted to assess the effect of the model in improving lesions recognition of the trainees. The model achieved 0.94, 0.90, 0.92, 0.94, and 0.91 accuracy in recognizing normal, VD, VH, RD, and other lesions. Compared with the ophthalmologists, the modal achieved a 0.73 accuracy in classifying RD, VD, and VH, which has a better performance than most experts (P < 0.05). In the videos, the model had a 0.81 accuracy. With the model assistant, the accuracy of the trainees improved from 0.84 to 0.94. The model could serve as a screening tool to rapidly identify patients with RD, VD, and VH. In addition, it also has potential to be a good tool to assist training. We developed a deep learning model to make the ultrasound work more accurately and efficiently.


Antibiofilm polysaccharides.
Bacterial extracellular polysaccharides have been shown to mediate many of the cell-to-cell and cell-to-surface interactions that are required for the formation, cohesion and stabilization of bacterial biofilms. However, recent studies have identified several bacterial polysaccharides that inhibit biofilm formation by a wide spectrum of bacteria and fungi both in vitro and in vivo. This review discusses the composition, modes of action and potential biological roles of antibiofilm polysaccharides recently identified in bacteria and eukarya. Some of these molecules may have technological applications as antibiofilm agents in industry and medicine.


Is there an association between coronary atherosclerosis and carcinoma of the prostate in men aged 50 years and older? An autopsy and coroner based post-mortem study.
Atherosclerotic disease is the most common cause of death in the United States and prostate cancer has the highest incidence among males in the United States. Reports have indicated that atherosclerosis and cancers my share common pathoetiologic and pathogenetic cascades. If atherosclerosis and cancers have common pathoetiologic and pathogenetic cascades, both diseases will co-occur and patients may represent a potential target group for cancer screening interventions. Prostates and coronary vessels were examined from 37 deceased men, aged 50 years and older, who died unexpectedly and suddenly from traumatic causes. Tissue sections of the entire prostate were examined for benign and malignant lesions. Analysis of Variance was used to compare mean coronary artery atherosclerosis scores among groups of men with diagnosis of adenocarcinoma, intraepithelial neoplasm, benign hyperplasia and normal prostate glands. Twelve prostates (32.5%) showed adenocarcinoma of the prostate, four with Gleason score 7 and eight with Gleason score 6. After adjustment for age and race, there remained no statistical difference between prostate pathology groups and atherosclerosis score (F = 0.72; P = 0.55). To our knowledge, ours is the first study to use direct pathological examination of tissues for definitive identification of atherosclerosis and prostate cancer. In our case series, the occurrence and progression of coronary atherosclerotic disease and cancer of the prostate were not associated.


Transcriptional and post-transcriptional regulation of ribulose 1,5-bisphosphate carboxylase gene expression in light- and dark-grown amaranth cotyledons.
The regulation of expression of the genes encoding the large subunit (LSU) and small subunit (SSU) of ribulose 1,5-bisphosphate carboxylase (RuBPCase) was examined in 1- through 8-day-old, dark-grown (etiolated) and light-grown amaranth cotyledons. RuBPCase specific activity in light-grown cotyledons increased during this 8-day period to a level 15-fold higher than in dark-grown cotyledons. Under both growth conditions, the accumulation of the LSU and SSU polypeptides was not coordinated. Initial detection of the SSU occurred 1 and 2 days after the appearance of the LSU in light- and dark-grown cotyledons, respectively. Furthermore, although the levels of the LSU were similar in both light- and dark-grown seedlings, the amount of the SSU followed clearly the changes in enzyme activity. Synthesis of these two polypeptides was dramatically different in etiolated versus light-grown cotyledons. In light the synthesis of both subunits was first observed on day 2 and continued throughout the growth of the cotyledons. In darkness the rate of synthesis of both subunits was much lower than in light and occurred only as a burst between days 2 and 5 after planting. However, mRNAs for both subunits were present in etiolated cotyledons at similar levels on days 4 through 7 (by Northern analysis) and were functional in vitro, despite their apparent inactivity in vivo after day 5. In addition, since both LSU and SSU mRNA levels were lower in dark- than in light-grown seedlings, our results indicate that both transcriptional and post-transcriptional controls modulate RuBPCase production in developing amaranth cotyledons.


Familial Alzheimer's disease coding mutations reduce Presenilin-1 expression in a novel genomic locus reporter model.
We have generated a physiologically relevant bacterial artificial chromosome (BAC)-based genomic DNA expression model to study PS1 gene expression and function. The PS1-WT-BAC construct restored γ-secretase function, whereas the mutant PS1 BACs demonstrated partial to complete loss of enzymatic activity when stably expressed in a PS double knock-out clonal cell line. We then engineered WT and mutant human PS1-BAC-Luciferase whole genomic locus reporter transgenes, which we transiently transduced in mouse and human non-neuronal and neuronal-like cells, respectively. PS1 ΔE9 and C410Y FAD were found to lower PS1 gene expression in both cell lines, whereas PS1-M146V showed a neuron-specific effect. The nonclinical γ-secretase inactive PS1-D257A mutation did not alter gene expression in either cell line. This is the first time that pathogenic coding mutations in the PS1 gene have been shown to lower PS1 gene expression. These findings may represent a pathologic mechanism for PS1 FAD mutations independent of their effects on γ-secretase activity and demonstrate how dominant PS1 mutations may exert their pathogenic effects by a loss-of-function mechanism.


Glucocorticoid receptor-mediated repression of gonadotropin-releasing hormone promoter activity in GT1 hypothalamic cell lines.
The synthesis and release of GnRH within a specific subset of neurons in the hypothalamus, which serves as the primary drive to the hypothalamic-pituitary-gonadal (HPG) axis, is subject to various levels of control. Although a number of direct synaptic connections to GnRH-containing neurons have been identified, which presumably provide some regulatory inputs, the mechanisms responsible for hormonal regulation of GnRH synthesis and release mediated by either cell surface or intracellular receptors remain controversial. The recent demonstration that a subset of GnRH-containing neurons in the rat hypothalamus possesses immunoreactive glucocorticoid receptors (GR) implies that this class of steroid hormones could exert a direct effect to regulate the functioning of these neurons and perhaps the HPG axis. We used the GT1-3 and GT1-7 cell lines of immortalized GnRH-secreting hypothalamic neurons as a model to study the direct effects of glucocorticoids on GnRH gene expression. We demonstrated that these cell lines possess GR that bind the synthetic glucocorticoid, dexamethasone, in vitro with high affinity (Kd = 2-3 nM). These receptors are functional, as indicated by their ability to activate transcription from exogenously introduced heterologous glucocorticoid-responsive promoters. Furthermore, dexamethasone represses both the endogenous mouse GnRH gene, decreasing steady state levels of GnRH mRNA, and the transcriptional activity of transfected rat GnRH promoter-reporter gene vectors. Glucocorticoid repression of rat GnRH promoter activity appears to be mediated by sequences contained within the promoter proximal 459 basepairs and not be influenced by the relative basal activity of the GnRH promoter. Thus, our results provide the first direct demonstration of glucocorticoid repression of transcription in a hypothalamic cell line and suggest that GR acting directly within GnRH neurons could be at least partly responsible for negative regulation of the HPG axis by glucocorticoids.


The humanistic burden of postpartum depression: a systematic literature review.
Postpartum depression (PPD) is the most common medical complication of childbirth. PPD can be disabling, with potential negative effects on maternal health-related quality-of-life (HRQoL) as well as on children and partners. The objective of this study was to systematically review and summarize recently published literature describing the humanistic burden of PPD on affected women, their children, and partners. Databases including Embase, MEDLINE, and PsycINFO, as well as conference proceedings were searched for keywords related to PPD. Searches were initially conducted in February 2017 and restricted to the prior 5 years for databases and the prior 2 years for conference proceedings. Searches were updated in February 2018. Two researchers independently reviewed 1154 unique records according to pre-defined inclusion and exclusion screening criteria. Forty-eight studies were identified; over 40 studies assessed the effects of PPD on children of affected mothers, with many demonstrating a negative association with elements of parenting and childhood development. Furthermore, five studies that evaluated the effects of PPD symptoms on partners suggested that certain aspects of their relationships were negatively affected. Partners of affected women also experienced greater levels of their own stress, anxiety, and depression compared with partners of women without PPD symptoms. Despite limited data on HRQoL among women with PPD symptoms (four studies), a negative impact on physical and mental sub-scales was observed. Findings suggest that PPD symptoms have a substantial humanistic burden on affected mothers as well as on their children and partners.


Simulation models of obesity: a review of the literature and implications for research and policy.
Simulation models (SMs) combine information from a variety of sources to provide a useful tool for examining how the effects of obesity unfold over time and impact population health. SMs can aid in the understanding of the complex interaction of the drivers of diet and activity and their relation to health outcomes. As emphasized in a recently released report of the Institute or Medicine, SMs can be especially useful for considering the potential impact of an array of policies that will be required to tackle the obesity problem. The purpose of this paper is to present an overview of existing SMs for obesity. First, a background section introduces the different types of models, explains how models are constructed, shows the utility of SMs and discusses their strengths and weaknesses. Using these typologies, we then briefly review extant obesity SMs. We categorize these models according to their focus: health and economic outcomes, trends in obesity as a function of past trends, physiologically based behavioural models, environmental contributors to obesity and policy interventions. Finally, we suggest directions for future research.


Molecular research in penile cancer-lessons learned from the past and bright horizons of the future?
Penile cancer is a rare tumor. There is a limited understanding of the biological mediators of prognostic and therapeutic importance in penile cancer. However, there exists some fundamental understanding of the major pathways involved in the development of penile pre-neoplastic lesions and neoplasms. The aim of the present review is to highlight our current state of molecular knowledge in penile cancer to foster the necessary tools for researchers to pave major advancements in our current treatment paradigms and cancer specific outcomes.


Texture segmentation in Williams syndrome.
Williams syndrome (WS) is a developmental disorder in which visuo-spatial cognition is poor relative to verbal ability. At the level of visuo-spatial perception, individuals with WS can perceive both the local and global aspects of an image. However, the manner in which local elements are integrated into a global whole is atypical, with relative strengths in integration by luminance, closure, and alignment compared to shape, orientation and proximity. The present study investigated the manner in which global images are segmented into local parts. Segmentation by seven gestalt principles was investigated: proximity, shape, luminance, orientation, closure, size (and alignment: Experiment 1 only). Participants were presented with uniform texture squares and asked to detect the presence of a discrepant patch (Experiment 1) or to identify the form of a discrepant patch as a capital E or H (Experiment 2). In Experiment 1, the pattern and level of performance of the WS group did not differ from that of typically developing controls, and was commensurate with the general level of non-verbal ability observed in WS. These results were replicated in Experiment 2, with the exception of segmentation by proximity, where individuals with WS demonstrated superior performance relative to the remaining segmentation types. Overall, the results suggest that, despite some atypical aspects of visuo-spatial perception in WS, the ability to segment a global form into parts is broadly typical in this population. In turn, this informs predictions of brain function in WS, particularly areas V1 and V4.


Ciprofloxacin-induced bone marrow depression.
Ciprofloxacin, a broad-spectrum fluoroquinolone antibacterial agent, is generally considered to be a safe drug. However, occasionally it may have life-threatening complications. Two instances of bone marrow failure following use of ciprofloxacin are reported. In one case, the bone marrow reverted to normal following withdrawal of the drug. In the other case, the patient succumbed to irreversible bone marrow depression leading to severe thrombocytopenia and uncontrolled bleeding. This could have been an idiosyncratic reaction.


Transcription-associated R-loop formation across the human FMR1 CGG-repeat region.
Expansion of a trinucleotide (CGG) repeat element within the 5' untranslated region (5'UTR) of the human FMR1 gene is responsible for a number of heritable disorders operating through distinct pathogenic mechanisms: gene silencing for fragile X syndrome (>200 CGG) and RNA toxic gain-of-function for FXTAS (∼ 55-200 CGG). Existing models have focused almost exclusively on post-transcriptional mechanisms, but co-transcriptional processes could also contribute to the molecular dysfunction of FMR1. We have observed that transcription through the GC-rich FMR1 5'UTR region favors R-loop formation, with the nascent (G-rich) RNA forming a stable RNA:DNA hybrid with the template DNA strand, thereby displacing the non-template DNA strand. Using DNA:RNA (hybrid) immunoprecipitation (DRIP) of genomic DNA from cultured human dermal fibroblasts with both normal (∼ 30 CGG repeats) and premutation (55<CGG<200 repeats) alleles, we provide evidence for FMR1 R-loop formation in human genomic DNA. Using a doxycycline (DOX)-inducible episomal system in which both the CGG-repeat and transcription frequency can be varied, we further show that R-loop formation increases with higher expression levels. Finally, non-denaturing bisulfite mapping of the displaced single-stranded DNA confirmed R-loop formation at the endogenous FMR1 locus and further indicated that R-loops formed over CGG repeats may be prone to structural complexities, including hairpin formation, not commonly associated with other R-loops. These observations introduce a new molecular feature of the FMR1 gene that is directly affected by CGG-repeat expansion and is likely to be involved in the associated cellular dysfunction.


Systematic analysis and functional annotation of variations in the genome of an Indian individual.
Whole genome sequencing of personal genomes has revealed a large repertoire of genomic variations and has provided a rich template for identification of common and rare variants in genomes in addition to understanding the genetic basis of diseases. The widespread application of personal genome sequencing in clinical settings for predictive and preventive medicine has been limited due to the lack of comprehensive computational analysis pipelines. We have used next-generation sequencing technology to sequence the whole genome of a self-declared healthy male of Indian origin. We have generated around 28X of the reference human genome with over 99% coverage. Analysis revealed over 3 million single nucleotide variations and about 490,000 small insertion-deletion events including several novel variants. Using this dataset as a template, we designed a comprehensive computational analysis pipeline for the systematic analysis and annotation of functionally relevant variants in the genome. This study follows a systematic and intuitive data analysis workflow to annotate genome variations and its potential functional effects. Moreover, we integrate predictive analysis of pharmacogenomic traits with emphasis on drugs for which pharmacogenomic testing has been recommended. This study thus provides the template for genome-scale analysis of personal genomes for personalized medicine.


Indoor air quality in California homes with code-required mechanical ventilation.
Data were collected in 70 detached houses built in 2011-2017 in compliance with the mechanical ventilation requirements of California's building energy efficiency standards. Each home was monitored for a 1-week period with windows closed and the central mechanical ventilation system operating. Pollutant measurements included time-resolved fine particulate matter (PM2.5 ) indoors and outdoors and formaldehyde and carbon dioxide (CO2 ) indoors. Time-integrated measurements were made for formaldehyde, NO2 , and nitrogen oxides (NOX ) indoors and outdoors. Operation of the cooktop, range hood, and other exhaust fans was continuously recorded during the monitoring period. Onetime diagnostic measurements included mechanical airflows and envelope and duct system air leakage. All homes met or were very close to meeting the ventilation requirements. On average, the dwelling unit ventilation fan moved 50% more airflow than the minimum requirement. Pollutant concentrations were similar to or lower than those reported in a 2006-2007 study of California new homes built in 2002-2005. Mean and median indoor concentrations were lower by 44% and 38% for formaldehyde and 44% and 54% for PM2.5 . Ventilation fans were operating in only 26% of homes when first visited, and the control switches in many homes did not have informative labels as required by building standards.


Observational insights into aerosol formation from isoprene.
Atmospheric photooxidation of isoprene is an important source of secondary organic aerosol (SOA) and there is increasing evidence that anthropogenic oxidant emissions can enhance this SOA formation. In this work, we use ambient observations of organosulfates formed from isoprene epoxydiols (IEPOX) and methacrylic acid epoxide (MAE) and a broad suite of chemical measurements to investigate the relative importance of nitrogen oxide (NO/NO2) and hydroperoxyl (HO2) SOA formation pathways from isoprene at a forested site in California. In contrast to IEPOX, the calculated production rate of MAE was observed to be independent of temperature. This is the result of the very fast thermolysis of MPAN at high temperatures that affects the distribution of the MPAN reservoir (MPAN / MPA radical) reducing the fraction that can react with OH to form MAE and subsequently SOA (F(MAE formation)). The strong temperature dependence of F(MAE formation) helps to explain our observations of similar concentrations of IEPOX-derived organosulfates (IEPOX-OS; ~1 ng m(-3)) and MAE-derived organosulfates (MAE-OS; ~1 ng m(-3)) under cooler conditions (lower isoprene concentrations) and much higher IEPOX-OS (~20 ng m(-3)) relative to MAE-OS (<0.0005 ng m(-3)) at higher temperatures (higher isoprene concentrations). A kinetic model of IEPOX and MAE loss showed that MAE forms 10-100 times more ring-opening products than IEPOX and that both are strongly dependent on aerosol water content when aerosol pH is constant. However, the higher fraction of MAE ring opening products does not compensate for the lower MAE production under warmer conditions (higher isoprene concentrations) resulting in lower formation of MAE-derived products relative to IEPOX at the surface. In regions of high NOx, high isoprene emissions and strong vertical mixing the slower MPAN thermolysis rate aloft could increase the fraction of MPAN that forms MAE resulting in a vertically varying isoprene SOA source.


Quantitative Analysis and Classification of the Nasal Base Using a Parametric Model.
The nasal base view is often overlooked in rhinoplasty analysis and, unlike lateral and frontal views, lacks detailed quantitative analysis and descriptors. While shape-category analysis of the nasal base is well established, these descriptive methods remain subjective and do not facilitate quantitative analysis. To establish a simple and quantitative classification scheme using a multiple-parameter numerical model for analyzing and describing the shape of the nasal base. Deidentified photographs of the nasal base view were analyzed without knowledge of patients' pathology or medical history. Each nose was classified into 1 of 6 categories derived from literature (equilateral, narrow, flat, cloverleaf, boxy, and round). Finite parametric modeling was performed on each nose, and the correlations between the resulting parameters and the 6 categories were analyzed. Photographs for this study were acquired from the practice of a single facial plastic surgeon (B.J.F.W.) at a tertiary care academic medical center. One hundred twenty-one consecutive patients who had nasal base view photographs taken were included in the study. All of the 121 images were classified into 1 of the 6 categories by 1 reviewer (C.H.B.). The contour of each nasal base was curve fit to a 5-parameter numerical model. The 5 parameters controlled base size, deviation from the midline, projection-to-width ratio, degree of nasal alar recurvature, and anterior-posterior positioning of nasal base bulk. A numerical value for each nasal base shape type was predicted by the parametric model. In 121 patient photographs, the parametric model generated shapes that accurately matched the tracing of the actual nasal base contours with an average correlation coefficient of greater than 0.98. This finding indicates close approximation of the nasal base shape with the curve fit constructed by the PM. Parameters b (projection-to-width ratio) and e (roundedness) were shown to have significant differences among the groups (F statistic, 8.88; P < .001 and F statistic, 13.05; P < .001, respectively). These two curve-fit parameters alone could be used to classify nasal shape into 1 of the 6 clinically determined base geometries. A numerical approach to classify nasal base shape was developed using a 5-parameter model and tested against subjective analysis. This model may aid in the advancement of algorithm-driven objective nasal analysis techniques, preoperative modeling, intraoperative guidance, and surgical outcome measures beyond using Likert scales. NA.


Molecular genetics of clear-cell renal cell carcinoma.
Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies.


Pathophysiology and clinical implications of microbubbles during hemodialysis.
Microbubbles have been detected in the human circulation of end-stage renal disease patients who are treated by hemodialysis throughout the past decade as a result of advanced ultrasound and Doppler technology. These detection tools uncovered signals of microbubbles, which originate in extracorporeal lines and tubing of hemodialysis machine, circulate in the blood stream until lodging in the capillary bed of various organs, mainly the lungs. During its course within the capillary, a bubble abrades the glycocalyx layer lining the surface of the vessels and thereafter obstructs blood flow through the capillary. This causes tissue ischemia, inflammatory response, and complement activation. Aggregation of platelets and clot formation occurs as well, leading to further obstruction of the microcirculation and subsequent tissue damage. In this review, we describe the biological and clinical effects of microbubbles during hemodialysis and discuss management with regard to prevention and treatment.


Vinegar intake reduces body weight, body fat mass, and serum triglyceride levels in obese Japanese subjects.
Acetic acid (AcOH), a main component of vinegar, recently was found to suppress body fat accumulation in animal studies. Hence we investigated the effects of vinegar intake on the reduction of body fat mass in obese Japanese in a double-blind trial. The subjects were randomly assigned to three groups of similar body weight, body mass index (BMI), and waist circumference. During the 12-week treatment period, the subjects in each group ingested 500 ml daily of a beverage containing either 15 ml of vinegar (750 mg AcOH), 30 ml of vinegar (1,500 mg AcOH), or 0 ml of vinegar (0 mg AcOH, placebo). Body weight, BMI, visceral fat area, waist circumference, and serum triglyceride levels were significantly lower in both vinegar intake groups than in the placebo group. In conclusion, daily intake of vinegar might be useful in the prevention of metabolic syndrome by reducing obesity.


[Quality of life in Chilean breast cancer survivors].
Quality of Life (QOL) assessment may evaluate the impact of diseases and their treatment on the overall well-being of patients. To assess QOL in Chilean breast cancer survivors. Ninety one female breast cancer patients aged 60 ± 10 years, who finished their oncologic treatment at least a year prior to the assessment, who were disease free and in medical follow-up were included in the study. They completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 core questionnaire and the breast cancer module QLQ-BR23. Forty eight percent of respondents were long term survivors (more than five years). Global QOL scores were high (73.6 ± 18.2), emotional scale had the lowest scores in QLQ-C30 functional scales (72.1). Symptoms with the highest scores were: Insomnia (= 21.2), pain (= 20.8), and fatigue (= 19.1). Body image, sexual function, and concern about the future were the most relevant problems. Body image was superior in patients with breast-conserving surgery (p = 0.008), and cognitive function was better in patients in early disease stage (p = 0.03) and in those with more than five years of survival (p = 0.04). Even when global QOL scores were high, some symptoms were prevalent. Awareness about these problems and symptoms should improve their diagnosis and treatment.


Police-related experiences and HIV risk among female sex workers in Andhra Pradesh, India.
Research suggests experiences with police are related to human immunodeficiency virus (HIV) sexual risk among women working as sex workers. However, little is known about the links between specific police-related behaviors and HIV vulnerability. We examine whether 5 police-related experiences are associated with measures of HIV risk and violence among a sample of female sex workers (FSWs) in Andhra Pradesh, India, and consider the implications for HIV prevention. FSWs at least 18 years of age (n = 835) were recruited through respondent-driven sampling for a cross-sectional survey conducted as part of Avahan, the India AIDS Initiative. Using logistic regression models adjusted for age, age at start of sex work, and sex work venue, we assessed police-related experiences reported by FSWs in relation to HIV risk behaviors and violence. Results showed having sex with police to avoid trouble, giving gifts to police to avoid trouble, having police take condoms away, experiencing a workplace raid, and being arrested were associated with sexually transmitted infection symptoms, inconsistent condom use, acceptance of more money for sex without a condom, and experience of client violence. These findings suggest a need for interventions targeting police-FSW interactions to reduce HIV vulnerability among FSWs.


Scrub typhus-associated acute kidney injury: A study from a South Indian Tertiary Care Hospital.
Infections including scrub typhus contribute to a significant proportion of community-acquired acute kidney injury (AKI) in the tropics. Scrub typhus infection now requires global attention since disease outbreaks are being reported across continents. We intended to study the clinical profile, renal involvement, and parameters predicting renal involvement in scrub typhus infection. This is a retrospective study. The medical records of all patients who were admitted and treated for scrub typhus infection for a study period of two years (from September 2015 to August 2017) were analyzed, and salient clinical features and laboratory results were collected from the hospital data. Statistical analysis was done from the collected data. Our study had 272 patients including 81 children. Adults constituted 70.96% (n = 193) and the remaining 29.04% (n = 81) were pediatric population. Among adults, females constituted 62.7% (n = 121) and males 37.3% (n = 72). The mean age of the adult population was 45.7 ± 15 years and that of pediatric patients was 8.56 ±5.1 years. 18.7% of adult cases and 3.70% of pediatric cases had AKI. Renal replacement therapy was required in 3.67% of adult cases. Mortality was 4.14% in adults and 1.23% in children. Hypotension, pulmonary involvement, central nervous system involvement, multiorgan dysfunction syndrome, increased total counts, elevated aspartate transaminase levels, and hypoalbuminemia predicted AKI in our adult population. Scrub typhus should be considered as a differential in cases presenting with fever and AKI. Outcomes of scrub typhus infection in terms of mortality seem to be improving in this region.


On the theory of ion transport across the nerve membrane, VII. Cooperativity between channels of a large square lattice.
The exact kinetics of a 10 x 10 Ising system (periodic boundary conditions) with two-state channels arranged in a square lattice was studied by computer simulation. With all three values of the cooperativity parameter used, no induction in the K(+)-current curve was obtained. This confirms one of our previous conclusions concerning K(+) channels in the squid axon membrane: models with interacting channels arranged in a twodimensional lattice (Adam's model) are apparently excluded. Other topics included: equilibrium properties; short-range pair correlation functions; phase transition.


The organization of foraging in the fire ant, Solenopsis invicta.
Although natural selection in ants acts most strongly at the colony, or superorganismal level, foraging patterns have rarely been studied at that level, focusing instead on the behavior of individual foragers or groups of foragers. The experiments and observations in this paper reveal in broad strokes how colonies of the fire ant, Solenopsis invicta Buren (Hymenoptera: Formicidae), allocate their available labor to foraging, how they disperse that force within their territory, and how this force changes with colony size, season and worker age. Territory area is positively related to colony size and the number of foragers, more so during the spring than fall. Changes of colony size and territory area are driven by seasonal variation of sexual and worker production, which in turn drive seasonal variation of worker age-distribution. During spring sexual production, colonies shrink because worker production falls below replacement. This loss is proportional to colony size, causing forager density in the spring to be negatively related to colony and territory size. In the fall, colonies emphasize worker production, bringing colony size back up. However, because smaller colonies curtailed spring worker production less than larger ones, their fall forager populations are proportionally greater, causing them to gain territory at the expense of large colonies. Much variation of territory area remains unexplained and can probably be attributed to pressure from neighboring colonies. Boundaries between territories are characterized by "no ants' zones" mostly devoid of fire ants. The forager population can be divided into a younger group of recruitable workers that wait for scouts to activate them to help retrieve large food finds. About one-third of the recruits wait near openings in the foraging tunnels that underlie the entire territory, while two-thirds wait in the nest. Recruitment to food is initially very rapid and local from the foraging tunnels, while sustained recruitment gradually involves the recruits waiting in the nest. As recruits age, they become scouts searching for food on the surface, and die about two weeks later. Foraging tunnels decrease in cross-sectional area with distance from the nest, in keeping with the gradual bleeding off of workers to the surface with distance. Foragers lack route-faithfulness, and having been marked and released at one point within the territory, they can be recaptured at any other point a day later. The size of the territory actually occupied may be limited during dry weather, resulting in very large no-ants' zones.


Fully implicit parallel simulation of single neurons.
When a multi-compartment neuron is divided into subtrees such that no subtree has more than two connection points to other subtrees, the subtrees can be on different processors and the entire system remains amenable to direct Gaussian elimination with only a modest increase in complexity. Accuracy is the same as with standard Gaussian elimination on a single processor. It is often feasible to divide a 3-D reconstructed neuron model onto a dozen or so processors and experience almost linear speedup. We have also used the method for purposes of load balance in network simulations when some cells are so large that their individual computation time is much longer than the average processor computation time or when there are many more processors than cells. The method is available in the standard distribution of the NEURON simulation program.


Aortic Annulus Stabilization Technique for Rapid Deployment Aortic Valve Replacement.
Rapid deployment aortic valve replacement (RDAVR) with the use of rapid deployment valve systems represents a smart alternative to the use of standard aortic bioprosthesis for aortic valve replacement. Nevertheless, its use is still debatable in patients with pure aortic valve regurgitation or true bicuspid aortic valve because of the risk of postoperative paravalvular leak. To address this issue, an optimal annulus-valve size match seems to be the ideal surgical strategy. This article describes a new technique developed to stabilize the aortic annulus and prevent paravalvular leak after RDAVR. To confirm the feasibility, this technique was performed in six patients with severe symptomatic aortic stenosis who were scheduled to undergo aortic valve replacement at our center. All patients survived surgery and were discharged from the hospital. There were no new intracardiac conduction system disturbances observed, and a permanent pacemaker implantation was not required in any of the patients. The intraoperative and postoperative echocardiogram confirmed successful positioning of the valve, and no paravalvular leak was observed. In this preliminary experience, RDAVR through a full sternotomy or an upper hemisternotomy approach with the use of aortic annulus stabilization technique was safe, and no leak was observed. Future studies on large series of patients are necessary to confirm the safety and effectiveness of this technique in preventing paravalvular leak in patients with true bicuspid aortic valves or pure aortic regurgitation.


Overlapping sequential pulses. A new waveform for transthoracic defibrillation.
A directionally changing shock electrical vector could facilitate defibrillation by depolarizing myocytes with different orientations vis-à-vis the shock field. Such a changing vector can be achieved by a new waveform for transthoracic defibrillation: overlapping sequential pulses. Our purpose was to evaluate this waveform. Ventricular fibrillation was induced in closed-chest dogs. Single and overlapping truncated exponential waveform pulse shocks were then administered from self-adhesive chest electrodes. Single pulse (control) shocks were 7.5-millisecond duration, while the sequential overlapping pulse shocks, using two different pathways, consisted of two pulses, each 5.0-millisecond duration; the second pulse began 2.5 milliseconds after the start of the first pulse and ended 2.5 milliseconds after the end of the first pulse. Thus, the total duration of the sequential overlapping shock was 7.5 milliseconds. During the overlap phase (2.5 milliseconds), the electrical vector orientation is the summation of the individual vectors. Two different electrode placements and corresponding electrical vector orientations were studied: group 1 (n = 14), left lower chest to right upper chest (pulse 1), overlapped by right lower chest to left upper chest (pulse 2), with the sequence then reversed; and group 2 (n = 11), left chest to right chest (pulse 1) overlapped by dorsal (vertebral column) to ventral (sternum) (pulse 2) with the sequence then reversed. At voltages equivalent to energies of 50, 100, and 150 J, the sequential overlapping pulse shocks achieve higher success rates than the single pulse shocks: At the low energy, 50 J, single pulse shock success rates were 0% (group 2) and 14% (group 1), while the overlapping pulse shocks achieved success rates of 39% (group 2) and 55% (group 1) (P < .05). Similarly, at the highest energy tested, 150 J, single pulse shock success rates were 45% (group 2) and 61% (group 1), while the overlapping pulse shock success was 91% (group 2) and 95% (group 1) (P < .05). In a third group of dogs (n = 3), intracardiac plunge electrodes placed orthogonally in the septum showed that the orthogonal components of intracardiac voltage gradient change varied markedly during the three phases of the sequential overlapping shocks, demonstrating the changing direction of the net electrical vector as the shock proceeded. In a fourth group of dogs (n = 5), short-duration (2.5-millisecond) single pulse shocks were compared with longer 7.5-millisecond single pulse shocks and with the sequential overlapping pulse shocks, all at equivalent energies. Despite substantially higher current flow, the 2.5-millisecond-duration single pulse shocks were not more effective than 7.5-millisecond single pulse shocks, and both 2.5- and 7.5-millisecond duration single pulse shocks had markedly inferior success rates compared with the sequential overlapping pulse shocks. Sequential overlapping pulse shock waveforms facilitate defibrillation compared with single pulse shocks of the same total energy. This is due at least in part to the changing orientation of the electrical vector during the multiple pulse shock.


Primary affective disorder criteria and the endogenous-reactive distinction.
Seventy-six patients hospitalized during the course of one year with a depressive episode and without prior history of other psychiatric illness were evaluated retrospectively using the primary affective disorder criteria. Symptom ratings were made by two raters uninvolved in the treatment of the patient and blind to the discharge diagnosis, hospital course, and treatment response. The patients were designated "endogenous" or reactive" based on whether the depressive syndrome was autonomous or responsive to environmental changes. Ninety-two percent of the patients with endogenous depression and 45% of those with reactive depression met the criteria for definite primary affective disorder. We suggest that the primary affective disorder criteria define a heterogeneous group of patients with respect to the endogenous-reactive distinction. The value of criteria that would identify a homogeneous group with an endogenous depressive state is discussed. The primary affective disorder symptoms that did identify patients with endogenous depression were psychomotor change, self-reproach, and decreased concentration.