A gene-centered C. elegans protein-DNA interaction network provides a framework for functional predictions.
Transcription factors (TFs) play a central role in controlling spatiotemporal gene expression and the response to environmental cues. A comprehensive understanding of gene regulation requires integrating physical protein-DNA interactions (PDIs) with TF regulatory activity, expression patterns, and phenotypic data. Although great progress has been made in mapping PDIs using chromatin immunoprecipitation, these studies have only characterized ~10% of TFs in any metazoan species. The nematode C. elegans has been widely used to study gene regulation due to its compact genome with short regulatory sequences. Here, we delineated the largest gene-centered metazoan PDI network to date by examining interactions between 90% of C. elegans TFs and 15% of gene promoters. We used this network as a backbone to predict TF binding sites for 77 TFs, two-thirds of which are novel, as well as integrate gene expression, protein-protein interaction, and phenotypic data to predict regulatory and biological functions for multiple genes and TFs.


Antibodies and a cysteine-modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels.
1. KCNQ K(+) channels are thought to underlie the M current of neurons. To probe if the KCNQ2 and KCNQ3 subtypes underlie the M current of rat superior cervical ganglia (SCG) neurons and of hippocampus, we raised specific antibodies against them and also used the cysteine-alkylating agent N-ethylmaleimide (NEM) as an additional probe of subunit composition. 2. Tested on tsA-201 (tsA) cells transfected with cloned KCNQ1-5 subunits, our antibodies showed high affinity and selectivity for the appropriate subtype. The antibodies immunostained SCG neurons and hippocampal sections at levels similar to those for channels expressed in tsA cells, indicating that KCNQ2 and KCNQ3 are present in SCG and hippocampal neurons. Some hippocampal regions contained only KCNQ2 or KCNQ3 subunits, suggesting the presence of M currents produced by channels other than KCNQ2/3 heteromultimers. 3. We found that NEM augmented M currents in SCG neurons and KCNQ2/3 currents in tsA cells via strong voltage-independent and modest voltage-dependent actions. Expression of individual KCNQ subunits in tsA cells revealed voltage-independent augmentation of KCNQ2, but not KCNQ1 nor KCNQ3, currents by NEM indicating that this action on SCG M currents likely localizes to KCNQ2. Much of the voltage-independent action is lost after the C242T mutation in KCNQ2. 4. The correspondence of NEM effects on expressed KCNQ2/3 and SCG M currents, along with the antibody labelling, provide further evidence that KCNQ2 and KCNQ3 subunits strongly contribute to the M current of neurons. The site of NEM action may be important for treatment of diseases caused by under-expression of these channels.


Nails of newborns in monitoring drug exposure during pregnancy.
This project was developed to investigate the usefulness of newborn nails for monitoring in utero drug exposure. Cocaine, benzoylecgonine, morphine, methadone, caffeine, nicotine, and cotinine were determined in nail samples from the first 3 months of life of 25 newborns abandoned immediately after birth (group 1) and of 33 babies born at the local maternity hospital whose families were recruited on a voluntary basis (group 2). All substances were measured by gas chromatography-mass spectrometry (detection limit: 0.025 ng/mg). Moreover, analytical results were compared with mothers' self-reported habits when the information was available. In group 1, 12 nails were found positive for caffeine and 13 for both nicotine and cotinine. Six samples tested cocaine- (range, median: 0.14-0.25, 0.175 ng/mg) and benzoylecgonine-positive (range, median: 0.12-0.20, 0.165 ng/mg). Both nicotine and cocaine were always retrieved together with their main metabolite. Morphine was found in four samples (range, median: 0.10-0.15, 0.125 ng/mg), methadone in five samples (range, median: 0.12-0.26, 0.170 ng/mg) that were found negative for all other compounds. In group 2, two samples tested positive for methadone (0.16, 0.17 ng/mg). The mothers self-report of the use of coffee always corresponded to caffeine positivity in the newborn nails (n=6), whereas six samples tested positive for nicotine and/or cotinine with a non-smoking mother. Sixteen out of the 33 samples of group 2 tested negative for all compounds. In conclusion, for the first time, results showed that, once that sample collection problems are solved, nails of the first period of life can be a very interesting indicator of in utero drug exposure.


Drosophila SnoN modulates growth and patterning by antagonizing TGF-beta signalling.
Signalling by TGF-beta ligands through the Smad family of transcription factors is critical for developmental patterning and growth. Disruption of this pathway has been observed in various cancers. In vertebrates, members of the Ski/Sno protein family can act as negative regulators of TGF-beta signalling, interfering with the Smad machinery to inhibit the transcriptional output of this pathway. In some contexts ski/sno genes function as tumour suppressors, but they were originally identified as oncogenes, whose expression is up-regulated in many tumours. These growth regulatory effects and the normal physiological functions of Ski/Sno proteins have been proposed to result from changes in TGF-beta signalling. However, this model is controversial and may be over-simplified, because recent findings indicate that Ski/Sno proteins can affect other signalling pathways. To address this issue in an in vivo context, we have analyzed the function of the Drosophila Ski/Sno orthologue, SnoN. We found that SnoN inhibits growth when overexpressed, indicating a tumour suppressor role in flies. It can act in multiple tissues to selectively and cell autonomously antagonise signalling by TGF-beta ligands from both the BMP and Activin sub-families. By contrast, analysis of a snoN mutant indicates that the gene does not play a global role in TGF-beta-mediated functions, but specifically inhibits TGF-beta-induced wing vein formation. We propose that SnoN normally functions redundantly with other TGF-beta pathway antagonists to finely adjust signalling levels, but that it can behave as an extremely potent inhibitor of TGF-beta signalling when highly expressed, highlighting the significance of its deregulation in cancer cells.


Peer relationship and adolescent smartphone addiction: The mediating role of self-esteem and the moderating role of the need to belong.
Background and aims Adolescent smartphone addiction has received increased attention in recent years, and peer relationship has been found to be a protective factor in adolescent smartphone. However, little is known about the mediating and moderating mechanisms underlying this relation. The aim of this study was to investigate (a) the mediating role of self-esteem in the association between student-student relationship and smartphone addiction, and (b) the moderating role of the need to belong in the indirect relationship between student-student relationship and adolescent smartphone addiction. Methods This model was examined with 768 Chinese adolescents (mean age = 16.81 years, SD = 0.73); the participants completed measurements regarding student-student relationship, self-esteem, the need to belong, and smartphone addiction. Results The correlation analyses indicated that student-student relationship was significantly negatively associated with adolescent smartphone addiction, and the need to belong was significantly positively associated with adolescent smartphone addiction. Mediation analyses revealed that self-esteem partially mediated the link between student-student relationship and adolescent smartphone addiction. Moderated mediation further indicated that the mediated path was weaker for adolescents with lower levels of the need to belong. Discussion and conclusion High self-esteem could be a protective factor against smartphone addiction for adolescents with a strong need to belong as these students appeared to be at elevated risk of developing smartphone addiction.


Slight/mild sensorineural hearing loss in children.
The goal was to determine the prevalence and effects of slight/mild bilateral sensorineural hearing loss among children in elementary school. A cross-sectional, cluster-sample survey of 6581 children (response: 85%; grade 1: n = 3367; grade 5: n = 3214) in 89 schools in Melbourne, Australia, was performed. Slight/mild bilateral sensorineural hearing loss was defined as a low-frequency pure-tone average across 0.5, 1, and 2 kHz and/or a high-frequency pure-tone average across 3, 4, and 6 kHz of 16 to 40 dB hearing level in the better ear, with air/bone-conduction gaps of < 10 dB. Parents reported children's health-related quality of life and behavior. Each child with slight/mild bilateral sensorineural hearing loss, matched to 2 normally hearing children (low-frequency pure-tone average and high-frequency pure-tone average of < or = 15 dB hearing level in both ears), completed standardized assessments. Whole-sample comparisons were adjusted for type of school, grade level, and gender, and matched-sample comparisons were adjusted for nonverbal IQ scores. Fifty-five children (0.88%) had slight/mild bilateral sensorineural hearing loss. Children with and without sensorineural hearing loss scored similarly in language (mean: 97.2 vs 99.7), reading (101.1 vs 102.8), behavior (8.4 vs 7.0), and parent- and child-reported child health-related quality of life (77.6 vs 80.0 and 76.1 vs 77.0, respectively), but phonologic short-term memory was poorer (91.0 vs 102.8) in the sensorineural hearing loss group. The prevalence of slight/mild bilateral sensorineural hearing loss was lower than reported in previous studies. There was no strong evidence that slight/mild bilateral sensorineural hearing loss affects adversely language, reading, behavior, or health-related quality of life in children who are otherwise healthy and of normal intelligence.


Self-calibrating measurement of high-speed electro-optic phase modulators based on two-tone modulation.
We propose a self-calibrating method for high-frequency response measurement of electro-optic phase modulators based on two-tone modulation. The method utilizes the electrical domain measurement of heterodyning spectrum between the two-tone modulation optical signal and the frequency-shifted optical carrier, and eliminates the need to correct the responsivity fluctuation in the photodetection. High-frequency modulation depth and half-wave voltages are measured and compared to those with the traditional optical spectrum analysis method in the experimental demonstration. The proposed method enables calibration-free and accurate frequency response measurement of electro-optic phase modulators by using high-resolution electrical spectrum analysis.


Neuropsychological findings in childhood neglect and their relationships to pediatric PTSD.
Although child neglect is the most prevalent form of child maltreatment, the neurocognitive effects of neglect are understudied. We examined IQ, reading, mathematics, and neurocognitive domains of fine-motor skills, language, visual-spatial, memory/learning, and attention/executive functions in two groups of nonsexually abused medically healthy neglected children, one with DSM-IV posttraumatic stress disorder (PTSD) and one without, and a demographically similar healthy nonmaltreated control group. Significantly lower IQ, reading, mathematics, and selected differences in complex visual attention, visual memory, language, verbal memory and learning, planning, problem solving, and speeded naming were seen in Neglect Groups. The Neglect with PTSD Group performed worse than controls on NEPSY Design Copying, NEPSY Tower, and Mathematics; and performed worse than controls and Neglect without PTSD on NEPSY Memory for Faces-Delayed. Negative correlations were seen between PTSD symptoms, PTSD severity, and maltreatment variables, and IQ, Academic Achievement, and neurocognitive domains. Neglected children demonstrated significantly lower neurocognitive outcomes and academic achievement than controls. Lower IQ, neurocognitive functions, and achievement may be associated with more PTSD symptoms (particularly re-experiencing symptoms), greater PTSD severity, and a greater number of maltreatment experiences. Trauma experiences may additionally contribute to subsequent neurodevelopmental risk in neglected children. (JINS, 2009, 15, 868-878.).


Preexisting memory CD4+ T cells contribute to the primary response in an HIV-1 vaccine trial.
Naive and memory CD4+ T cells reactive with human immunodeficiency virus type 1 (HIV-1) are detectable in unexposed, unimmunized individuals. The contribution of preexisting CD4+ T cells to a primary immune response was investigated in 20 HIV-1-seronegative volunteers vaccinated with an HIV-1 envelope (Env) plasmid DNA prime and recombinant modified vaccinia virus Ankara (MVA) boost in the HVTN 106 vaccine trial (clinicaltrials.gov NCT02296541). Prevaccination naive or memory CD4+ T cell responses directed against peptide epitopes in Env were identified in 14 individuals. After priming with DNA, 40% (8/20) of the elicited responses matched epitopes detected in the corresponding preimmunization memory repertoires, and clonotypes were shared before and after vaccination in 2 representative volunteers. In contrast, there were no shared epitope specificities between the preimmunization memory compartment and responses detected after boosting with recombinant MVA expressing a heterologous Env. Preexisting memory CD4+ T cells therefore shape the early immune response to vaccination with a previously unencountered HIV-1 antigen.


Infection of laboratory colonies of Anopheles mosquitoes with Plasmodium vivax from cryopreserved clinical isolates.
Plasmodium vivax is the most geographically widespread malaria parasite. Unique features of transmission biology complicate P. vivax control. Interventions targeting transmission are required for malaria eradication. In the absence of an in vitro culture, transmission studies rely on live isolates from non-human primates or endemic regions. Here, we demonstrate P. vivax gametocytes from both India and Brazil are stable during cryopreservation. Importantly, cryopreserved gametocytes from Brazil were capable of infecting three anopheline mosquito species in feedings done in the United States. These findings create new opportunities for transmission studies in diverse locales.


Lung cancer, smoking, and employment in foundries.
A case-referent study on lung cancer was conducted in Cracow, Poland. Men dying of lung cancer within a 6-year period (1980-1985) formed the case group. The reference series was selected from death registers and was frequency-matched with the cases by sex and age. Deaths due to other respiratory diseases were excluded. Information on the occupation, smoking habits, and residency of 901 cases and 875 referents was collected from their next-of-kin. The combined effect of smoking and industrial exposure, in particular employment in steel or iron foundries, was investigated by multivariate analyses and was very well fitted by a multiplicative model. Foundry employment, in particular in the younger age (less than 70 years) group, occupational exposure to known carcinogens in other industries for more than 20 years, and smoking were found to be risk factors.


[Spanish influenza in France from 1918-1919].
In 1918-19 the so-called spanish influenza pandemic killed about 20 to 40 millions people all over the world. In France the loss of life was reckoned between 125,000 and 250,000 civilians and 30,000 soldiers though the epidemiological data have been incomplete. The virus allegedly came from the United States of America with the American forces which landed in the western harbours of France and probably with Indochina's troops or Chinese workers hired in the French factories. The disease spread in three waves from April 1918 to February 1919. The second wave was the most severe in September, October and November. Half of the dead occured among the 20-40 old people as the older people were more disease-resistant. Lethal forms were due to respiratory complications which often killed in a few days. The government did to preventive measures that were unequally applied as the treatment could be only symptomatic. The reactions of people were astonishingly cautions probably because the papers were ordered not to deal with the epidemic as long as the war lasted for.Some new serological studies and molecular biology techniques led up to clarify the strain of the 1918 influenza virus without further understanding of its special virulence.


Mode of questionnaire administration can have serious effects on data quality.
One of the main primary data collection instruments in social, health and epidemiological research is the survey questionnaire. Modes of data collection by questionnaire differ in several ways, including the method of contacting respondents, the medium of delivering the questionnaire to respondents, and the administration of the questions. These are likely to have different effects on the quality of the data collected. This paper is based on a narrative review of systematic and non-systematic searches of the literature on the effects of mode of questionnaire administration on data quality. Within different modes of questionnaire administration, there were many documented potential, biasing influences on the responses obtained. These were greatest between different types of mode (e.g. self-administered versus interview modes), rather than within modes. It can be difficult to separate out the effects of the different influences, at different levels. The biasing effects of mode of questionnaire administration has important implications for research methodology, the validity of the results of research, and for the soundness of public policy developed from evidence using questionnaire-based research. All users of questionnaires need to be aware of these potential effects on their data.


Obsessive-Compulsive Disorder, 5-HTTLPR polymorphism and treatment response.
Recently, a role for a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR) in conferring susceptibility to Obsessive Compulsive Disorder (OCD) has been suggested. The aim of this study was to test the hypothesis that allelic variation of the 5-HTTLPR could be associated with OCD susceptibility or influence the drug response in OCD. One hundred and eighty-one OCD patients were recruited; 92 patients underwent a standardized treatment with fluvoxamine. No significant differences in allele/genotype distribution of the 5-HTTLPR were found between 191 controls and OCD. No differences in fluvoxamine response in the three genotypes groups in OCD were found, considering Yale-Brown Obsessive Compulsive Scale (YBOCS) total scores. Nevertheless, a significant time per genotype interaction was found for the YBOCS subtotal compulsion scores. Considering patients without tic disorder co-diagnosis, a significant time per genotype interaction for both YBOCS total scores and compulsion scores was found.


Percutaneous Interventions in Acute Necrotizing Pancreatitis.
Acute pancreatitis (AP) is a disease of varying severity with acute necrotizing pancreatitis (ANP) being the severe form of AP. ANP needs multidisciplinary management and is associated with significant mortality and morbidity. Local complications of ANP viz. acute necrotic collections (ANC) and walled off pancreatic necrosis (WOPN) need intervention if they are associated with symptoms, sepsis or worsening organ failure. As surgery is associated with higher morbidity and mortality, there is paradigm shift in the management of these local complications with an increased emphasis on conservative and minimally invasive treatment approach. Image-guided percutaneous drainage (PCD) is a minimally invasive intervention that helps in drainage of infected collections, temporizes sepsis and improves outcomes in these patients. The present review discusses the utility of various percutaneous interventions in management of variety of pancreatic collections occurring in ANP. The available evidence, technical details and complications and emerging innovations in the field are also summarized.


Formation and characterization of the trimeric form of the fusion protein of Semliki Forest Virus.
Enveloped animal viruses infect cells via fusion of the viral membrane with a host cell membrane. Fusion is mediated by a viral envelope glycoprotein, which for a number of enveloped animal viruses rearranges itself during fusion to form a trimeric alpha-helical coiled-coil structure. This conformational change from the metastable, nonfusogenic form of the spike protein to the highly stable form involved in fusion can be induced by physiological activators of virus fusion and also by a variety of destabilizing conditions. The E1 spike protein subunit of Semliki Forest virus (SFV) triggers membrane fusion upon exposure to mildly acidic pH and forms a homotrimer that appears necessary for fusion. We have here demonstrated that formation of the E1 homotrimer was efficiently triggered under low-pH conditions but not by perturbants such as heat or urea, despite their induction of generalized conformational changes in the E1 and E2 subunits and partial exposure of an acid-specific E1 epitope. We used a sensitive fluorescence assay to show that neither heat nor urea treatment triggered SFV-liposome fusion at neutral pH, although either treatment inactivated subsequent low-pH-triggered fusion activity. Once formed, the low-pH-induced E1 homotrimer was very stable and was only dissociated under harsh conditions such as heating in sodium dodecyl sulfate. Taken together, these data, as well as protein structure predictions, suggest a model in which the less stable native E1 subunit specifically responds to low pH to form the more stable E1 homotrimer via conformational changes different from those of the coiled-coil type of fusion proteins.


Bilateral paraneoplastic optic neuropathy and unilateral retinal compromise in association with prostate cancer: a differential diagnostic challenge in a patient with unexplained visual loss.
We report a 77-year-old Caucasian man with a 1-year complaint of unexplained visual loss and a 4-year history of prostate cancer. A complete ophthalmologic exam, Goldmann visual fields (GVFs), intravenous fluorescein angiography (IVFA), macular and disc optical coherence tomography (OCT), pattern-reversal visual evoked potentials (PVEPs), and flash electroretinograms (ERGs) were performed. On examination, visual acuity was reduced bilaterally. Fundus exam showed juxtapapillary changes (OS > OD) and, in OS, disc pallor, peripheral RPE dropout and whitish retinal discoloration along the arcades. OCTs were normal OU. Cancer-associated retinopathy (CAR) was suspected. A flash ERG was normal OD and markedly reduced and electronegative OS. An IVFA showed bilateral juxtapapillary staining and changes highly suggestive of sequelae of central retinal artery occlusion (CRAO) OS , in which a cilioretinal artery existed along the papillomacular bundle. GVFs showed bilateral blind spot enlargement and centrocecal scotomas, and PVEPs were delayed. These findings suggested cancer-associated optic neuropathy (CAON), confirmed by presence of anti-optic nerve autoantibodies (auto-Abs). No anti-retinal auto-Abs were found. CAON is a less common paraneoplastic manifestation than CAR and it is rarely observed in association with prostate cancer. A combination of visual function testing methods permitted the recognition, in this highly unusual case, of the concurrent presence of unilateral ERG changes most likely attributable to CRAO complications in OS, in all likelihood unrelated to CAON, and not to be confused with unilateral CAR. Auto-Ab testing in combination with visual function tests helps achieve a better understanding of the pathophysiology of vision loss in paraneoplastic visual syndromes.


Safety evaluation of sous vide-processed ready meals.
To assess survival, growth and toxin production of spore-forming bacteria in sous vide products exposed to a relatively high heat treatment. During a three-year period, 2,168 sous vide-processed, commercially available ready-made meals with a shelf life of 3-5 weeks were examined. The products were stored at 4 degrees C for the first 1/3 and at 7 degrees C for the remaining 2/3 of their shelf life period. Three-fourths of the samples had less than 10 bacteria per gram the day after production, and none had more than 1,000. Similar numbers were found at the end of the shelf life when stored as described above. At abuse temperature (20 degrees C), the number of bacteria increased to 10(6)-10(7) cfu g(-1) 7 d after production. A total of 350 isolates of Bacillus spp. were collected, but no Clostridium strains were detected. Only 11 of the 113 tested strains were able to grow at 7 degrees C in broth, and none of the psychrotrophic strains were able to produce substantial amounts of toxins causing food poisoning. The health risk of these products is small as long as the temperature during storage is low. For microbial testing of the end products, traditional plating will suffice.


Structure-Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics.
Structure-based virtual screening using a D2 receptor homology model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D2 ligands were identified (47.6% success rate, among them D2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compounds ranged from 58 nm to about 24 μM. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction.


Indoor Localization using Computer Vision and Visual-Inertial Odometry.
Indoor wayfinding is a major challenge for people with visual impairments, who are often unable to see visual cues such as informational signs, land-marks and structural features that people with normal vision rely on for wayfinding. We describe a novel indoor localization approach to facilitate wayfinding that uses a smartphone to combine computer vision and a dead reckoning technique known as visual-inertial odometry (VIO). The approach uses sign recognition to estimate the user's location on the map whenever a known sign is recognized, and VIO to track the user's movements when no sign is visible. The ad-vantages of our approach are (a) that it runs on a standard smartphone and re-quires no new physical infrastructure, just a digital 2D map of the indoor environment that includes the locations of signs in it; and (b) it allows the user to walk freely without having to actively search for signs with the smartphone (which is challenging for people with severe visual impairments). We report a formative study with four blind users demonstrating the feasibility of the approach and suggesting areas for future improvement.


Fungal diagnosis: how do we do it and can we do better?
Morbidity and mortality remain high for patients with invasive fungal infections (IFIs) despite an increasing number of antifungals and other treatments. Many studies indicate that delayed or inaccurate diagnosis and treatment are major causes of poor outcomes in patients with IFIs. The aim of the current paper is to provide a review of traditional and newer approaches to the diagnosis of IFIs, with a particular focus on invasive candidiasis (IC) and aspergillosis (IA). Recent studies from the author's institution are highlighted, along with an advancement in cryptococcal meningitis diagnosis that should improve the care of AIDS and its opportunistic infection in many developing countries. Currently available tools for the diagnosis of IFIs include traditional methods like histopathology, culture, and radiology, and newer antigen- and PCR-based diagnostic assays. Attempts have also been made to predict IFIs based on colonization or other factors, including genetic polymorphisms impacting IFI susceptibility in high-risk patients. Biopsy with histopathologic analysis is often not possible in patients suspected of pulmonary aspergillosis due to increased bleeding risk, and blood cultures for IC, IA, or other IFIs are hindered by poor sensitivity and slow turnaround time which delays diagnosis. Radiology is often used to predict IFI but suffers from inability to differentiate certain pathogens and does not generally provide certainty of IFI diagnosis. Newer antigen-based diagnostics for early diagnosis include the β-glucan assay for IFIs, galactomannan assay for IA, and a recent variation on the traditional cryptococcal antigen (CRAG) test with a Lateral Flow Assay for invasive cryptococcosis. PCR-based diagnostics represent additional tools with high sensitivity for the rapid diagnosis of IFIs, although better standardization of these methods is still required for their routine clinical use. Better understanding of the strengths and weaknesses of currently available diagnostic tools, and further devising linked strategies to best implement them either alone or in combination, would greatly improve early and accurate diagnosis of IFIs and improve their successful management.


Therapeutic Innovations: Tyrosine Kinase Inhibitors in Cancer.
Conventional cytotoxic chemotherapy involving DNA-interacting agents and indiscriminate cell death is no longer the future of cancer management. While chemotherapy is not likely to completely disappear from the armamentarium; the use of targeted therapies in combination with conventional treatment is becoming the standard of care in human medicine. Tyrosine kinases are pivotal points of functional cellular pathways and have been implicated in malignancy, inflammatory, and immune-mediated diseases. Pharmaceutical interventions targeting aberrant tyrosine kinase signaling has exploded and is the second most important area of drug development. The "Valley of Death" between drug discovery and approval threatens to blunt the enormous strides in cancer management seen thus far. Kinase inhibitors, as targeted small molecules, hold promise in the treatment and diagnosis of cancer. However, there are still many unanswered questions regarding the use of kinase inhibitors in the interpretation and management of cancer. Comparative oncology has the potential to address restrictions and limitations in the advancement in kinase inhibitor therapy.


Inequality and City Size.
Between 1979 and 2007 a strong positive monotonic relationship between wage inequality and city size has developed. This paper investigates the links between this emergent city size inequality premium and the contemporaneous nationwide increase in wage inequality. After controlling for the skill composition of the workforce across cities of different sizes, we show that at least 23 percent of the overall increase in the variance of log hourly wages in the United States from 1979 to 2007 is explained by the more rapid growth in the variance of log wages in larger locations relative to smaller locations. This influence occurred throughout the wage distribution and was most prevalent during the 1990s. More rapid growth in within skill group inequality in larger cities has been by far the most important force driving these city size specific patterns in the data. Differences in the industrial composition of cities of different sizes explain up to one-third of this city size effect. These results suggest an important role for agglomeration economies in generating changes in the wage structure during the study period.


Trends in knee arthroscopy utilization: a gap in knowledge translation.
To evaluate the longitudinal trends in knee arthroscopy utilization in relation to published negative randomized controlled trials, focusing on annual rates, patient demographics and associated 30-day post-operative complications. The American College of Surgeons National Surgical Quality Improvement Program database was queried using Current Procedural Terminology billing codes to identify arthroscopy cases between 2006 and 2016. 30-day post-operative complications were identified, and potential risk factors analysed using univariate and multivariate analyses. 68,346 patients underwent knee arthroscopy, of which 47,446 (69.5%) represented partial meniscectomies. The annual procedural rate, as a proportion of all reported cases, increased significantly from 2006 (0.3%) to 2016 (1.6%; p < 0.001), along with a significant increase in average patient age (44.3 ± 15.5 to 48.4 ± 14.5; p < 0.001). Specifically focusing on the meniscectomy cohort, average patient age significantly increased from 47.9 ± 15.1 to 50.7 ± 13.5 (p = 0.001). The overall incidence of complications was 2.0% (n = 1333), with major complications in 0.9% (n = 639) and minor complications in 1.0% (n = 701). Common complications included a return to the operating room (0.5%), deep vein thrombosis/thrombophlebitis (0.4%), and superficial infection (0.2%). Operating time > 90 min, diabetes, steroid use, ASA class 2+, and dialysis-dependency were the predictors of overall complication rates. Despite the publication of negative trials and new clinical practice guidelines, knee arthroscopy utilization and average patient age continue to increase. Given the high utilization, even low adverse event rates equate to substantial numbers of patients with minor and major complications. The NSQIP data show a gap in knowledge translation to clinical practice and highlight the need for improved clinical guidelines. Cohort study; Level III.


Twisted light in a nonlinear mirror.
Opposite directionality of the Poynting vector and the wave vector, an inherent property of negative index metamaterials (NIMs), was predicted to enable backward phase-matching condition for a second harmonic generation (SHG) process. As a result, such a nonlinear negative index slab acts as a nonlinear mirror. In this Letter, we predict that SHG with structured light carrying orbital angular momentum (OAM) and propagating in NIMs results in a possibility of generating a backward propagating beam with simultaneously doubled frequency, OAM, and reversed rotation direction of the wavefront. These results may find applications in high-dimensional communication systems, quantum information processing, and optical manipulation on a nanoscale.


A Rational Design of a Multi-Epitope Vaccine Against SARS-CoV-2 Which Accounts for the Glycan Shield of the Spike Glycoprotein.
The ongoing global health crisis caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus which leads to Coronavirus Disease 2019 (COVID-19) has impacted not only the health of people everywhere, but the economy in nations across the world. While vaccine candidates and therapeutics are currently undergoing clinical trials, there is yet to be a proven effective treatment or cure for COVID-19. In this study, we have presented a synergistic computational platform, including molecular dynamics simulations and immunoinformatics techniques, to rationally design a multi-epitope vaccine candidate for COVID-19. This platform combines epitopes across Linear B Lymphocytes (LBL), Cytotoxic T Lymphocytes (CTL) and Helper T Lymphocytes (HTL) derived from both mutant and wild-type spike glycoproteins from SARS-CoV-2 with diverse protein conformations. In addition, this vaccine construct also takes the considerable glycan shield of the spike glycoprotein into account, which protects it from immune response. We have identified a vaccine candidate (a 35.9 kDa protein), named COVCCF, which is composed of 5 LBL, 6 HTL, and 6 CTL epitopes from the spike glycoprotein of SARS-CoV-2. Using multi-dose immune simulations, COVCCF induces elevated levels of immunoglobulin activity (IgM, IgG1, IgG2), and induces strong responses from B lymphocytes, CD4 T-helper lymphocytes, and CD8 T-cytotoxic lymphocytes. COVCCF induces cytokines important to innate immunity, including IFN-γ, IL4, and IL10. Additionally, COVCCF has ideal pharmacokinetic properties and low immune-related toxicities. In summary, this study provides a powerful, computational vaccine design platform for rapid development of vaccine candidates (including COVCCF) for effective prevention of COVID-19.


Next generation sequencing in patients with nephrolithiasis: how does it perform compared with standard urine and stone cultures?
Our aim was to compare microorganism detection between standard culture (Ctx) and next generation sequencing (NGS) in patients undergoing surgery for nephrolithiasis; we prospectively compared both urine and stone culture results using these two techniques. We prospectively compared microorganism detection of urine and stone cultures using Ctx versus NGS in patients undergoing surgery for nephrolithiasis. We analyzed preoperative voided urine (Voided) using both Ctx and NGS. Intraoperatively, renal stone (Stone) cultures were analyzed with Ctx and NGS. The primary outcome was concordance in microorganism detection between Voided Ctx and Stone NGS, as well as between Stone Ctx and Stone NGS. We prospectively evaluated 84 patients. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of Voided Ctx predicting Stone Ctx were 66.7%, 73.7%, 54.5%, and 82.4%, respectively. Concordance of Voided Ctx microorganisms to Stone microorganisms decreased when NGS was used for the Stone compared with Ctx. The sensitivity, specificity, PPV, and NPV of Voided NGS to predict Stone Ctx microorganisms were 85.2%, 24.6%, 34.8%, and 77.8%, respectively. The concordance of Voided NGS to Stone microorganisms improved when the Stone was analyzed via NGS compared with Ctx. NGS has a higher detection rate of microorganisms than standard culture for both preoperative urine and stone cultures. Voided NGS was the most sensitive in predicting a positive Stone sample, but the specificity and PPV were, overall, low. Further correlation of NGS microorganism detection with patient outcomes will determine which clinical situations may benefit most from NGS versus standard culture in patients with urinary-tract stones.


Regionally distinct phasic dopamine release patterns in the striatum during reversal learning.
Striatal dopamine (DA) plays a central role in reward-related learning and behavioral adaptation to changing environments. Recent studies suggest that rather than being broadcast as a uniform signal throughout the entire region, DA release dynamics diverge between different striatal regions. In a previous study, we showed that phasic DA release patterns in the ventromedial striatum (VMS) rapidly adapt during reversal learning. However, it is unknown how DA dynamics in the dorsolateral striatum (DLS) are modulated during such adaptive behavior. Here, we used fast-scan cyclic voltammetry to measure phasic DA release in the DLS during spatial reversal learning. In the DLS, we observed minor DA release after the onset of a visual cue signaling reward availability, followed by more pronounced DA release during more proximal reward cues (e.g., lever extension) and execution of the operant response (i.e., lever press), both in rewarded and non-rewarded trials. These release dynamics (minor DA after onset of the predictive visual cue, prominent DA during the operant response) did not change significantly during or following a reversal of response-reward contingencies. Notably, the DA increase to the lever press did not reflect a general signal related to the initiation of any motivated motor response, as we did not observe DA release when rats initiated nose pokes into the food receptacle during inter-trial intervals. This suggests that DA release in the DLS occurs selectively during the initiation and execution of a learned operant response. Together with our previous results obtained in the VMS, these findings reveal distinct phasic DA release patterns during adaptation of established behavior in DLS and VMS. The VMS DA signal, which is highly sensitive to reversal of response-reward contingences, may provide a teaching signal to guide reward-related learning and facilitate behavioral adaptation, whereas DLS DA may reflect a 'response execution signal' largely independent of outcome, that may be involved in initiation and energizing of operant behavior.


Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells.
Expression of the tight junction protein claudin-1 is dysregulated in colon tumors and associates with their progression. Up-regulation of claudin-1 reduces expression of E-cadherin. We investigated the mechanisms by which claudin-1 regulates E-cadherin expression and its effects in colon cancer cells. We used gene expression analysis, immunoblotting, and reverse transcription polymerase chain reaction to associate expression of the repressor of transcription Zinc Finger E-box binding homeobox-box1 (ZEB-1) with claudin-1. We analyzed SW480 colon cancer cells that overexpressed claudin-1, or SW620 cells in which claudin-1 expression was repressed, to determine the effects on ZEB-1 and E-cadherin expression, invasive activity, and resistance to anoikis. We studied cells that expressed constitutively active or dominant negative forms of factors in the Wnt or phosphotidylinositol-3-kinase signaling pathways and used pharmacologic inhibitors of these pathways to study their role in claudin-1-dependent regulation of ZEB-1. We used microarray analysis to examine gene expression patterns in 260 colorectal tumor and normal colon samples. Claudin-1 down-regulates E-cadherin expression by up-regulating expression of ZEB-1. Claudin-1 activates Wnt and phosphotidylinositol-3-kinase/Akt signaling. ZEB-1 mediates claudin-1-regulated changes in cell invasion and anoikis. Expression of claudin-1 correlated with that of ZEB-1 in human colon tumor samples. In the progression from normal colonic epithelium to colon adenocarcinoma, levels of E-cadherin decreased, whereas levels of claudin-1 and ZEB-1 increased. Down-regulation of E-cadherin and up-regulation of ZEB-1 in colon tumors were associated with shorter survival times. Claudin-1 up-regulates the repressor ZEB-1 to reduce expression of E-cadherin in colon cancer cells, increasing their invasive activity and reducing anoikis. This pathway is associated with colorectal cancer progression and patient survival.


Real-time ultrasound-guided infraclavicular axillary vein cannulation: A prospective study in mechanically ventilated critically ill patients.
The main purpose of this study was to define the venipuncture and catheterization success rates and early mechanical complication rates of ultrasound-guided infraclavicular axillary vein cannulation. We performed in-plane, real-time, ultrasound-guided infraclavicular axillary vein catheterizations under emergency and nonemergency conditions in mechanically ventilated, critically ill patients. We performed 202 cannulation attempts. One hundred and twenty-six procedures (62.4%) were performed under emergency conditions. The puncture of the axillary vein was successful in 98.5% of patients, and the entire procedure success rate was 95.1% (95% confidence interval, 91.1%-97.6%). For the majority of patients (84.1%; P<.001, exact test), the venipuncture occurred during the first attempt. We noted a 22.4% overall complication rate, and most of the complications were malpositions (13.4%). We observed 8.5% of cases with potentially serious complications (puncture of the axillary artery and needle contact with the brachial plexus) and 1 case (0.5%) of pneumothorax. The puncture of the axillary artery occurred in 5 (2.5%) patients. In-plane, real-time, ultrasound-guided, infraclavicular axillary vein cannulation in mechanically ventilated, critically ill patients is a safe and reliable method of central venous cannulation and can be considered to be a reasonable alternative to other central venous catheterization techniques.


Sleep and the heart: Interoceptive differences linked to poor experiential sleep quality in anxiety and depression.
Interoception is the sense through which internal bodily changes are signalled and perceived. Individual differences in interoception are linked to emotional style and vulnerability to affective disorders. Here we test how experiential sleep quality relates to dimensions of interoceptive ability. 180 adults (42 'non-clinical' individuals, 138 patients accessing mental health services) rated their quality of sleep before performing tests of cardiac interoception. Poor sleep quality was associated with lower measures of interoceptive performance accuracy, and higher self-report measures of interoceptive sensibility in individuals with diagnoses of depression and/or anxiety. Additionally, poor sleep quality was associated with impaired metacognitive interoceptive awareness in patients with diagnoses of depression (alone or with anxiety). Thus, poor sleep quality, a common early expression of psychological disorder, impacts cardiac interoceptive ability and experience across diagnoses. Sleep disruption can contribute to the expression of affective psychopathology through effects on perceptual and interpretative dimensions of bodily awareness.


Eye-tracking, autonomic, and electrophysiological correlates of emotional face processing in adolescents with autism spectrum disorder.
Individuals with autism spectrum disorder (ASD) often have difficulty with social-emotional cues. This study examined the neural, behavioral, and autonomic correlates of emotional face processing in adolescents with ASD and typical development (TD) using eye-tracking and event-related potentials (ERPs) across two different paradigms. Scanning of faces was similar across groups in the first task, but the second task found that face-sensitive ERPs varied with emotional expressions only in TD. Further, ASD showed enhanced neural responding to non-social stimuli. In TD only, attention to eyes during eye-tracking related to faster face-sensitive ERPs in a separate task; in ASD, a significant positive association was found between autonomic activity and attention to mouths. Overall, ASD showed an atypical pattern of emotional face processing, with reduced neural differentiation between emotions and a reduced relationship between gaze behavior and neural processing of faces.


Distinct XPPX sequence motifs induce ribosome stalling, which is rescued by the translation elongation factor EF-P.
Ribosomes are the protein synthesizing factories of the cell, polymerizing polypeptide chains from their constituent amino acids. However, distinct combinations of amino acids, such as polyproline stretches, cannot be efficiently polymerized by ribosomes, leading to translational stalling. The stalled ribosomes are rescued by the translational elongation factor P (EF-P), which by stimulating peptide-bond formation allows translation to resume. Using metabolic stable isotope labeling and mass spectrometry, we demonstrate in vivo that EF-P is important for expression of not only polyproline-containing proteins, but also for specific subsets of proteins containing diprolyl motifs (XPP/PPX). Together with a systematic in vitro and in vivo analysis, we provide a distinct hierarchy of stalling triplets, ranging from strong stallers, such as PPP, DPP, and PPN to weak stallers, such as CPP, PPR, and PPH, all of which are substrates for EF-P. These findings provide mechanistic insight into how the characteristics of the specific amino acid substrates influence the fundamentals of peptide bond formation.


Treatment of neck pain: noninvasive interventions: results of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders.
Best evidence synthesis. To identify, critically appraise, and synthesize literature from 1980 through 2006 on noninvasive interventions for neck pain and its associated disorders. No comprehensive systematic literature reviews have been published on interventions for neck pain and its associated disorders in the past decade. We systematically searched Medline and screened for relevance literature published from 1980 through 2006 on the use, effectiveness, and safety of noninvasive interventions for neck pain and associated disorders. Consensus decisions were made about the scientific merit of each article; those judged to have adequate internal validity were included in our best evidence synthesis. Of the 359 invasive and noninvasive intervention articles deemed relevant, 170 (47%) were accepted as scientifically admissible, and 139 of these related to noninvasive interventions (including health care utilization, costs, and safety). For whiplash-associated disorders, there is evidence that educational videos, mobilization, and exercises appear more beneficial than usual care or physical modalities. For other neck pain, the evidence suggests that manual and supervised exercise interventions, low-level laser therapy, and perhaps acupuncture are more effective than no treatment, sham, or alternative interventions; however, none of the active treatments was clearly superior to any other in either the short- or long-term. For both whiplash-associated disorders and other neck pain without radicular symptoms, interventions that focused on regaining function as soon as possible are relatively more effective than interventions that do not have such a focus. Our best evidence synthesis suggests that therapies involving manual therapy and exercise are more effective than alternative strategies for patients with neck pain; this was also true of therapies which include educational interventions addressing self-efficacy. Future efforts should focus on the study of noninvasive interventions for patients with radicular symptoms and on the design and evaluation of neck pain prevention strategies.


Experimental method and statistical analysis to fit tumor growth model using SPECT/CT imaging: a preclinical study.
Over the last decade, several theoretical tumor-models have been developed to describe tumor growth. Oncology imaging is performed using various modalities including computed tomography (CT), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and fluorodeoxyglucose-positron emission tomography (FDG-PET). Our goal is to extract useful, otherwise hidden, quantitative biophysical parameters (such as growth-rate, tumor-necrotic-factor, etc.) from these serial images of tumors by fitting mathematical models to images. These biophysical features are intrinsic to the tumor types and specific to the study-subject, and expected to add valuable information on the tumor containment or spread and help treatment plans. Thus, fitting realistic but practical models and assessing parameter-errors and degree of fit is important. We implemented an existing theoretical ode-compartment model and variants and applied them for the first time, in vivo. We developed an inversion algorithm to fit the models for tumor growth for simulated as well as in vivo experimental data. Serial SPECT/CT scans of mice breast-tumors were acquired, and SPECT data was used to segment the proliferating-layers of tumors. Results of noisy data simulation and inversion show that 5 out of 7 parameters were recovered to within 4.3% error. In particular, tumor "growth-rate" parameter was recovered to 0.07% error. For model fitting to in vivo mice-tumors, regression analysis on the P-layer volume showed R2 of 0.99 for logistic and Gompertzian while surface area model yielded R2=0.96. For the necrotic layer the R2 values were 0.95, 0.93 and 0.94 respectively for surface-area, logistic and Gompertzian. The Akaike Information Criterion (AIC) weights of the models (giving their relative probability of being the best Kullback-Leibler (K-L) model among the set of candidate models) were ~0, 0.43 and 0.57 for surface-area, logistic and Gompertzian models. Model-fitting to mice tumor studies demonstrates feasibility of applying the models to in vivo imaging data to extract features. Akaike information criterion (AIC) evaluations show Gompertzian or logistic growth model fits in vivo breast-tumors better than surface-area based growth model.


Clinicopathologic evidence of disseminated intravascular coagulation in horses with acute colitis.
To detect subclinical disseminated intravascular coagulation (DIC) in horses with colitis and to determine any association between the diagnosis of subclinical DIC and outcome or occurrence of complications in horses with colitis. Prospective study. 37 horses admitted to a veterinary teaching hospital for treatment of acute colitis. Coagulation profiles were obtained on each horse 0, 24, and 48 hours after admission. Six tests were performed: platelet count, plasma fibrinogen concentration, prothrombin time, activated partial thromboplastin time, antithrombin activity, and serum fibrin degradation products concentration. A clinicopathologic diagnosis of subclinical DIC was made if 3 of the 6 tests had abnormal results at any 1 sample period. No horse had clinical signs of DIC at the time of sampling. Twelve of 37 (32%) horses met the criteria for diagnosis of subclinical DIC within a 1-year period. Outcome was defined as survival or nonsurvival. Five of 12 horses with subclinical DIC and 2 of 25 horses without subclinical DIC did not survive. Crude odds ratio analysis revealed a horse with acute colitis was 8 times as likely to die or be euthanatized if a diagnosis of subclinical DIC was made. Clinicopathologic evidence of DIC is common and is significantly associated with a poor outcome in horses with acute colitis. Treatment of subclinical DIC may influence outcome in horses with acute colitis.


Cytoprotective effects of alpha tocopherol against liver injury induced by extrahepatic biliary obstruction.
There are several important aetiologies of extrahepatic biliary obstruction (EBO). If EBO is surgically reconstructed in the critical time period, liver damage can be halted or reversed. In this golden period, lipid peroxidations significantly intensify liver defects. We hypothesised that alpha tocopherol (alpha-T) could protect the liver from the damage caused by response to EBO. In standard conditions, albino rats of Wistar strain were divided into two groups. All rats underwent double ligations and divisions of common bile ducts (CBD). One of these groups received alpha-T (CBDL-alpha-T). The other CBDL animals received intramuscular injections of normal saline (CBDL-NS). Serum samples were taken for biochemical analyses by light microscopy. The data showed a decrease in plasma bilirubin and liver enzyme levels in CBDL-alpha-T group, when compared with CBDL-NS (p < 0.05). Morphologic analyses showed better results for CBD-alpha-T. Serum levels of Malonyldialdehyd (MDA) in the CBDL-alpha-T group was 9.2 +/- 3.4 nmol/g compared to that in CBDL-NS, 12.3 +/- 4.4 nmol/g (p < 0.05). In conclusion, a dramatic protective effect of alpha-T on functional and structural features of the liver in rats with EBO was demonstrated. The data suggest that EBO may cause liver damage by stimulation of lipid peroxidation and that alpha-T may slow down liver damage in this setting.


Shared genetic diversity across the global invasive range of the monk parakeet suggests a common restricted geographic origin and the possibility of convergent selection.
While genetic diversity is hypothesized to be an important factor explaining invasion success, there is no consensus yet on how variation in source populations or demographic processes affects invasiveness. We used mitochondrial DNA haplotypic and microsatellite genotypic data to investigate levels of genetic variation and reconstruct the history of replicate invasions on three continents in a globally invasive bird, the monk parakeet (Myiopsitta monachus). We evaluated whether genetic diversity at invasive sites could be explained by (i) the native source populations from which they were derived and (ii) demographic bottlenecks during introduction. Genetic data indicated a localized source area for most sampled invasive populations, with limited evidence for admixing of native source populations. This pattern largely coincides with historical data on pet trade exports. However, the invasive populations are genetically more similar than predicted from the export data alone. The extent of bottleneck effects varied among invasive populations. The observed low genetic diversity, evidence of demographic contraction and restricted source area do not support the hypothesis that invasion is favoured by the mixing and recombining of genetic variation from multiple source populations. Instead, they suggest that reduced genetic variation through random processes may not inhibit successful establishment and invasion in this species. However, convergent selection across invasive sites could also explain the observed patterns of reduction and similarity in genetic variation and/or the restricted source area. In general, the alternative explanation of intraspecific variation in invasive potential among genotypes or geographic areas is neglected, but warrants more attention as it could inform comparative studies and management of biological invaders.


Non-small cell lung cancer: identifying prognostic imaging biomarkers by leveraging public gene expression microarray data--methods and preliminary results.
To identify prognostic imaging biomarkers in non-small cell lung cancer (NSCLC) by means of a radiogenomics strategy that integrates gene expression and medical images in patients for whom survival outcomes are not available by leveraging survival data in public gene expression data sets. A radiogenomics strategy for associating image features with clusters of coexpressed genes (metagenes) was defined. First, a radiogenomics correlation map is created for a pairwise association between image features and metagenes. Next, predictive models of metagenes are built in terms of image features by using sparse linear regression. Similarly, predictive models of image features are built in terms of metagenes. Finally, the prognostic significance of the predicted image features are evaluated in a public gene expression data set with survival outcomes. This radiogenomics strategy was applied to a cohort of 26 patients with NSCLC for whom gene expression and 180 image features from computed tomography (CT) and positron emission tomography (PET)/CT were available. There were 243 statistically significant pairwise correlations between image features and metagenes of NSCLC. Metagenes were predicted in terms of image features with an accuracy of 59%-83%. One hundred fourteen of 180 CT image features and the PET standardized uptake value were predicted in terms of metagenes with an accuracy of 65%-86%. When the predicted image features were mapped to a public gene expression data set with survival outcomes, tumor size, edge shape, and sharpness ranked highest for prognostic significance. This radiogenomics strategy for identifying imaging biomarkers may enable a more rapid evaluation of novel imaging modalities, thereby accelerating their translation to personalized medicine.


Composite Measures for Routine Clinical Practice in Psoriatic Arthritis: Testing of Shortened Versions in a UK Multicenter Study.
To test shortened versions of the psoriatic arthritis (PsA) composite measures for use in routine clinical practice. Clinical and patient-reported outcome measures (PROMs) were assessed in patients with PsA at 3 consecutive follow-up visits in a UK multicenter observational study. Shortened versions of the Composite Psoriatic Arthritis Disease Activity Index (CPDAI) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite Exercise (GRACE) measures were developed using PROMs and tested against the Disease Activity Score in 28 joints (DAS28), composite Disease Activity in Psoriatic Arthritis, and Routine Assessment of Patient Index Data (RAPID3). Discrimination between disease states and responsiveness were tested with the t-score, standardized response mean (SRM), and effect size (ES). Data were presented to members at the GRAPPA 2020 annual meeting and members voted on the recommended composite routine practice. The SRM for the GRACE, 3 visual analog scale (VAS), and 4VAS were 0.67, 0.77, and 0.63, respectively, and for CPDAI and shortened CPDAI (sCPDAI) were 0.54 and 0.55, respectively. Shortened versions of the GRACE increased the t-score from 7.8 to 8.7 (3VAS) and 9.0 (4VAS), but reduced the t-score in the CPDAI/sCPDAI from 6.8 and 6.1. The 3VAS and 4VAS had superior performance characteristics to the sCPDAI, DAS28, Disease Activity in Psoriatic Arthritis, and RAPID3 in all tests. Of the members, 60% agreed that the VAS scales contained enough information to assess disease and response to treatment, 53% recommended the 4VAS for use in routine care, and 26% the 3VAS, while leaving 21% undecided. Conclusion. Shortening the GRACE to VAS scores alone enhances the ability to detect status and responsiveness and has the best performance characteristics of the tested composite measures. GRAPPA members recommend further testing of the 3VAS and 4VAS in observational and trial datasets.


Sensitivity of global and regional terrestrial carbon storage to the direct CO2 effect and climate change based on the CMIP5 model intercomparison.
Global and regional land carbon storage has been significantly affected by increasing atmospheric CO2 concentration and climate change. Based on fully coupled climate-carbon-cycle simulations from the Coupled Model Intercomparison Project Phase 5 (CMIP5), we investigate sensitivities of land carbon storage to rising atmospheric CO2 concentration and climate change over the world and 21 regions during the 130 years. Overall, the simulations suggest that consistently spatial positive effects of the increasing CO2 concentrations on land carbon storage are expressed with a multi-model averaged value of 1.04 PgC per ppm. The stronger positive values are mainly located in the broad areas of temperate and tropical forest, especially in Amazon basin and western Africa. However, large heterogeneity distributed for sensitivities of land carbon storage to climate change. Climate change causes decrease in land carbon storage in most tropics and the Southern Hemisphere. In these regions, decrease in soil moisture (MRSO) and enhanced drought somewhat contribute to such a decrease accompanied with rising temperature. Conversely, an increase in land carbon storage has been observed in high latitude and altitude regions (e.g., northern Asia and Tibet). The model simulations also suggest that global negative impacts of climate change on land carbon storage are predominantly attributed to decrease in land carbon storage in tropics. Although current warming can lead to an increase in land storage of high latitudes of Northern Hemisphere due to elevated vegetation growth, a risk of exacerbated future climate change may be induced due to release of carbon from tropics.


Male and LGBT survivors of sexual violence in conflict situations: a realist review of health interventions in low-and middle-income countries.
Conflict-related sexual violence (CRSV) against women and girls has been the subject of increasing research and scholarship. Less is known about the health of men, boys and lesbian, gay, bisexual, transgender (LGBT) and other gender non-binary persons who survive CRSV. This paper is the first systematic realist review on medical, mental health and psychosocial support (MHPSS) interventions that focusses on male and LGBT survivors of CRSV. The review explores the gender differences in context, mechanisms and outcomes that underpin interventions addressing the health and psychosocial wellbeing of male and LGBT survivors. The aim is to contribute to the design and delivery of gender-sensitive and, when needed, gender-specific approaches for interventions that respond to specific needs of different groups of all survivors. We conducted a systematic search of academic and grey literature to identify medical and MHPSS interventions that included men, boys and LGBT survivors. We identified interventions specifically targeting women and girls that we used as comparators. We then purposively sampled studies from the fields of gender and health, and sexual abuse against men and LGBT people for theory building and testing. We identified 26 evaluations of interventions for survivors of CRSV. Nine studies included male survivors, twelve studies focussed exclusively on female survivors and one study targeted children and adolescents. No intervention evaluation focussed on LGBT survivors of CRSV. The interventions that included male survivors did not describe specific components for this population. Results of intervention evaluations that included male survivors were not disaggregated by gender, and some studies did not report the gender composition. Although some mental health and psychosocial consequences of sexual violence against men and boys may be similar among male and female survivors, the way each process trauma, display symptoms, seek help, adhere to treatment and improve their mental health differ by gender. Initiatives targeting male and LGBT survivors of CRSV need to be designed to actively address specific gender differences in access, adherence and response to MHPSS interventions. Models of care that are gender-sensitive and integrated to local resources are promising avenues to promote the health of male and LGBT survivors of CRSV.


Longitudinal study of the activities of daily living and quality of life in Japanese patients with fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva is a rare congenital disorder that causes systemic heterotopic ossification, leading to systemic ankyloses and mobility losses. This study aimed to ascertain the natural history of fibrodysplasia ossificans progressiva. In addition to the medical history questionnaire, patients aged 16 years and older were asked to complete activities of daily living and quality of life surveys using the Barthel Index, MOS 36-Item Short-Form Health Survey, and Health Assessment Questionnaire. The surveys were conducted over a 4-years period. Of the 15 participating patients, 13 reported swelling during the study period. The Barthel Index and Health Assessment Questionnaire surveys indicated a tendency for questionnaire items related to arm function to reflect early decreases in the activities of daily living. Decreases in activities of daily living functioning were closely related to decreases in the quality of life in physical function domains. Activities of daily living and quality of life were maintained at a similar level to baseline values over the study period (Barthel Index: p = 0.42, MOS 36-Item Short-Form Health Survey: p = 0.43, Health Assessment Questionnaire: p = 0.87). We obtained longitudinal information relating to natural history on fibrodysplasia ossificans progressiva patients. Implications for rehabilitation Fibrodysplasia ossificans progressiva is a rare congenital disease that causes heterotopic ossification of muscle tissue throughout the body, leading to systemic ankyloses and mobility losses. When the Barthel Index was high and the activities of daily living were relatively stable, the items on the Health Assessment Questionnaire that are related to arm function began to show impairment. Early focus on upper extremity function that includes the use of assistive devices during the period when a patient is still able to perform many activities of daily living is important. Although decreases in activities of daily living functioning were closely related to decreases in the quality of life in the physical function domains, the scores of the domains other than physical function were similar to the national standard score.


The filifolium1 mutation perturbs shoot architecture in Zea mays (Poaceae).
Plant architecture is elaborated through the activity of shoot apical meristems (SAMs), which produce repeating units known as phytomers, that are comprised of leaf, node, internode, and axillary bud. Insight into how SAMs function and how individual phytomer components are related to each other can been obtained through characterization of recessive mutants with perturbed shoot development. In this study, we characterized a new mutant to further understand mechanisms underlying shoot development in maize. The filifolium1-0 (ffm1-0) mutants develop narrow leaves on dwarfed shoots. Shoot growth often terminates at the seedling stage from depletion of the SAM, but if plants survive to maturity they are invariably bushy. KN1-like homeobox (KNOX) proteins are inappropriately regulated in mutant apices, adaxial identity is not specified in mutant leaves, and axillary meristems develop precociously. We propose that FFM1 acts to demarcate zones within the SAM so that appropriate fates can be conferred on cells within those zones by other factors. On the basis of the mutant phenotype, we also speculate about different relationships between phytomer components in maize and Arabidopsis.


Comparison of sensory nerve conduction velocities in horses versus ponies.
Normal sensory nerve conduction velocity (SNCV) values in 8 ponies and 8 horses were compared by use of a percutaneous signal-averaging technique. Nerve fibers evaluated included those in the medial and lateral palmar and plantar digital nerves. Mean SNCV values were significantly slower (P less than 0.0002) for horses, compared with those values for ponies. Animal height and nerve segment length were inversely related to SNCV consistently. The SNCV values were affected by surface skin temperature by a factor of approximately 1.2 m/s change for 1 degree C change in temperatures from 35 C. The ability to calculate warning limits to define those SNCV values in normal and abnormal ranges were developed from these data for both ponies and horses.


Validation of an ex vivo Xenopus liver slice bioassay for environmental estrogens and estrogen mimics.
A sensitive ex vivo bioassay for detecting environmental estrogens and estrogen mimics was developed using Xenopus liver slice culture. Vitellogenin synthesis by these cultures was used as biomarker for estrogenic activity of environmental water samples. Sensitization of the assay for estrogens and mimics was accomplished by employing tissue from animals after in vivo preexposure to estrogen. Effects of various tissue culture factors were investigated in order to obtain optimum conditions for the bioassay. It was found that endogenous vitellogenin and/or estrogen could be "washed out" of cultures and that not only uncontaminated males but also estrogen-pretreated males and females can successfully be used as bioindicators. Estrogenicity was detected, using the ex vivo Xenopus liver slice culture assay, in sewage effluent, lake water, and dam water. This article presents an optimized protocol for effective estrogen detection in environmental water samples.


The precuneus and the insula in self-attributional processes.
Attributions are constantly assigned in everyday life. A well-known phenomenon is the self-serving bias: that is, people's tendency to attribute positive events to internal causes (themselves) and negative events to external causes (other persons/circumstances). Here, we investigated the neural correlates of the cognitive processes implicated in self-serving attributions using social situations that differed in their emotional saliences. We administered an attributional bias task during fMRI scanning in a large sample of healthy subjects (n = 71). Eighty sentences describing positive or negative social situations were presented, and subjects decided via buttonpress whether the situation had been caused by themselves or by the other person involved. Comparing positive with negative sentences revealed activations of the bilateral posterior cingulate cortex (PCC). Self-attribution correlated with activation of the posterior portion of the precuneus. However, self-attributed positive versus negative sentences showed activation of the anterior portion of the precuneus, and self-attributed negative versus positive sentences demonstrated activation of the bilateral insular cortex. All significant activations were reported with a statistical threshold of p ≤ .001, uncorrected. In addition, a comparison of our fMRI task with data from the Internal, Personal and Situational Attributions Questionnaire, Revised German Version, demonstrated convergent validity. Our findings suggest that the precuneus and the PCC are involved in the evaluation of social events with particular regional specificities: The PCC is activated during emotional evaluation, the posterior precuneus during attributional evaluation, and the anterior precuneus during self-serving processes. Furthermore, we assume that insula activation is a correlate of awareness of personal agency in negative situations.


Nanomechanical properties of proteins and membranes depend on loading rate and electrostatic interactions.
Knowing the dynamic mechanical response of tissue, cells, membranes, proteins, nucleic acids, and carbohydrates to external perturbations is important to understand various biological and biotechnological problems. Atomic force microscopy (AFM)-based approaches are the most frequently used nanotechnologies to determine the mechanical properties of biological samples that range in size from microscopic to (sub)nanoscopic. However, the dynamic nature of biomechanical properties has barely been addressed by AFM imaging. In this work, we characterizethe viscoelastic properties of the native light-driven proton pump bacteriorhodopsin of the purple membrane of Halobacterium salinarum. Using force-distance curve (F-D)-based AFM we imaged purple membranes while force probing their mechanical response over a wide range of loading rates (from ∼0.5 to 100 μN/s). Our results show that the mechanical stiffness of protein and membrane increases with the loading rate up to a factor of 10 (from ∼0.3 to 3.2 N/m). In addition, the electrostatic repulsion between AFM tip and sample can alter the mechanical stiffness measured by AFM up to ∼60% (from ∼0.8 to 1.3 N/m).These findings indicate that the mechanical response of membranes and proteins and probably of other biomolecular systems should be determined at different loading rates to fully understand their properties.


The evolution of genome size in ants.
Despite the economic and ecological importance of ants, genomic tools for this family (Formicidae) remain woefully scarce. Knowledge of genome size, for example, is a useful and necessary prerequisite for the development of many genomic resources, yet it has been reported for only one ant species (Solenopsis invicta), and the two published estimates for this species differ by 146.7 Mb (0.15 pg). Here, we report the genome size for 40 species of ants distributed across 10 of the 20 currently recognized subfamilies, thus making Formicidae the 4th most surveyed insect family and elevating the Hymenoptera to the 5th most surveyed insect order. Our analysis spans much of the ant phylogeny, from the less derived Amblyoponinae and Ponerinae to the more derived Myrmicinae, Formicinae and Dolichoderinae. We include a number of interesting and important taxa, including the invasive Argentine ant (Linepithema humile), Neotropical army ants (genera Eciton and Labidus), trapjaw ants (Odontomachus), fungus-growing ants (Apterostigma, Atta and Sericomyrmex), harvester ants (Messor, Pheidole and Pogonomyrmex), carpenter ants (Camponotus), a fire ant (Solenopsis), and a bulldog ant (Myrmecia). Our results show that ants possess small genomes relative to most other insects, yet genome size varies three-fold across this insect family. Moreover, our data suggest that two whole-genome duplications may have occurred in the ancestors of the modern Ectatomma and Apterostigma. Although some previous studies of other taxa have revealed a relationship between genome size and body size, our phylogenetically-controlled analysis of this correlation did not reveal a significant relationship. This is the first analysis of genome size in ants (Formicidae) and the first across multiple species of social insects. We show that genome size is a variable trait that can evolve gradually over long time spans, as well as rapidly, through processes that may include occasional whole-genome duplication. The small genome sizes of ants, combined with their ecological, evolutionary and agricultural importance, suggest that some of these species may be good candidates for future whole-genome sequencing projects.


Moving beyond the therapeutic relationship: a selective review of intimacy in the sexual health encounter in nursing practice.
For the purposes of this study, a selective review of the literature was undertaken with the aim of examining nurses' preparedness to engage in intimate interactions within the context of sexual health care. Kirk's (2007) model of interactional intimacy is used as a lens to examine the literature. The provision of sexual health care is often a neglected area of nursing care despite being recognised as a component of holistic nursing practice. Despite theoretical discussion about various forms of intimacy and intimate care, there has been little examination of the interface between intimacy and sexual health care that usefully informs practice. Selective review and synthesis of the literature. The literature of humanistic interpretations of caring that has dominated nursing discourse over the last half-century has limited progress on defining and developing forms of clinical interaction that are suited to promoting nurses engagement in sexual health care. We propose that Kirk's model has useful utility in preparing nurses to engage more readily with sexual health care as a routine component of their practice. Sexual health adversity can often accompany ill health, and therefore, the provision of appropriate care is required to negate detrimental outcomes and promote positive well-being. Although sexual health care is often not prioritised in practice, nurses are in a prime position to promote sexual health care and well-being. By conducting sexual health assessments and providing sexual health care routinely, the gap that exists between patients' sexual healthcare needs and the lack of sexual health care provided can be minimised.


Investigation of serum leptin levels in professional male football players and healthy sedentary males.
In the present study we aimed at investigating leptin levels in professional male athletes who have been exercising regularly for a long time and leptin levels in healthy sedentary males. The study included 10 male professional football players and 17 healthy sedentary males. The relations between groups in terms of leptin levels, Max VO2 levels, blood lactic acid levels before and after exercise and effort durations were investigated. It was found in the study that although BMI of professional male athletes was higher than that of the healthy sedentary males, leptin levels of the former were significantly lower (p<0.01), while VO2Max levels (p<0.05) and test periods (p<0.01) were significantly higher than those in the latter. As for lactic acid levels after exercise and between groups, these were also higher in athletes, but the difference was not statistically significant (p>0.05). Leptin levels of those who exercised regularly were found lower than the levels in healthy males. Although the increase in serum leptin levels is in direct proportion with BMI in general, the major determinant of serum leptin level is the body fat rate. As regular exercising reduces body fat rate, it also reduces serum leptin levels.


Intravital two-photon microscopy of immune cell dynamics in corneal lymphatic vessels.
The role of lymphatic vessels in tissue and organ transplantation as well as in tumor growth and metastasis has drawn great attention in recent years. We now developed a novel method using non-invasive two-photon microscopy to simultaneously visualize and track specifically stained lymphatic vessels and autofluorescent adjacent tissues such as collagen fibrils, blood vessels and immune cells in the mouse model of corneal neovascularization in vivo. The mouse cornea serves as an ideal tissue for this technique due to its easy accessibility and its inducible and modifiable state of pathological hem- and lymphvascularization. Neovascularization was induced by suture placement in corneas of Balb/C mice. Two weeks after treatment, lymphatic vessels were stained intravital by intrastromal injection of a fluorescently labeled LYVE-1 antibody and the corneas were evaluated in vivo by two-photon microscopy (TPM). Intravital TPM was performed at 710 nm and 826 nm excitation wavelengths to detect immunofluorescence and tissue autofluorescence using a custom made animal holder. Corneas were then harvested, fixed and analyzed by histology. Time lapse imaging demonstrated the first in vivo evidence of immune cell migration into lymphatic vessels and luminal transport of individual cells. Cells immigrated within 1-5.5 min into the vessel lumen. Mean velocities of intrastromal corneal immune cells were around 9 µm/min and therefore comparable to those of T-cells and macrophages in other mucosal surfaces. To our knowledge we here demonstrate for the first time the intravital real-time transmigration of immune cells into lymphatic vessels. Overall this study demonstrates the valuable use of intravital autofluorescence two-photon microscopy in the model of suture-induced corneal vascularizations to study interactions of immune and subsequently tumor cells with lymphatic vessels under close as possible physiological conditions.


Requirement of yeast Rad1-Rad10 nuclease for the removal of 3'-blocked termini from DNA strand breaks induced by reactive oxygen species.
The Rad1-Rad10 nuclease of yeast and its human counterpart ERCC1-XPF are indispensable for nucleotide excision repair, where they act by cleaving the damaged DNA strand on the 5'-side of the lesion. Intriguingly, the ERCC1- and XPF-deficient mice show a severe postnatal growth defect and they die at approximately 3 wk after birth. Here we present genetic and biochemical evidence for the requirement of Rad1-Rad10 nuclease in the removal of 3'-blocked termini from DNA strand breaks induced on treatment of yeast cells with the oxidative DNA damaging agent H(2)O(2). Our genetic studies indicate that 3'-blocked termini are removed in yeast by the three competing pathways that involve the Apn1, Apn2, and Rad1-Rad10 nucleases, and we show that the Rad1-Rad10 nuclease proficiently cleaves DNA modified with a 3'-phosphoglycolate terminus. From these observations, we infer that deficient removal of 3'-blocking groups formed from the action of oxygen free radicals generated during normal cellular metabolism is the primary underlying cause of the inviability of apn1Delta apn2Delta rad1Delta and apn1Deltaapn2Delta rad10Delta mutants and that such a deficiency accounts also for the severe growth defects of ERCC1- and XPF-deficient mice.


Regrowth of Serotonin Axons in the Adult Mouse Brain Following Injury.
It is widely believed that damaged axons in the adult mammalian brain have little capacity to regrow, thereby impeding functional recovery after injury. Studies using fixed tissue have suggested that serotonin neurons might be a notable exception, but remain inconclusive. We have employed in vivo two-photon microscopy to produce time-lapse images of serotonin axons in the neocortex of the adult mouse. Serotonin axons undergo massive retrograde degeneration following amphetamine treatment and subsequent slow recovery of axonal density, which is dominated by new growth with little contribution from local sprouting. A stab injury that transects serotonin axons running in the neocortex is followed by local regression of cut serotonin axons and followed by regrowth from cut ends into and across the stab rift zone. Regrowing serotonin axons do not follow the pathways left by degenerated axons. The regrown axons release serotonin and their regrowth is correlated with recovery in behavioral tests.


Genetic structure in a fragmented Northern Hemisphere rainforest: large effective sizes and high connectivity among populations of the epiphytic lichen Lobaria pulmonaria.
An extraordinary diversity of epiphytic lichens is found in the boreal rainforest of central Norway, the highest-latitude rainforest in the world. These rainforest relicts are located in ravine systems, and clear cutting has increased the distance between remaining patches. We hypothesized that the relatively small lichen populations in the remaining forest stands have suffered a depletion of genetic diversity through bottlenecks and founder events. To test this hypothesis, we assessed genetic diversity and structure in the populations of the tripartite lichen Lobaria pulmonaria using eight SSR loci. We sampled thalli growing on Picea abies branches and propagules deposited in snow at three localities. Contrary to expectations, we found high genetic diversity in lichen and snow samples, and high effective sizes of the studied populations. Also, limited genetic differentiation between populations, high historical migration rates, and a high proportion of first generation immigrants were estimated, implying high connectivity across distances <30km. Almost all genetic variation was attributed to variation within sites; spatial genetic structures within populations were absent or appeared on small scales (5-10m). The high genetic diversity in the remaining old boreal rainforests shows that even relict forest patches might be suitable for conservation of genetic diversity.


Lessons learned from respondent-driven sampling recruitment in Nairobi: experiences from the field.
Respondent-driven sampling (RDS) is used in a variety of settings to study hard-to-reach populations at risk for HIV and sexually transmitted infections. However, practices leading to successful recruitment among diverse populations in low-resource settings are seldom reported. We implemented the first, integrated, bio-behavioural surveillance survey among men who have sex with men, female sex workers and people who injected drugs in Nairobi, Kenya. The survey period was June 2010 to March 2011, with a target sample size of 600 participants per key populations. Formative research was initially conducted to assess feasibility of the survey. Weekly monitoring reports of respondent characteristics and recruitment chain graphs from NetDraw illustrated patterns and helped to fill recruitment gaps. RDS worked well with men who have sex with men and female sex workers with recruitment initiating at a desirable pace that was maintained throughout the survey. Networks of people who injected drugs were well-integrated, but recruitment was slower than the men who have sex with men and female sex workers surveys. By closely monitoring RDS implementation and conducting formative research, RDS studies can effectively develop and adapt strategies to improve recruitment and improve adherence to the underlying RDS theory and assumptions.


Inhibition of tyrosine kinase receptors by SU6668 promotes abnormal stromal development at the periphery of carcinomas.
Dynamic contrast-enhanced (albumin-Gd-DTPA) magnetic resonance imaging, performed during 2 weeks of daily administration of an inhibitor of tyrosine kinase receptors (SU6668) in an HT-29 colon carcinoma model, revealed the onset of a hyper-enhancing rim, not observed in untreated tumours. To account for tissue heterogeneity in the quantitative analysis, we segmented tumours into three subunits automatically identified by cluster analysis of the enhancement curves using a k-means algorithm. Transendothelial permeability (Kps) and fractional plasma volume (fPV) were calculated in each subunit. An avascular and necrotic region, an intermediate zone and a well-vascularised periphery were reliably identified. During untreated tumour growth, the identified sub-regions did not substantially change their enhancement pattern. Treatment with SU6668 induced major changes at tumour periphery where a significant increase of Kps and fPV was observed with respect to control tumours. Histology revealed a sub-capsular layer composed of hyper-dense viable tumour cells in the periphery of untreated tumours. The rim of viable neoplastic cells was reduced in treated tumours, and replaced by loose connective tissue characterised by numerous vessels, which explains the observed hyper-enhancement. The present data show a peripheral abnormal development of cancer-associated stroma, indicative of an adaptive response to anti-angiogenic treatment.


Top five flashpoints in the assessment of teaching effectiveness.
Despite thousands of publications over the past 90 years on the assessment of teaching effectiveness, there is still confusion, misunderstanding, and hand-to-hand combat on several topics that seem to pop up over and over again on listservs, blogs, articles, books, and medical education/teaching conference programs. If you are measuring teaching performance in face-to-face, blended/hybrid, or online courses, then you are probably struggling with one or more of these topics or flashpoints. To decrease the popping and struggling by providing a state-of-the-art update of research and practices and a "consumer's guide to trouble-shooting these flashpoints." Five flashpoints are defined, the salient issues and research described, and, finally, specific, concrete recommendations for moving forward are proffered. Those flashpoints are: (1) student ratings vs. multiple sources of evidence; (2) sources of evidence vs. decisions: which come first?' (3) quality of "home-grown" rating scales vs. commercially-developed scales; (4) paper-and-pencil vs. online scale administration; and (5) standardized vs. unstandardized online scale administrations. The first three relate to the sources of evidence chosen and the last two pertain to online administration issues. Many medical schools/colleges and higher education in general fall far short of their potential and the available technology to comprehensively assess teaching effectiveness. Specific recommendations were given to improve the quality and variety of the sources of evidence used for formative and summative decisions and their administration procedures. Multiple sources of evidence collected through online administration, when possible, can furnish a solid foundation from which to infer teaching effectiveness and contribute to fair and equitable decisions about faculty contract renewal, merit pay, and promotion and tenure.


Farr's law applied to AIDS projections.
Farr's Law of Epidemics, first promulgated in 1840 and resurrected by Brownlee in the early 1900s, states that epidemics tend to rise and fall in a roughly symmetrical pattern that can be approximated by a normal bell-shaped curve. We applied this simple law to the reported annual incidence of cases of acquired immunodeficiency syndrome in the United States from 1982 through 1987. The 6 years of incidence data closely fit a normal distribution that crests in late 1988 and then declines to a low point by the mid-1990s. The projected size of the epidemic falls in the range of 200 000 cases. A continuing incidence of endemic cases can be expected to emerge, but we believe it will occur at a low level.


Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy.
To investigate the matrix metalloproteinase (MMP) species and their activation associated with the pathogenesis of proliferative diabetic retinopathy (PDR). Sandwich enzyme immunoassays were used to measure concentrations of MMP-1, -2, -3, -7, -8, -9, and -13 in vitreous samples from patients with PDR and nondiabetic vitreoretinal diseases. To evaluate activation ratios of the zymogen of MMP-2 (proMMP-2) and -9 (proMMP-9) in the vitreous samples and fibrovascular tissues, gelatin zymography was performed. Production and tissue localization of MMP-2, membrane type 1-MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP)-2, and MMP-9 in the fibrovascular tissues were examined by immunohistochemistry. mRNA expression of MT1-MMP in the tissues was determined by reverse transcription-polymerase chain reaction (RT-PCR). Among the seven different MMPs examined in the vitreous samples, only the levels of MMP-2 and -9 were significantly higher in the PDR samples than in the control. However, activation ratios of proMMP-2 (10.6% +/- 11.8%) and proMMP-9 (2.5% +/- 5.1%) in PDR vitreous samples were low and not significantly different from those of the control. In contrast, high activation ratios of proMMP-2 (54.3% +/- 13.6%) and notable activation of proMMP-9 (19.5% +/- 7.8%) were observed in the fibrovascular tissues. Immunohistochemical study demonstrated the localization of MMP-2 and -9 in the endothelial cells and glial cells of the fibrovascular tissues. MMP-2 was colocalized with MT1-MMP and TIMP-2, which are an activator and an activation-enhancing factor, respectively, for proMMP-2. RT-PCR analysis indicated the gene expression of MT1-MMP in the tissues. These data demonstrate that proMMP-2 is efficiently activated in the fibrovascular tissues of PDR, probably through interaction with MT1-MMP and TIMP-2, and suggest the possibility that the activity of MMP-2 and MT1-MMP is involved in the formation of the fibrovascular tissues.


HiSStology: high spectral and spatial resolution magnetic resonance imaging detection of vasculature validated by histology and micro-computed tomography.
High spectral and spatial resolution (HiSS) data, acquired with echo-planar spectroscopic imaging (EPSI), can be used to acquire water spectra from each small image voxel. These images are sensitive to changes in local susceptibility caused by superparamagnetic iron oxide particles (SPIO); therefore, we hypothesized that images derived from HiSS data are very sensitive to tumor neovasculature following injection of SPIO. Accurate image registration was used to validate HiSS detection of neovasculature with histology and micro-computed tomographic (microCT) angiography. Athymic nude mice and Copenhagen rats were inoculated with Dunning AT6.1 prostate tumor cells in the right hind limb. The tumor region was imaged pre- and post-intravenous injection of SPIO. Three-dimensional assemblies of the CD31-stained histologic slices of the mouse legs and the microCT images of the rat vascular casts were registered with EPSI. The average distance between HiSS-predicted regions of high vascular density on magnetic resonance imaging and CD31-stained regions on histology was 200 μm. Similarly, vessels identified by HiSS in the rat images coincided with vasculature in the registered microCT image. The data demonstrate a strong correlation between tumor vasculature identified using HiSS and two gold standards: histology and microCT angiography.


Endovascular closure of a patent foramen ovale in the fat embolism syndrome: changes in the embolic patterns as detected by transcranial Doppler.
The posttraumatic fat embolism syndrome (FES) is characterized by petechiae and pulmonary and cerebral dysfunction. A patent foramen ovale (PFO) could worsen the prognosis of FES by allowing larger emboli to reach the systemic circulation. Transcranial Doppler ultrasonography can be used to diagnose and monitor cerebral microembolism in FES. To describe a case of successful percutaneous closure of PFO in a patient with posttraumatic FES with excellent clinical outcome. A 17-year-old girl presented with a posttraumatic long-bone fracture complicated by typical severe FES. Transcranial Doppler disclosed multiple microembolic signals over both middle cerebral and basilar arteries. A large PFO was diagnosed by transesophageal echocardiogram. A brain magnetic resonance image with diffusion-weighted sequences showed multiple bilateral areas of abnormal diffusion in watershed territories. Percutaneous PFO closure with a buttoned device was successfully performed. Closure of PFO was associated with marked reduction in the number and intensity of microembolic signals. Subsequent surgical repair of the fracture with the patient under transcranial Doppler monitoring was uneventful. There was excellent correlation between clinical course and microembolic signal load by transcranial Doppler. Cerebral fat embolism after long-bone fractures can be detected in vivo and monitored over time with the use of transcranial Doppler techniques. If a PFO is present, its closure before surgical manipulation of the fracture is feasible and could have important protective effects against massive systemic embolization.