Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia.
Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death. In two in vitro models of hypoxia reperfusion and an in vivo model of thromboembolic stroke with thrombolysis by PLAT/tPA, we found that ischemia enhances neuronal deleterious autophagy. Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both in vitro and in vivo. We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed in vitro, in vivo and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation.Abbreviations: AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGDreox: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin.


Improved Photoinduced Fluorogenic Alkene-Tetrazole Reaction for Protein Labeling.
The 1,3-dipolar cycloaddition reaction between an alkene and a tetrazole represents one elegant and rare example of fluorophore-forming bioorthogonal chemistry. This is an attractive reaction for imaging applications in live cells that requires less intensive washing steps and/or needs spatiotemporal resolutions. In the present work, as an effort to improve the fluorogenic property of the alkene-tetrazole reaction, an aromatic alkene (styrene) was investigated as the dipolarophile. Over 30-fold improvement in quantum yield of the reaction product was achieved in aqueous solution. According to our mechanistic studies, the observed improvement is likely due to an insufficient protonation of the styrene-tetrazole reaction product. This finding provides useful guidance to the future design of alkene-tetrazole reactions for biological studies. Fluorogenic protein labeling using the styrene-tetrazole reaction was demonstrated both in vitro and in vivo. This was realized by the genetic incorporation of an unnatural amino acid containing the styrene moiety. It is anticipated that the combination of styrene with different tetrazole derivatives can generally improve and broaden the application of alkene-tetrazole chemistry in real-time imaging in live cells.


30 Days Wild: Development and Evaluation of a Large-Scale Nature Engagement Campaign to Improve Well-Being.
There is a need to increase people's engagement with and connection to nature, both for human well-being and the conservation of nature itself. In order to suggest ways for people to engage with nature and create a wider social context to normalise nature engagement, The Wildlife Trusts developed a mass engagement campaign, 30 Days Wild. The campaign asked people to engage with nature every day for a month. 12,400 people signed up for 30 Days Wild via an online sign-up with an estimated 18,500 taking part overall, resulting in an estimated 300,000 engagements with nature by participants. Samples of those taking part were found to have sustained increases in happiness, health, connection to nature and pro-nature behaviours. With the improvement in health being predicted by the improvement in happiness, this relationship was mediated by the change in connection to nature.


Deep-Learning Markerless Tracking of Infant General Movements using Standard Video Recordings.
Monitoring spontaneous General Movements (GM) of infants 6-20 weeks post-term age is a reliable tool to assess the quality of neurodevelopment in early infancy. Abnormal or absent GMs are reliable prognostic indicators of whether an infant is at risk of developing neurological impairments and disorders such as cerebral palsy (CP). Therapeutic interventions are most effective at improving neuromuscular outcomes if administered in early infancy. Current clinical protocols require trained assessors to rate videos of infant movements, a time-intensive task. This work proposes a simple, inexpensive, and broadly applicable markerless pose-estimation approach for automatic infant movement tracking using conventional video recordings from handheld devices (e.g., tablets and mobile phones). We leverage the enhanced capabilities of deep-learning technology in image processing to identify 12 anatomical locations (3 per limb) in each video frame, tracking a baby's natural movement throughout the recordings. We validate the capability of resnet152 and a mobile-net-v2-1 to identify body-parts in unseen frames from a full-term male infant, using a novel automatic unsupervised approach that fuses likelihood outputs of a Kalman filter and the deep-nets. Both deep-net models were found to perform very well in the identification of anatomical locations in the unseen data with high average Percentage of Correct Keypoints (aPCK) performances of >99.65% across all locations.Clinical relevance-Results of this research confirm the feasibility of a low-cost and publicly accessible technology to automatically track infants' GMs and diagnose those at higher risk of developing neurological conditions early, when clinical interventions are most effective.


Center variation and outcomes associated with delayed sternal closure after stage 1 palliation for hypoplastic left heart syndrome.
There is debate whether primary or delayed sternal closure is the best strategy after stage 1 palliation for hypoplastic left heart syndrome. We describe center variation in delayed sternal closure after stage 1 palliation and associated outcomes. Society of Thoracic Surgeons Congenital Database participants performing stage 1 palliation for hypoplastic left heart syndrome from 2000 to 2007 were included. We examined center variation in delayed sternal closure and compared in-hospital mortality, prolonged length of stay (length of stay > 6 weeks), and postoperative infection in centers with low (< or = 25% of cases), middle (26%-74% of cases), and high (> or = 75% of cases) delayed sternal closure use, adjusting for patient and center factors. There were 1283 patients (45 centers) included. Median age at surgery was 6 days (interquartile range, 4-9 days), and median weight at surgery was 3.2 kg (interquartile range, 2.8-3.5 kg); 59% were male. Delayed sternal closure was used in 74% of cases (range, 3%-100% of cases/center). In centers with high (n = 23) and middle (n = 17) versus low (n = 5) delayed sternal closure use, there was a greater proportion of patients with prolonged length of stay and infection, and a trend toward increased in-hospital mortality in unadjusted analysis. In multivariable analysis, there was no difference in mortality. Centers with high and middle delayed sternal closure use had prolonged length of stay (odds ratio, 2.83; 95% confidence interval, 1.46-5.47; P = .002 and odds ratio, 2.23; confidence interval, 1.17-4.26; P = .02, respectively) and more infection (odds ratio, 2.34; confidence interval, 1.20-4.57; P = .01 and odds ratio, 2.37; confidence interval, 1.36-4.16; P = .003, respectively). Use of delayed sternal closure after stage 1 palliation varies widely. These observational data suggest that more frequent use of delayed sternal closure is associated with longer length of stay and higher postoperative infection rates. Further evaluation of the risks and benefits of delayed sternal closure in the management of these complex infants is necessary.


Small RNA changes in synthetic Brassica napus.
Small RNAs and microRNAs were found to vary extensively in synthetic Brassica napus and subsequent generations, accompanied by the activation of transposable elements in response to hybridization and polyploidization. Resynthesizing B. napus by hybridization and chromosome doubling provides an approach to create novel polyploids and increases the usable genetic variability in oilseed rape. Although many studies have shown that small RNAs (sRNAs) act as important factor during hybridization and polyploidization in plants, much less is known on how sRNAs change in synthetic B. napus, particularly in subsequent generations after formation. We performed high-throughput sequencing of sRNAs in S1-S4 generations of synthetic B. napus and in the homozygous B. oleracea and B. rapa parent lines. We found that the number of small RNAs (sRNAs) and microRNAs (miRNAs) doubled in synthetic B. napus relative to the parents. The proportions of common sRNAs detected varied from the S1 to S4 generations, suggesting sRNAs are unstable in synthetic B. napus. The majority of miRNAs (67.2 %) were non-additively expressed in the synthesized Brassica allotetraploid, and 33.3 % of miRNAs were novel in the resynthesized B. napus. The percentage of miRNAs derived from transposable elements (TEs) also increased, indicating transposon activation and increased transposon-associated miRNA production in response to hybridization and polyploidization. The number of target genes for each miRNA in the synthesized Brassica allotetraploid was doubled relative to the parents, enhancing the complexity of gene expression regulation. The potential roles of miRNAs and their targets are discussed. Our data demonstrate generational changes in sRNAs and miRNAs in synthesized B. napus.


Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma.
Cisplatin-based chemotherapy is a standard treatment of metastatic urothelial carcinoma (UC), though carboplatin-based chemotherapy is frequently substituted due to improved tolerability. Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking, a meta-analysis was carried out. PubMed was searched for articles published from 1966 to 2010. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in patients with metastatic UC. Individual patient data were not available and survival data were inconsistently reported. Therefore, the analysis focused on overall response (OR) and complete response (CR) rates. The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RRs). A total of 286 patients with metastatic UC from four randomized trials were included. Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR [RR = 3.54; 95% confidence interval (CI) 1.48-8.49; P = 0.005] and OR (RR = 1.34; 95% CI 1.04-1.71; P = 0.02). Survival end points could not be adequately assessed due to inconsistent reporting among trials. Cisplatin-based, as compared with carboplatin-based, chemotherapy significantly increases the likelihood of both OR and CR in patients with metastatic UC. The impact of improved response proportions on survival end points could not be assessed.


Sex Differences in Hookah-Related Images Posted on Tumblr: A Content Analysis.
Hookah tobacco smoking is prevalent, widespread, and associated with large amounts of toxicants. Hookah tobacco smoking may be viewed differently by males and females. For example, females have been drawn to types of tobacco that are flavored, milder, and marketed as more social and exotic. Individuals often use the growing segment of anonymous social networking sites, such as Tumblr, to learn about potentially dangerous or harmful behaviors. We used a systematic process involving stratification by time of day, day of week, and search term to gather a sample of 140 Tumblr posts related to hookah tobacco smoking. After a structured codebook development process, 2 coders independently assessed all posts in their entirety, and all disagreements were easily adjudicated. When data on poster sex and age were available, we found that 77% of posts were posted by females and 35% were posted by individuals younger than 18. The most prominent features displayed in all posts were references to or images of hookahs themselves, sexuality, socializing, alcohol, hookah smoke, and tricks performed with hookah smoke. Compared with females, males more frequently posted images of hookahs and alcohol-related images or references. This information may help guide future research in this area and the development of targeted interventions to curb this behavior.


Behavioral medicine treatment in chronic constipation with paradoxical anal sphincter contraction.
Nine women and five children with severe chronic constipation received behavioral medicine therapy. Before treatment, all patients had a paradoxical contraction of the external anal sphincter at defecation attempts as demonstrated with electromyography and/or anorectal manometry. An electromyographic biofeedback device connected to an anal probe was used for the training that was performed on a regular toilet seat during five 1-hour sessions. Thirteen of the patients improved considerably and could learn to defecate spontaneously, and the use of laxatives ceased or diminished. Simultaneously with improvement, the paradoxical anal contraction disappeared. The results remained after 6 months, although two of the patients had received booster sessions of biofeedback training during follow-up.


EGF receptor signaling enhances in vivo invasiveness of DU-145 human prostate carcinoma cells.
Carcinomas of the prostate and other lineages often present an autocrine stimulatory loop acting via the EGF receptor (EGFR). We have recently shown that EGFR-mediated signals enhance DU-145 prostate carcinoma cell transmigration of an extracellular matrix in vitro, and that this increased invasiveness was independent of proteolytic degradation of the matrix (Xie et al., 1995, Clin Exp Metastasis, 13, 407). To determine whether up-regulated EGFR signaling promotes tumor progression in vivo and to define the EGFR-induced cell property responsible, we inoculated athymic mice with genetically-engineered DU-145 cells. Parental DU-145 cells and those transduced to overexpress a full-length wild type (WT) EGFR formed tumors and metastasized to the lung when inoculated in the prostate and peritoneal cavity. The WT DU-145 tumors were more invasive. DU-145 cells expressing a mitogenically-active, but motility-deficient (c'973) EGFR formed small, non-invasive tumors without evidence of metastasis. All three sublines demonstrated identical, EGFR-dependent rates of cell growth in vitro, suggesting that the differential invasiveness was not due to altered growth rates. To determine whether cell motility may be, in part, responsible for tumor invasiveness, we treated WT DU-145 intraperitoneal tumors with a pharmacologic agent (U73122) which blocks EGFR-mediated cell motility but not mitogenesis. Under this treatment regimen, the WT DU-145 cells formed tumors of similar numbers and size to those formed without treatment; however, these tumors were much less invasive. These data suggest that EGFR-mediated cell motility is an important mechanism involved in tumor progression, and that this cell property may represent a novel target to limit the spread of tumors.


Public health as a distinct profession: has it arrived?
This article reviews the elements consistent with the definition of a "profession" in the contemporary United States and argues that public health should be considered a distinct profession, recognizing that it has a unique knowledge base and career paths independent of any other occupation or profession. The Welch-Rose Report of 1915 prescribed education for public health professionals and assumed that, although at first the majority of students would be drawn from other professions, such as medicine, nursing, and sanitary engineering, public health was on its way to becoming "a new profession." Nearly a century later, the field of public health has evolved dramatically in the direction predicted. It clearly meets the criteria for being a "profession" in that it has (1) a distinct body of knowledge, (2) an educational credential offered by schools and programs accredited by a specialized accrediting body, (3) career paths that include autonomous practice, and (4) a separate credential, Certified in Public Health (CPH), indicative of self-regulation based on the newly launched examination of the National Board of Public Health Examiners. Barriers remain that challenge independent professional status, including the breadth of the field, more than one accrediting body, wide variation in graduate school curricula, and the newness of the CPH. Nonetheless, the benefits of recognizing public health as a distinct profession are considerable, particularly to the practice and policy communities. These include independence in practice, the ability to recruit the next generation, increased influence on health policy, and infrastructure based on a workforce of strong capacity and leadership capabilities.


Vapor sensing characteristics of nanoelectromechanical chemical sensors functionalized using surface-initiated polymerization.
Surface-initiated polymerization has been used to grow thick, uniform poly(methyl methacrylate) films on nanocantilever sensors. Cantilevers with these coatings yielded significantly greater sensitivity relative to bare devices as well as relative to devices that had been coated with drop-cast polymer films. The devices with surface-initiated polymer films also demonstrated high selectivity toward polar analytes. Surface-initiated polymerization can therefore provide a straightforward, reproducible method for large-scale functionalization of nanosensors.


First-visit diagnosis of preperimetric glaucoma.
To present a revised interpretation of the work-up data that enabled diagnosis of preperimetric glaucoma (PPG) at the first examination. a) Literature analysis on PPG; b) 6-year follow-up of a glaucoma-suspect patient. TWO NEW CONCEPTS MAY BE ADAPTED: (a) the objective finding of retinal nerve fiber layer (RNFL) thinning below the normal border in the opposing typical glaucoma locations, the inferior and superior quadrants, and in a non-diffuse pattern, appears asymptomatically and simultaneously only in glaucoma; and (b) the imaging-related RNFL thickness may be considered the reference glaucoma standard, whereas the suspicious early glaucomatous optic neuropathy, having a potential diagnostic inaccuracy, would serve as a complementary revealing finding. That approach enabled, in retrospect, a first-visit diagnosis of low-tension PPG in the patient. Diagnosis was confirmed after 6 years, when cecocentral scotoma and further RNFL thinning emerged despite treatment. A revised approach enabled PPG diagnosis during the first visit.


The claustrophobia scale: a psychometric evaluation.
This article presents a psychometric evaluation of the Claustrophobia Scale (CS), consisting of one subscale for measuring anxiety (20 items, 0-4) and one for avoidance (18 items, 0-2). Participants were 87 claustrophobic patients and 200 normal controls randomly selected from the community. The results show that CS has excellent internal consistency, high test-retest reliability, concurrent and discriminant validity. The patients and controls differ significantly on the total scores of anxiety and avoidance, as well as on each individual item scores. The CS was also found to be sensitive to change after cognitive behavioral treatment. Preliminary factor analyses yielded two factors for each subscale; "Being in small enclosed spaces" and "Other people present", accounting for large proportions of the variance. The CS is useful both as a state, and as an outcome self-report measure of claustrophobia.


Genome-wide identification and functional analysis of Apobec-1-mediated C-to-U RNA editing in mouse small intestine and liver.
RNA editing encompasses a post-transcriptional process in which the genomically templated sequence is enzymatically altered and introduces a modified base into the edited transcript. Mammalian C-to-U RNA editing represents a distinct subtype of base modification, whose prototype is intestinal apolipoprotein B mRNA, mediated by the catalytic deaminase Apobec-1. However, the genome-wide identification, tissue-specificity and functional implications of Apobec-1-mediated C-to-U RNA editing remain incompletely explored. Deep sequencing, data filtering and Sanger-sequence validation of intestinal and hepatic RNA from wild-type and Apobec-1-deficient mice revealed 56 novel editing sites in 54 intestinal mRNAs and 22 novel sites in 17 liver mRNAs, all within 3' untranslated regions. Eleven of 17 liver RNAs shared editing sites with intestinal RNAs, while 6 sites are unique to liver. Changes in RNA editing lead to corresponding changes in intestinal mRNA and protein levels for 11 genes. Analysis of RNA editing in vivo following tissue-specific Apobec-1 adenoviral or transgenic Apobec-1 overexpression reveals that a subset of targets identified in wild-type mice are restored in Apobec-1-deficient mouse intestine and liver following Apobec-1 rescue. We find distinctive polysome profiles for several RNA editing targets and demonstrate novel exonic editing sites in nuclear preparations from intestine but not hepatic apolipoprotein B RNA. RNA editing is validated using cell-free extracts from wild-type but not Apobec-1-deficient mice, demonstrating that Apobec-1 is required. These studies define selective, tissue-specific targets of Apobec-1-dependent RNA editing and show the functional consequences of editing are both transcript- and tissue-specific.


Modelling charge transport in organic semiconductors: from quantum dynamics to soft matter.
The charge carrier dynamics in organic semiconductors has been traditionally discussed with the models used in inorganic crystalline and amorphous solids but this analogy has severe limitations because of the more complicated role of nuclear motions in organic materials. In this perspective, we discuss how a new approach to the modelling of charge transport is emerging from the alliance between the conventional quantum chemical methods and the methods more traditionally used in soft-matter modelling. After describing the conventional limit cases of charge transport we discuss the problems arising from the comparison of the theory with the experimental and computational results. Several recent applications of numerical methods based on the propagation of the wavefunction or kinetic Monte Carlo methods on soft semiconducting materials are reviewed.


Customised simple limbal epithelial transplantation for recurrent limbal stem cell deficiency.
A 4-year-old boy developed unilateral, total limbal stem cell deficiency (LSCD) following an acid injury. A stable ocular surface was achieved with autologous simple limbal epithelial transplantation (SLET), performed 4 months after the injury. Focal areas of conjunctivalisation were noted in the postoperative period. These were addressed using a novel modification of SLET. A very small piece of limbus from the healthy eye was split into multiple pieces, and applied to the bare corneal stroma with fibrin glue after pannus resection. The surface was covered with amniotic membrane. This resulted in a stable surface, and visual acuity improved to 20/50. The donor remained healthy despite two biopsies being harvested. This case demonstrates that early ocular surface reconstruction may be considered in children with LSCD if amblyopia is a concern. Customised SLET allows surgeons to tackle focal recurrences of LSCD effectively, using minimal limbal tissue from the donor site.


A Rice Autophagy Gene OsATG8b Is Involved in Nitrogen Remobilization and Control of Grain Quality.
Enhancing nitrogen (N) use efficiency is a potential way to reduce excessive nitrogen application and increase yield. Autophagy is a conserved degradation system in the evolution of eukaryotic cells and plays an important role in plant development and stress response. Autophagic cores have two conjugation pathways that attach the product of autophagy-related gene 8 (ATG8) to phosphatidylethanolamine (PE) and ATG5 to ATG12, respectively, which then help with vesicle elongation and enclosure. Rice has six ATG8 genes, which have not been functionally confirmed so far. We identified the rice gene OsATG8b and characterized its role in N remobilization to affect grain quality by generating transgenic plants with its over-expression and knockdown. Our study confirmed the autophagy activity of OsATG8b through the complementation of the yeast autophagy-defective mutant scatg8 and by observation of autophagosome formation in rice. The autophagy activity is higher in OsATG8b-OE lines and lower in OsATG8b-RNAi than that in wild type (ZH11). 15N pulse-chase analysis revealed that OsATG8b-OE plants conferred higher N recycling efficiency to grains, while OsATG8b-RNAi transgenic plants exhibited lower N recycling efficiency and poorer grain quality. The autophagic role of OsATG8b was experimentally confirmed, and it was concluded that OsATG8b-mediated autophagy is involved in N recycling to grains and contributes to the grain quality, indicating that OsATG8b may be a potential gene for molecular breeding and cultivation of rice.


Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis.
Halogenation plays a significant role in the activity of the glycopeptide antibiotics (GPAs), although up until now the timing and therefore exact substrate involved was unclear. Here, we present results combined from in vivo and in vitro studies that reveal the substrates for the halogenase enzymes from GPA biosynthesis as amino acid residues bound to peptidyl carrier protein (PCP)-domains from the non-ribosomal peptide synthetase machinery: no activity was detected upon either free amino acids or PCP-bound peptides. Furthermore, we show that the selectivity of GPA halogenase enzymes depends upon both the structure of the bound amino acid and the PCP domain, rather than being driven solely via the PCP domain. These studies provide the first detailed understanding of how halogenation is performed during GPA biosynthesis and highlight the importance and versatility of trans-acting enzymes that operate during peptide assembly by non-ribosomal peptide synthetases.


Visual outcome and complications of 25-gauge vitrectomy for rhegmatogenous retinal detachment; 84 consecutive cases.
To assess the visual outcome and complications of 25-G transconjunctival sutureless vitrectomy (25G-TSV) for rhegmatogenous retinal detachments. Retrospective, consecutive, interventional case series of 84 eyes of 84 consecutive patients with RRD who underwent 25G-TSV. All surgeries were performed by a single surgeon at a single centre. The initial and final reattachment rates were 95.2 and 100%, respectively. The mean visual acuity improved from 0.78 logarithm of the minimum angle of resolution (logMAR) units to 0.17 logMAR units at the final examination (P<0.001). A macula-off RRD was present preoperatively in 45 of the 84 eyes, and 11 of these eyes (24.4%) developed postoperative retinal complications. Of these complications, one eye had an intraoperative choroidal detachment, five developed a postoperative macular pucker, one eye had a postoperative macular hole, and four eyes developed a retinal redetachment. The percentages of eyes developing retinal complications in the macula-on group (2.6%) was significantly lower than that in the macula-off group (P=0.004). An intraocular pressure (IOP)>or=35 mm Hg was detected in five eyes (6.0%) within the first postoperative week. All of these eyes had a macula-off RRD, and none of the eyes with a macula-on RRD had an elevation of the IOP (P=0.04). Our findings indicate that 25G-TSV is a feasible treatment for RRD and leads to retinal reattachment rates comparable with those following conventional vitrectomy. However, intra- and postoperative retinal complications and postoperative elevation of the IOP can occur especially in eyes with a preoperative macula-off RRD.


Use of plaster casts in the management of diabetic neuropathic foot ulcers.
Neuropathic foot ulceration is a major medical and economic problem among diabetic patients, and the traditional treatment involves bed rest with complete freedom from weight-bearing. We have investigated the use of walking plaster casts in the management of seven diabetic patients with long-standing, chronic plantar ulcers. Although all ulcers healed in a median time of 6 wk, this therapy was not without side effects, which are described in detail. We conclude that casting is a useful therapy for neuropathic ulcers, although several clinic visits, including cast removal and foot inspection, are necessary to avoid potential side effects caused by the casting of insensitive feet.


Investigation of the anti-inflammatory potential of Aloe vera gel (97.5%) in the ultraviolet erythema test.
Aloe vera is a natural product that is frequently used in soothing skin care products such as aftersun lotions. In the present study we aimed to explore the anti-inflammatory potential of a highly concentrated A. vera gel in the UV erythema test in vivo. 40 volunteers with skin types II and III were included in the randomized, double-blind, placebo-controlled, phase III monocenter study. Test areas on the back were irradiated with the 1.5-fold minimal erythema dose of UVB. Subsequently, the test areas were treated occlusively on 2 subsequent days with A. vera gel (97.5%), the positive controls (0.25% prednicarbate, 1% hydrocortisone in placebo gel and 1% hydrocortisone cream) and a placebo gel. Erythema values were determined photometrically after 24 and 48 h. A. vera gel (97.5%) significantly reduced UV-induced erythema after 48 h, being superior to 1% hydrocortisone in placebo gel. In contrast, 1% hydrocortisone in cream was more efficient than A. vera gel. In this study after 48 h the A. vera gel (97.5%) displayed some anti-inflammatory effects superior to those of 1% hydrocortisone in placebo gel. The A. vera gel tested here might be useful in the topical treatment of inflammatory skin conditions such as UV-induced erythema.


Towards a composite scoring solution for the Neurobehavioral Functioning Inventory.
Little research has been conducted towards the development and evaluation of a measure of quality of life specific to head/brain injury populations. Accordingly, we examined responses to the Neurobehavioral Functioning Inventory in the context of a clinical trial for head injury patients (n = 655) conducted in 14 countries. To reduce the 66 item scale into a smaller number of composite scales, principal components analysis was conducted. Scales were constructed assessing four categories of symptoms: cognitive deficits, depression, aggression and somatization. The internal reliabilities (alpha coefficient) of the four scales were generally acceptable (range = 0.79-0.92). Scores on all four scales correlated significantly with patient-rated overall quality of life and all but the aggression scale correlated significantly with overall clinical severity. The need for more formal evaluation of this and other disease-specific measures is discussed.


Characterization of calcium-dependent membrane binding proteins of brain cortex.
Proteins of Mr 68 000, 34 000 and 32 000 were selectively extracted by EGTA from brain cortex. The three proteins that were extracted along with calmodulin were acidic, monomeric, and did not exhibit structural homology, as demonstrated by one-dimensional peptide mapping. The Mr-68 000 protein was purified to homogeneity and had a Stokes radius of 3.54 nm and S20,W value of 5.1S. Purified calmodulin, Mr-68 000 protein and two proteins of Mr 34 000 and Mr 32 000, interacted with the brain particulate fraction, with half-maximal binding occurring at 3.5 microM, 8.3 microM and 150 microM-Ca2+ respectively. Proteins were bound independently of each other and calmodulin. Pretreatment of the particulate fraction with trypsin prevented the Ca2+-dependent binding of calmodulin; however, the binding of the Mr-68 000 protein or the Mr-32 000 and -34 000 proteins was unaffected. The Mr-68 000 protein of bovine brain did not cross-react immunologically with Mr-67 000 calcimedin from chicken gizzard.


Are neighborhood-level characteristics associated with indoor allergens in the household?
Individual home characteristics have been associated with indoor allergen exposure; however, the influence of neighborhood-level characteristics has not been well studied. We defined neighborhoods as community districts determined by the New York City Department of City Planning. We examined the relationship between neighborhood-level characteristics and the presence of dust mite (Der f 1), cat (Fel d 1), cockroach (Bla g 2), and mouse (MUP) allergens in the household. Using data from the Puerto Rican Asthma Project, a birth cohort of Puerto Rican children at risk of allergic sensitization (n = 261), we examined associations between neighborhood characteristics (percent tree canopy, asthma hospitalizations per 1,000 children, roadway length within 100 meters of buildings, serious housing code violations per 1000 rental units, poverty rates, and felony crime rates), and the presence of indoor allergens. Allergen cutpoints were used for categorical analyses and defined as follows: dust mite: >0.25 microg/g; cat: >1 microg/g; cockroach: >1 U/g; mouse: >1.6 microg/g. Serious housing code violations were statistically significantly positively associated with dust mite, cat, and mouse allergens (continuous variables), adjusting for mother's income and education, and all neighborhood-level characteristics. In multivariable logistic regression analyses, medium levels of housing code violations were associated with higher dust mite and cat allergens (1.81, 95%CI: 1.08, 3.03 and 3.10, 95%CI: 1.22, 7.92, respectively). A high level of serious housing code violations was associated with higher mouse allergen (2.04, 95%CI: 1.15, 3.62). A medium level of housing code violations was associated with higher cockroach allergen (3.30, 95%CI: 1.11, 9.78). Neighborhood-level characteristics, specifically housing code violations, appear to be related to indoor allergens, which may have implications for future research explorations and policy decisions.


Resuscitation in the out-of-hospital setting: medical futility criteria for on-scene pronouncement of death.
The complete and irreversible cessation of life is often difficult to determine with complete confidence in the dynamic environment of out-of-hospital emergency care. As a result, resuscitation efforts often are initiated and maintained by emergency medical services (EMS) providers in many hopeless situations. Medical guidelines are reviewed here to aid EMS organizations with respect to decisions about: 1) initiating or waiving resuscitation efforts; 2) the appropriate duration of resuscitation efforts; and 3) recommended procedures for on-scene or prehospital pronouncement of death (termination of resuscitation). In cases of nontraumatic cardiac arrest, few unassailable criteria, other than certain physical signs of irreversible tissue deterioration, exist for determining medical futility at the initial encounter with the patient. Thus, the general medical recommendation is to attempt to resuscitate all patients, adult or child, in the absence of rigor mortis or dependent lividity. Conversely, wellfounded guidelines now are available for decisions regarding termination of resuscitation in such patients once they have received a trial of advanced cardiac life support. In practice, however, the final decision to proceed with on-scene pronouncement of death for these patients may be determined more by family and provider comfort levels and the specific on-scene environment. For patients with posttraumatic circulatory arrest, the type of injury (blunt or penetrating), the presence of vital signs, and the electrocardiographic findings are used to determine the futility of initiating or continuing resuscitation efforts. In general, patients who are asystolic on-scene are candidates for on-scene pronouncement, regardless of mechanism. With a few exceptions, blunt trauma patients with a clearly associated mechanism of lethal injury are generally candidates for immediate cessation of efforts once they lose their pulses and respirations. Regardless of the medical futility criteria, specialized training of EMS providers and targeted related testing of operational issues need to precede field implementation of on-scene pronouncement policies. Such policies also must be modified and adapted for local issues and resources. In addition, although the current determinations of medical futility, as delineated here, are important to establish for societal needs, the individual patient's right to live must be kept in mind always as new medical advances are developed.


Two-timescale projection neural networks in collaborative neurodynamic approaches to global optimization and distributed optimization.
In this paper, we propose a two-timescale projection neural network (PNN) for solving optimization problems with nonconvex functions. We prove the convergence of the PNN with sufficiently different timescales to a local optimal solution. We develop a collaborative neurodynamic approach with multiple such PNNs to search for global optimal solutions. In addition, we develop a collaborative neurodynamic approach with multiple PNNs connected via a directed graph for distributed global optimization. We elaborate on four numerical examples to illustrate the characteristics of the approaches.


Importance of exposure dynamics of metal-based nano-ZnO, -Cu and -Pb governing the metabolic potential of soil bacterial communities.
Metal-based engineered nanomaterials (ENMs) are known to affect bacterial processes and metabolic activities. While testing their negative effects on biological components, studies traditionally rely on initial exposure concentrations and thereby do not take into consideration the dynamic behavior of ENMs that ultimately determines exposure and toxicity (e.g. ion release). Moreover, functional responses of soil microbial communities to ENMs exposure can be caused by both the particulate forms and the ionic forms, yet their relative contributions remain poorly understood. Therefore, we investigated the dynamic changes of exposure concentrations of three different types of ENMs (nano-ZnO, -Cu and -Pb) and submicron particles (SMPs) in relation to their impact on the capacity of soil bacterial communities to utilize carbon substrates. The different ENMs were chosen to differ in dissolution potential. The dynamic exposures of ENMs were considered using a time weighted average (TWA) approach. The joint toxicity of the particulate forms and the ionic forms of ENMs was evaluated using a response addition model. Our results showed that the effect concentrations of spherical nano-ZnO, -Cu and SMPs, and Pb-based perovskites expressed as TWA were lower than expressed as initial concentrations. Both particulate forms and ionic forms of spherical 18nm, 43nm nano-ZnO and 50nm, 100nm nano-Cu contribute to the overall response at the EC50 levels. The particulate forms for 150nm, 200nm and 900nm ZnO SMPs and rod-shaped 78nm nano-Cu mainly affected the soil microbial metabolic potential, while the Cu ions released from spherical 25nm nano-Cu, 500nm Cu SMPs and Pb ions released from perovskites mainly described the effects to bacterial communities. Our results indicate that the dynamic exposure of ENMs and relative contributions of particles and ions require consideration in order to pursue a naturally realistic assessment of environmental risks of metal-based ENMs.


Preparation and evaluation of gelling granules to improve oral administration.
We investigated the preparation of oral granules that are solid when stored and that will swell and gel via water absorption, to address problems experienced by patients when taking medication. Important physical properties of gelling granules include elasticity that is normally smooth, quick water absorption and swelling properties that allow easy swallowing. We selected gelatin (GEL), succinylated gelatin (SUC-GEL) and ι-carrageenan (CAR) as matrix polymers that can undergo gelation at room temperature or at cold temperatures. Saccharide and polyethylene glycol (PEG) were added to prepare the experimental granules. The best matrix gelling granule was SUC-GEL. When xylitol (XYL), sorbitol (SOR) and maltitol (MAL) were added, elasticity was improved, and PEG improved the granule's water absorption behavior, which is an important element involved in gelation. The best granules were prepared by selecting SUC-GEL as the matrix and adding a small amount of PEG and XYL in amounts equal to that of SUC-GEL.


Oxytocin receptor antagonists for inhibiting preterm labour.
Preterm birth, defined as birth before 37 completed weeks, is the single most important cause of perinatal mortality and morbidity in high-income countries. Oxytocin receptor antagonists have been proposed as effective tocolytic agents for women in preterm labour to postpone the birth, with fewer side-effects than other tocolytic agents. To assess the effects on maternal, fetal and neonatal outcomes of tocolysis with oxytocin receptor antagonists for women with preterm labour compared with placebo or no intervention and compared with any other tocolytic agent. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (September 2004), CENTRAL (The Cochrane Library, Issue 3, 2004), MEDLINE (1965 to June 2004), EMBASE (1988 to June 2004). Randomised trials of oxytocin receptor antagonists for tocolysis in the management of women in labour between 20 and 36 weeks' gestation. Two authors independently evaluated methodological quality and extracted trial data. We sought additional information from trial authors. Six trials (1695 women) were included. Compared with placebo, atosiban did not reduce incidence of preterm birth or improve neonatal outcome. In one trial (583 infants), atosiban was associated with an increase in infant deaths at 12 months of age compared with placebo (relative risk (RR) 6.15; 95% confidence intervals (CI) 1.39 to 27.22). However, this trial randomised significantly more women to atosiban before 26 weeks' gestation. Use of atosiban resulted in lower infant birthweight (weighted mean difference -138.31 gm; 95% CI -248.76 to -27.86) and more maternal adverse drug reactions (RR 4.02; 95% CI 2.05 to 7.85, 2 trials, 613 women).Compared with betamimetics, atosiban increased the numbers of infants born under 1500 gm (RR 1.96; 95% CI 1.15 to 3.35, 2 trials, 575 infants). Atosiban was associated with fewer maternal drug reactions requiring treatment cessation (RR 0.04; 95% CI 0.02 to 0.11, number needed to treat 6; 95% CI 5 to 7, 4 trials, 1035 women). This review failed to demonstrate the superiority of atosiban over betamimetics or placebo in terms of tocolytic efficacy or infant outcomes. The finding of an increase in infant deaths in one placebo controlled trial warrants caution. A recent Cochrane review suggests that calcium channel blockers (mainly nifedipine) are associated with better neonatal outcome and fewer maternal side-effects than betamimetics. However, a randomised comparison of nifedipine with placebo is not available. Further well-designed randomised controlled trials of tocolytic therapy are needed. Such trials should incorporate a placebo arm.


Posttraumatic Growth After MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder.
3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder (PTSD) has been shown to significantly reduce clinical symptomatology, but posttraumatic growth (PTG), which consists of positive changes in self-perception, interpersonal relationships, or philosophy of life, has not been studied with this treatment. Participant data (n = 60) were pooled from three Phase 2 clinical studies employing triple-blind crossover designs. Participants were required to meet DSM-IV-R criteria for PTSD with a score higher than 50 on the Clinician-Administered PTSD Scale (CAPS-IV) as well as previous inadequate response to pharmacological and/or psychotherapeutic treatment. Data were aggregated into two groups: an active MDMA dose group (75-125 mg of MDMA; n = 45) or placebo/active control (0-40 mg of MDMA; n = 15). Measures included the Posttraumatic Growth Inventory (PTGI) and the CAPS-IV, which were administered at baseline, primary endpoint, treatment exit, and 12-month follow-up. At primary endpoint, the MDMA group demonstrated more PTG, Hedges' g = 1.14, 95% CI [0.49, 1.78], p < .001; and a larger reduction in PTSD symptom severity, Hedges' g = 0.88, 95% CI [-0.28, 1.50], p < .001, relative to the control group. Relative to baseline, at the 12-month follow-up, within-subject PTG was higher, p < .001; PTSD symptom severity scores were lower, p < .001; and two-thirds of participants (67.2%) no longer met criteria for PTSD. MDMA-assisted psychotherapy for PTSD resulted in PTG and clinical symptom reductions of large-magnitude effect sizes. Results suggest that PTG may provide a new mechanism of action warranting further study.


Coating carbon nanotubes with humic acid using an eco-friendly mechanochemical method: Application for Cu(II) ions removal from water and aquatic ecotoxicity.
In this work, industrial grade multi-walled carbon nanotubes (MWCNT) were coated with humic acid (HA) for the first time by means of a milling process, which can be considered an eco-friendly mechanochemical method to prepare materials and composites. The HA-MWCNT hybrid material was characterized by atomic force microscopy (AFM), scanning electron microscopies (SEM and STEM), X-ray photoelectron spectroscopy (XPS), termogravimetric analysis (TGA), and Raman spectroscopy. STEM and AFM images demonstrated that the MWCNTs were efficiently coated by the humic acid, thus leading to an increase of 20% in the oxygen content at the nanotube surface as observed by the XPS data. After the milling process, the carbon nanotubes were shortened as unveiled by SEM images and the values of ID/IG intensity ratio increased due to shortening of the nanotubes and increasing in the number defects at the graphitic structure of carbon nanotubes walls. The analysis of TGA data showed that the quantity of the organic matter of HA on the nanotube surface was 25%. The HA coating was responsible to favor the dispersion of MWCNTs in ultrapure water (i.e. -42mV, zeta-potential value) and to improve their capacity for copper removal. HA-MWCNTs hybrid material adsorbed 2.5 times more Cu(II) ions than oxidized MWCNTs with HNO3, thus evidencing that it is a very efficient adsorbent material for removing copper ions from reconstituted water. The HA-MWCNTs hybrid material did not show acute ecotoxicity to the tested aquatic model organisms (Hydra attenuata, Daphnia magna, and Danio rerio embryos) up to the highest concentration evaluated (10mgL-1). The results allowed concluding that the mechanochemical method is effective to coat carbon nanotubes with humic acid, thus generating a functional hybrid material with low aquatic toxicity and great potential to be applied in environmental nanotechnologies such as the removal of heavy metal ions from water.


[In relation to the terms infection and infestation].
A study on the terms "infection" and "infestation" is made according to the definitions found in different works. Confusions emerging from their use are commented. The solution of the problem could be achieved by the use of definitions which determine with precision the expresive content of both terms.


Effects of chemical factors on the infectivity of Decapod iridescent virus 1 (DIV1).
The effects of chemical factors on the infectivity of DIV1 have not been fully accessed yet. In order to investigate the stability of DIV1 to strong brine, pH, and other chemical conditions, we conducted a bioassay using clinically healthy Penaeus vannamei individuals. DIV1 inoculum was exposed to various chemical conditions, and the infectivity of DIV1 was determined through intramuscular injection. The results showed that DIV1 lost its infectivity when exposed to strong brine, specifically in a 3 mol/L NaCl solution for a duration of 1 h. Moreover, DIV1 was found to be inactivated within 1 h when subjected to pH levels below 3.1 or above 9.6. Additionally, both Triton X-100 and 1 % formaldehyde demonstrated the ability to inactivate DIV1. These results provide valuable insights into the tolerance of DIV1 towards certain chemical factors, serving as a reference for the establishment of biosecurity measures against DIV1.


Bound transcription factor suppresses photoproduct formation in the NF-kappa B promoter.
The relationship between purified transcription factor p50 binding and ultraviolet light-induced DNA damage formation in the NF-kappa B promoter element was investigated. The effect of bound transcription factor on cyclobutane dimer formation was quantified using Maxam-Gilbert analysis of irradiated substrate digested with T4 phage endonuclease V. Two methods were employed for cleaving (6-4) photoproducts. Sites of (6-4) photoproducts cleaved by piperidine showed a general suppression in the presence of bound p50 protein similar to that observed for cyclobutane dimers. In contrast to piperidine, digestion with ultraviolet damage endonuclease (UVDE) from Saccharomyces pombe subsequent to cyclobutane dimer reversal by photolyase displayed a broader spectrum of damaged sites. Whereas some of these sites were suppressed by bound p50 protein, some remained unaffected and one site showed increased (6-4) photoproduct induction. These data illustrate the advantage of UVDE over piperidine for studying (6-4) photoproducts at the sequence level and suggest that this approach may be useful for footprinting transcription factor binding in other promoters.


Binding of salivary agglutinin to IgA.
SAG (salivary agglutinin), which is identical to gp-340 (glycoprotein-340) from the lung, is encoded by DMBT1 (deleted in malignant brain tumours 1). It is a member of the SRCR (scavenger receptor cysteine-rich) superfamily and contains 14 SRCR domains, 13 of which are highly similar. SAG in saliva is partially complexed with IgA, which may be necessary for bacterial binding. The goal of the present study was to characterize the binding of purified SAG to IgA. SAG binds to a variety of proteins, including serum and secretory IgA, alkaline phosphatase-conjugated IgGs originating from rabbit, goat, swine and mouse, and lactoferrin and albumin. Binding of IgA to SAG is calcium dependent and is inhibited by 0.5 M KCl, suggesting that electrostatic interactions are involved. Binding of IgA was destroyed after reduction of SAG, suggesting that the protein moiety is involved in binding. To pinpoint further the binding domain for IgA on SAG, a number of consensus-based peptides of the SRCR domains and SRCR interspersed domains were designed and synthesized. ELISA binding studies with IgA indicated that only one of the peptides tested, comprising amino acids 18-33 (QGRVEVLYRGSWGTVC) of the 109-amino-acid SRCR domain, exhibited binding to IgA. This domain is identical to the domain of SAG that is involved in binding to bacteria. Despite this similar binding site, IgA did not inhibit binding of Streptococcus mutans to SAG or peptide. These results show that the binding of IgA to SAG is specifically mediated by a peptide sequence on the SRCR domains.


Diet and cancer: one view at the start of the millennium.
The large differences in cancer rates among countries, striking changes in these rates among migrating populations, and rapid changes over time within countries indicate that some aspect of lifestyle or environment is largely responsible for the common cancers in Western countries. Dietary fat has been hypothesized to be the key factor because national consumption is correlated with the international differences, but these correlations are potentially confounded by other aspects of Western lifestyles. Detailed analyses in large prospective studies have not supported an important role of dietary fat. Instead, positive energy balance, reflected in early age at menarche and weight gain as an adult, is an important determinant of breast and colon cancers, consistent with numerous studies in animals. Physical inactivity has also been shown to be a risk factor for these diseases, and in part accounts for the international differences in cancer rates. Although the percentage of calories from fat in the diet does not appear related to risk of colon cancer, greater risks have been seen with higher consumption of red meat, suggesting that factors other than fat per se may be important. In many case-control studies a high consumption of fruits and vegetables has been associated with reduced risks of numerous cancers, but recent prospective studies suggest these associations may have been overstated. Among the factors in fruits and vegetables that have been examined in relation to cancer risk, present data most strongly support a benefit of higher folic acid consumption in reducing risks of colon and breast cancers. These findings have been bolstered by an association between incidence of colon cancer and a polymorphism in the gene for methylenetetrahydrofolate reductase, an enzyme involved in folic acid metabolism. The benefits of folic acid appear strongest among persons who regularly consume alcohol, which itself is associated with risk of these cancers. Numerous other aspects of diet are hypothesized to influence the risks of cancers in Western countries, but for the moment the evidence is unclear. Two decades of effort in developing, evaluating, and refining methods of dietary assessment have laid the groundwork for further insights into the role of diet in cancer etiology that will emerge from the more than 30 large prospective studies that are currently underway.


Structural basis for the rescue of stalled ribosomes: structure of YaeJ bound to the ribosome.
In bacteria, the hybrid transfer-messenger RNA (tmRNA) rescues ribosomes stalled on defective messenger RNAs (mRNAs). However, certain gram-negative bacteria have evolved proteins that are capable of rescuing stalled ribosomes in a tmRNA-independent manner. Here, we report a 3.2 angstrom-resolution crystal structure of the rescue factor YaeJ bound to the Thermus thermophilus 70S ribosome in complex with the initiator tRNA(i)(fMet) and a short mRNA. The structure reveals that the C-terminal tail of YaeJ functions as a sensor to discriminate between stalled and actively translating ribosomes by binding in the mRNA entry channel downstream of the A site between the head and shoulder of the 30S subunit. This allows the N-terminal globular domain to sample different conformations, so that its conserved GGQ motif is optimally positioned to catalyze the hydrolysis of peptidyl-tRNA. This structure gives insights into the mechanism of YaeJ function and provides a basis for understanding how it rescues stalled ribosomes.


Identification of factors influencing the pharmacokinetics of voriconazole and the optimization of dosage regimens based on Monte Carlo simulation in patients with invasive fungal infections.
The objective of this study was to estimate the population pharmacokinetics of voriconazole, to identify the factors influencing voriconazole pharmacokinetics and to identify optimal dosage regimens for attaining target pharmacokinetic/pharmacodynamic indices against Aspergillus and Candida infections in patients with invasive fungal infections (IFIs). To prospectively quantify the relationships between the pharmacokinetic parameters of voriconazole and covariates, a population pharmacokinetic analysis was conducted on pooled data from 406 samples taken from 151 patients with IFIs. Voriconazole plasma concentrations were measured by HPLC. The following covariates were tested: demographic factors, laboratory data, concomitant medications and CYP2C19 genotype. Monte Carlo simulation was used to evaluate the effectiveness of the currently recommended dosage regimen and to design an optimized pharmacodynamic dosage strategy for voriconazole. The data were appropriately fit by a one-compartment model with first-order absorption and elimination. The voriconazole clearance (CL) was 6.95 L/h, the volume of distribution (V) was 200 L and the oral bioavailability (F) was 89.5%. CL was significantly associated with age, the serum concentration of alkaline phosphatase and the CYP2C19 genotype. Based on the results of the Monte Carlo stimulation, we concluded that Aspergillus infections could be treated effectively with 200 mg of voriconazole administered intravenously or orally twice daily and that Candida infections could be treated with 300 mg administered orally twice daily or with 200 mg administered intravenously twice daily. This study showed that optimal voriconazole dosage regimens could be determined successfully with prospective population pharmacokinetic analyses and Monte Carlo simulations.


NuSTAR Observation of Energy Release in 11 Solar Microflares.
Solar flares are explosive releases of magnetic energy. Hard X-ray (HXR) flare emission originates from both hot (millions of Kelvin) plasma and nonthermal accelerated particles, giving insight into flare energy release. The Nuclear Spectroscopic Telescope ARray (NuSTAR) utilizes direct-focusing optics to attain much higher sensitivity in the HXR range than that of previous indirect imagers. This paper presents 11 NuSTAR microflares from two active regions (AR 12671 on 2017 August 21 and AR 12712 on 2018 May 29). The temporal, spatial, and energetic properties of each are discussed in context with previously published HXR brightenings. They are seen to display several "large flare" properties, such as impulsive time profiles and earlier peak times in higher-energy HXRs. For two events where the active region background could be removed, microflare emission did not display spatial complexity; differing NuSTAR energy ranges had equivalent emission centroids. Finally, spectral fitting showed a high-energy excess over a single thermal model in all events. This excess was consistent with additional higher-temperature plasma volumes in 10/11 microflares and only with an accelerated particle distribution in the last. Previous NuSTAR studies focused on one or a few microflares at a time, making this the first to collectively examine a sizable number of events. Additionally, this paper introduces an observed variation in the NuSTAR gain unique to the extremely low livetime (<1%) regime and establishes a correction method to be used in future NuSTAR solar spectral analysis.


Simulation of Lipid-Lowering Therapy Intensification in a Population With Atherosclerotic Cardiovascular Disease.
In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend optimizing statin treatment, and consensus pathways suggest use of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with persistently elevated low-density lipoprotein cholesterol (LDL-C) levels despite use of statins. Recent trials have provided evidence of benefit in reduction of cardiovascular events with these agents. To estimate the percentage of patients with ASCVD who would require a PCSK9 inhibitor when oral lipid-lowering therapy (LLT) is intensified first. This simulation model study used a large administrative database of US medical and pharmacy claims to identify a cohort of 105 269 patients with ASCVD enrolled from January 1, 2012, through December 31, 2013, who met the inclusion criteria (database cohort). Patients were sampled with replacement (bootstrapping) to match the US epidemiologic distribution and entered into a Monte Carlo simulation (simulation cohort) that applied stepwise treatment intensification algorithms in those with LDL-C levels of at least 70 mg/dL. All patients not initially receiving a statin were given atorvastatin, 20 mg, and the following LLT intensification steps were applied: uptitration to atorvastatin, 80 mg; add-on ezetimibe therapy; add-on alirocumab therapy, 75 mg (a PCSK9 inhibitor); and uptitration to alirocumab, 150 mg. Sensitivity analyses included evolocumab as a PCSK9 inhibitor. Efficacy was estimated from published studies and incorporated patient-level variation. Data were analyzed from December 2015 to May 2017. Treatment intensification strategies with LLT. Use of LLT among the population with ASCVD and distributions of LDL-C levels under various treatment intensification scenarios. Inclusion criteria were met by 105 269 individuals in the database cohort (57.2% male and 42.8% female; mean [SD] age, 65.1 [12.1] years). In the simulation cohort (1 million patients; 54.8% male and 45.2% female; mean [SD] age, 66.4 [12.2] years), before treatment intensification, 51.5% used statin monotherapy and 1.7% used statins plus ezetimibe. Only 25.2% achieved an LDL-C level of less than 70 mg/dL. After treatment intensification, 99.3% could achieve an LDL-C level of less than 70 mg/dL, including 67.3% with statin monotherapy, 18.7% with statins plus ezetimibe, and 14% with add-on PCSK9 inhibitor. Large gaps exist between recommendations and current practice regarding LLT in the population with ASCVD. In our model that assumes no LLT intolerance and full adherence, intensification of oral LLT could achieve an LDL-C level of less than 70 mg/dL in most patients, with only a modest percentage requiring a PCSK9 inhibitor.


Safety and Efficacy of Cortisol Phosphate in Hyaluronic Acid Vehicle in the Treatment of Dry Eye in Sjogren Syndrome.
Evaluation of 0.3% cortisol phosphate eye drops in hyaluronic acid vehicle in the treatment of dry eye in Sjogren Syndrome. This prospective, single-center, masked (single blind), randomized controlled study included 40 female patients divided into 2 groups, group 1 treated with Idracemi, 0.3% cortisol phosphate eye drops twice a day, and group 2 treated with Cortivis, 0.3% cortisol phosphate in hyaluronic acid vehicle, with the same posology. Screening (day -7), randomization (day 0), follow-up (day 7), and termination (day 28) visits were conducted. Symptoms (VAS) questionnaire, tear film breakup time, corneo-conjunctival stain, intraocular pressure (IOP) measurement, and fundus examination were performed at each visit. Conjunctival impression cytology for human leukocyte antigen-DR (HLA-DR) expression at visit 1 and 4 was also performed. No changes in IOP or fundus examination were observed in either group at each time point. Group 1 showed at day 28 a statistically significant amelioration of symptoms and reduction of HLA-DR expression. Group 2 showed at day 7 statistically significant improvement of corneal and conjunctival stain versus baseline and versus group 1; the symptom score was statistically significantly better than baseline and versus group 1 after 28 days too. The HLA-DR expression and the epithelial cell area were statistically significantly reduced versus baseline and versus group 1 at the same time. Cortisol phosphate proved to be safe and effective in treating dry eye in Sjogren Syndrome patients in both formulations. However, the formula with hyaluronic acid vehicle proved to be more effective. Both formulations were very well tolerated.


Ozaki procedure-re-construction of aortic valve leaflets using autologous pericardial tissue: a review.
The Ozaki procedure has emerged as a valuable option for treating various aortic valve pathologies. This review article delves into the intricacies of this innovative surgical approach by exploring its adaptation to the complex anatomy and physiology of the aortic root. The diverse etiologies of aortic valve diseases, ranging from congenital anomalies to degenerative changes, make treatment selection a complex challenge. Aortic valve replacement has traditionally been the gold standard, but emerging evidence supports valve repair techniques, emphasizing the importance of preserving native tissue. Nevertheless, issues like lifelong anticoagulation with mechanical valves and patient-prosthetic mismatch remain. The Ozaki procedure offers a compelling alternative by utilizing autologous pericardium or a tissue substitute to construct new aortic valve leaflets. This technique, standardized by Dr. Ozaki in 2007, provides a customizable and adaptable solution. The article highlights the anatomy of the aortic root, emphasizing the critical role of the sinus of Valsalva and interleaflet triangles in maintaining proper valve function. The procedure's unique adaptation to aortic root dynamics allows for reduced mechanical stress during systole and diastole, mimicking the natural valve's behavior. Furthermore, Ozaki leaflets exhibit promising hemodynamics and reduced risks of complications, such as permanent pacemaker implantation and patient-prosthetic mismatch. The use of autologous pericardium in the Ozaki procedure presents advantages, including enhanced tissue strength, minimal immunogenicity, and reduced risk of immune-mediated calcification. These factors contribute to the longevity and resilience of the reconstructed valve. This comprehensive review aims to shed light on the procedure's intricacies, its alignment with aortic root anatomy and physiology, and its potential as a valuable tool in the armamentarium of aortic surgeons.


Contrast Adaptation in Face Perception Revealed Through EEG and Behavior.
Exposure to a face can produce biases in the perception of subsequent faces. Typically, these face aftereffects are studied by adapting to an individual face or category (e.g., faces of a given gender) and can result in renormalization of perceptions such that the adapting face appears more neutral. These shifts are analogous to chromatic adaptation, where a renormalization for the average adapting color occurs. However, in color vision, adaptation can also adjust to the variance or range of colors in the distribution. We examined whether this variance or contrast adaptation also occurs for faces, using an objective EEG measure to assess response changes following adaptation. An average female face was contracted or expanded along the horizontal or vertical axis to form four images. Observers viewed a 20 s sequence of the four images presented in a fixed order at a rate of 6 Hz, while responses to the faces were recorded with EEG. A 6 Hz signal was observed over right occipito-temporal channels, indicating symmetric responses to the four images. This test sequence was repeated after 20 s adaptation to alternations between two of the faces (e.g., horizontal contracted and expanded). This adaptation resulted in an additional signal at 3 Hz, consistent with asymmetric responses to adapted and non-adapted test faces. Adapting pairs have the same mean (undistorted) as the test sequence and thus should not bias responses driven only by the mean. Instead, the results are consistent with selective adaptation to the distortion axis. A 3 Hz signal was also observed after adapting to face pairs selected to induce a mean bias (e.g., expanded vertical and expanded horizontal), and this signal was not significantly different from that observed following adaption to a single image that did not form part of the test sequence (e.g., a single image expanded both vertically and horizontally). In a further experiment, we found that this variance adaptation can also be observed behaviorally. Our results suggest that adaptation calibrates face perception not only for the average characteristics of the faces we experience but also for the gamut of faces to which we are exposed.


Patient Perspectives on the Use of Artificial Intelligence for Skin Cancer Screening: A Qualitative Study.
The use of artificial intelligence (AI) is expanding throughout the field of medicine. In dermatology, researchers are evaluating the potential for direct-to-patient and clinician decision-support AI tools to classify skin lesions. Although AI is poised to change how patients engage in health care, patient perspectives remain poorly understood. To explore how patients conceptualize AI and perceive the use of AI for skin cancer screening. A qualitative study using a grounded theory approach to semistructured interview analysis was conducted in general dermatology clinics at the Brigham and Women's Hospital and melanoma clinics at the Dana-Farber Cancer Institute. Forty-eight patients were enrolled. Each interview was independently coded by 2 researchers with interrater reliability measurement; reconciled codes were used to assess code frequency. The study was conducted from May 6 to July 8, 2019. Artificial intelligence concept, perceived benefits and risks of AI, strengths and weaknesses of AI, AI implementation, response to conflict between human and AI clinical decision-making, and recommendation for or against AI. Of 48 patients enrolled, 26 participants (54%) were women; mean (SD) age was 53.3 (21.7) years. Sixteen patients (33%) had a history of melanoma, 16 patients (33%) had a history of nonmelanoma skin cancer only, and 16 patients (33%) had no history of skin cancer. Twenty-four patients were interviewed about a direct-to-patient AI tool and 24 patients were interviewed about a clinician decision-support AI tool. Interrater reliability ratings for the 2 coding teams were κ = 0.94 and κ = 0.89. Patients primarily conceptualized AI in terms of cognition. Increased diagnostic speed (29 participants [60%]) and health care access (29 [60%]) were the most commonly perceived benefits of AI for skin cancer screening; increased patient anxiety was the most commonly perceived risk (19 [40%]). Patients perceived both more accurate diagnosis (33 [69%]) and less accurate diagnosis (41 [85%]) to be the greatest strength and weakness of AI, respectively. The dominant theme that emerged was the importance of symbiosis between humans and AI (45 [94%]). Seeking biopsy was the most common response to conflict between human and AI clinical decision-making (32 [67%]). Overall, 36 patients (75%) would recommend AI to family members and friends. In this qualitative study, patients appeared to be receptive to the use of AI for skin cancer screening if implemented in a manner that preserves the integrity of the human physician-patient relationship.


Assessment of left ventricular regional wall motion and ejection fraction with low-radiation dose helical dual-source CT: comparison to two-dimensional echocardiography.
Electrocardiographic (ECG)-based tube current modulation during cardiac CT reduces radiation exposure but significantly increases noise in parts of the cardiac cycle where tube current is minimized. We evaluated the effect of maximal ECG-based tube current reduction on left ventricular (LV) regional wall motion assessment and ejection fraction (EF) by comparing low-radiation helical dual-source CT (DSCT) to 2-dimensional transthoracic echocardiography (2D-TTE). We studied 83 consecutive patients (15 with prior myocardial infarction) who underwent helically acquired DSCT coronary angiography with maximal ECG-based tube current modulation (low-radiation helical DSCT) and 2D-TTE within a 6-month period (median, 1 day), without any change in clinical status between the studies. In all patients, full tube current was applied only at 70% of the R-R interval, with minimal tube current (4% of maximum) in all other parts of the cardiac cycle. Reduced tube voltage (100 kVp) was combined with the maximal dose modulation in 34 patients. DSCT datasets were evaluated by a blinded, experienced cardiologist. Regional wall motion was assessed with the standard 17-segment model, with each segment scored as normal, hypokinetic, akinetic, and dyskinetic. Mean effective radiation dose for the low-radiation helical DSCT was 5.2 ± 1.7 mSv. Regional wall motion was evaluable in all segments on low-radiation helical DSCT. There was excellent agreement of wall motion scoring by low-radiation helical DSCT and 2D-TTE in 1382 of 1411 segments (98%; Cohen's κ value 0.83; 95% confidence interval, 0.76-0.89; P < 0.0001). Mean LVEF was 67.6% ± 10.3% on low-radiation helical DSCT and 61.8% ± 10.3% on 2D-TTE (P < 0.0001). Low-radiation dose helical coronary CT angiography with maximal ECG-based tube current modulation is comparable to 2D-TTE for regional wall motion and EF assessment.


Expression of insulin-like growth factor-II and insulin-like growth factor binding proteins during Caco-2 cell proliferation and differentiation.
The components of the insulin-like growth factor (IGF) axis and their roles in regulating proliferation and differentiation of the human colon adenocarcinoma cell line, Caco-2, have been investigated. Caco-2 cells proliferated in serum-free medium at 75% the rate observed in medium containing 10% fetal bovine serum. IGF-I (10 nM) increased Caco-2 cell growth in serum-free medium, but not to the rate seen with serum. Multiple IGF-II mRNA species were produced by Caco-2 cells, but IGF-I mRNA was undetectable. Secretion of radioimmunoassayable IGF-II corresponded with steady-state levels of IGF-II mRNA, neither of which was observed to change markedly over the course of 16 days of Caco-2 cell differentiation. Levels of sucrase-isomaltase mRNA, a marker for enterocytic differentiation, increased 12-fold between days 5 and 16 of culture. Northern blotting of total RNA and ligand blot and immunoblot analyses of serum-free conditioned medium revealed that Caco-2 cells produce several IGF binding proteins (IGFBPs), including IGFBP-2, -3, and -4, as well as a 31,000 M(r) species that was not identified. The pattern of IGFBP secretion changed dramatically during Caco-2 cell differentiation: IGFBP-3 and IGFBP-2 increased 8.5-fold and 5-fold, respectively, whereas IGFBP-4 and the 31,000 M(r) species decreased 43% and 90%. Caco-2 cell clones stably transfected with a human IGFBP-4 cDNA construct exhibited a 60% increase in steady-state level of IGFBP-4 mRNA, and secreted twice as much IGFBP-4 protein as controls. Moreover, IGFBP-4-overexpressing cells proliferated at only 25% the rate of control cells in serum-free medium, in conjunction with a 70% increase in expression of sucrase-isomaltase. In summary, these studies indicate that a complex IGF axis is involved in autocrine regulation of Caco-2 cell proliferation and differentiation.


Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice.
Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8-10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6-8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain.


Clinical and microbiological characteristics of bloodstream infections in a tertiary hospital in Maceió, Alagoas, Brazil.
We observed the clinical and microbiological characteristics of several stages of bloodstream infections (BSI), as well as the mortality attributed to it in a tertiary hospital in the northeast of Brazil (in the city of Maceió, Alagoas). A prospective cohort of 143 patients who had at least one positive blood culture was enrolled in the study. Their clinical evolution was followed up for 30 days from October 2005 to December 2006. The relation among the qualitative variables was verified through Chi-square test. The significance level was 5%. The statistical package adopted was SPSS 15.0 for Windows. Up to the thirtieth day, 30.1% of the patients presented bacteremia and 69.9% developed sepsis. Among these, 20.3% developed severe sepsis and 10.5% septic shock. The mortality attributed to it was 37.8%. In bacteremia, sepsis, severe sepsis, and septic shock conditions, mortality rates were 9.3%, 50%, 65.5%, and 84.6%, respectively. Respiratory (32.2%) and urinary (14%) sources and the ones related to central venous catheter (14%) were prevalent. In the wards 55.12% of the cases developed sepsis, whereas in the intensive care units, the rate was 87.69% (p < 0.05). Chronic renal failure, diabetes mellitus, and neuropathy were present in 21.7%, 26.6%, and 29.4% of the cases, respectively. Coagulase-negative Staphylococcus (25.9%), Staphylococcus aureus (21%), and Klebsiella pneumoniae (14%) were the most present microorganism in the sample. The high morbidity and mortality rates in this study are attributed to the lack of knowledge on BSI characteristics and on instituted protocols for detection and treatment in early stages.


Middle-third facial advancement: treatment considerations in atypical cases.
A systematic evaluation of facial esthetics in individuals with dentofacial and craniofacial deformities is necessary to achieve optimum results. This is especially true in deformities of the middle third of the face, as cephalometric analyses provide minimal useful information about frontal facial esthetics. Further, three-dimensional interrelations of the appearance of the forehead, nasal dorsum, globe, infraorbital, malar, and paranasal regions cannot be adequately evaluated through cephalometric examination. Many individuals with facial deformities do not have stereotyped deformities, and, therefore, the use of "standard" operations to correct apparently similar deformities will result in less than optimal results.


Evaluation of Liver Function Tests and Risk Score Assessment to Screen Patients for Significant Liver Disease Prior to Bariatric and Metabolic Surgery.
Bariatric and metabolic surgery is associated with significant improvement in obesity-related comorbidities, but for patients with non-alcoholic fatty liver disease (NAFLD), clinical outcomes are dependent on the severity of liver disease, i.e. improvement of NAFLD in most patients but increased risks of fulminant hepatic failure and/or bleeding varices in patients with more advanced cirrhosis. Our study showed that absolute values of liver enzymes were poor indicator of risk of liver fibrosis. The use of AST/ALT ratio, Fib 4 or NAFLD scores were appropriate screening tools, with each risk score appearing to pick out a certain phenotype of patients based on age, BMI or individual values of ALT, AST or platelet count. There is lack of agreement in some cases between FIB-4 scores and NAFLD scores when ruling out patients at high risk of liver fibrosis. Meticulous screening of patients at risk of liver fibrosis is crucial in order to reduce the risk of liver-related complications following bariatric and metabolic surgery.


An immunohistochemical study of chromogranin A and Sp-1 immunoreactive cells in the gastrointestinal tract of ovariectomized rats.
The changes on the regional distributions and frequencies of two types of chromogranin, chromogranin A (CGA) and bovine Sp-1 chromogranin (BCG)-immunoreactive (IR) cells in gastrointestinal (GI) tract of osteoporotic Sprague-Dawley rat induced by ovariectomy were studied by immunohistochemical methods. The experimental animals were divided into two groups, one is non-ovariectomized group (Sham) and the other is ovariectomized group (OVX). Samples were collected from each part of GI tract at 10th week after ovariectomy or sham operation. CGA-IR cells were restricted to the stomach regions with various frequencies regardless of ovariectomy except for the fundus of OVX in which no cells were detected. In addition, BCG-IR cells were also restricted to the pylorus and duodenum regardless of ovariectomy. A significantly decrease of CGA IR cells was detected in OVX compared to that of Sham in both fundus and pylorus, and BCG-IR cells were also significantly decreased in the duodenum(p < 0.05). However, in the pylorus, BCG-IR cells in OVX showed similar frequency compared to that of Sham. In conclusion, the abnormality in density of chromogranin, a generally used GI endocrine cell marker, detected in this study may contribute to the development of GI symptoms in osteoporosis such as impairments of calcium and some lipids, frequently encountered in patients with postmenopausal osteoporosis.


Increased 5-hydroxytryptamine-2 receptor binding in the frontal cortex of depressed patients responding to paroxetine treatment: a positron emission tomography scan study.
The changes in aminergic receptors elicited by antidepressant treatments have been extensively examined in the brain of experimental animals using radioligand and molecular techniques. However, there is a very limited direct information regarding the changes effected by such treatments in the human brain, as well as its relationship to clinical improvement. Using positron emission tomography (PET) scanning, the authors examined the cortical 5-Hydroxytryptamine-2A (5-HT2A) receptor binding of [18F]fluoro-ethyl-spiperone after a 4-week treatment with the selective serotonin reuptake inhibitor paroxetine. [18F]fluoro-ethyl-spiperone labels 5-HT2A receptors in the cortex and dopamine D2 receptors in the basal ganglia. A binding index (BI) was calculated in the frontal cortex and the basal ganglia (mostly caudate-putamen) by reference to cerebellum. Thirty-seven inpatients with major depression with a mean +/- SD score on the 21-item Hamilton Rating Scale for Depression (HAM-D-21) of 26.3 +/- 4.3 at admission were treated with paroxetine 40 mg/day. After 4 weeks of treatment, the BI in the frontal cortex of remitted patients (HAM-D-21 score = 4.7 +/- 4.0; N = 20) was significantly greater than the score in nonresponder patients (HAM-D-21 score = 21.2 +/- 4.0; N = 17) (BI = 0.54 +/- 0.15 and 0.41 +/- 0.17, respectively; p < 0.02). No such difference was observed in the basal ganglia (5.45 +/- 1.11 and 5.39 +/- 0.82, respectively; p = 0.85). The significant difference in cortical BI persisted when age was used as covariate (p < 0.016). These data suggest that clinical improvement in patients treated with paroxetine is associated with an increase in the density of 5-HT2A receptors in the frontal cortex.


No Difference Between Posterolateral Corner Repair and Reconstruction With Concurrent ACL Surgery: Results From a Prospective Multicenter Cohort.
Injuries to the posterolateral corner (PLC) may occur concurrently with anterior cruciate ligament (ACL) injury. This study evaluated the outcomes of patients who underwent operative management of PLC injuries concurrently with ACL reconstruction in a prospective multicenter cohort. We hypothesized that there would be no differences in outcomes between patients who were treated with PLC repair and PLC reconstruction. Cohort study; Level of evidence, 3. Patients undergoing ACL reconstruction were enrolled into a prospective longitudinal multicenter cohort between 2002 and 2008. Those with complete 6-year follow-up data (patient-reported outcomes and subsequent surgery information) were identified. Excluded from the study were patients with posterior cruciate ligament injuries. Patients who underwent PLC repair were compared with those who underwent PLC reconstruction with regard to interval from injury to surgery, need for revision surgery, and long-term outcomes at 6 years. During the identified time frame, 3026 identified patients underwent primary ACL reconstruction; 34 (1.1%) also underwent concurrent PLC surgery (15 repairs, 19 reconstructions [18 allografts, 1 autograft]). With the numbers available, we did not detect significant differences between groups regarding the rate of meniscal or chondral injuries. Median time to PLC reconstruction was 121 days as compared with 19 days for concurrent ACL reconstruction and PLC repair (P = .01). There were no between-group differences in Marx activity scores prior to surgery (P = .4). At 6-year follow-up, there were no between-group differences in Knee injury and Osteoarthritis Outcome Score (P = .36-.83) or International Knee Documentation Committee score (P = .84); however, patients treated with PLC reconstructions had lower Marx activity scores (4.1 vs 9.4; P = .02). There was 1 ACL revision in the PLC reconstruction group, and 1 of the PLC repairs was revised to a reconstruction during the follow-up period. Good outcomes were achieved at 6-year follow-up with both repair and reconstruction of PLC injuries treated concurrently with ACL reconstruction. The PLC reconstruction group had lower activity levels 6 years after surgery. The present data suggest that, for appropriately selected patients undergoing acute surgical treatment of combined ACL and PLC injuries, PCL repair can achieve good long-term outcomes.


IL-7Rαlow memory CD8+ T cells are significantly elevated in patients with systemic lupus erythematosus.
Human effector memory (EM) CD8(+) T cells include IL-7Rα(high) and IL-7Rα(low) cells with distinct cellular characteristics, including the expression of cytotoxic molecules. Both NK cells and the NK cell-associated molecule 2B4 that is expressed on CD8(+) T cells promote cytotoxicity. Here we analysed the expression of 2B4 on IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells and its contribution to cytotoxicity. We also analysed the frequency of IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells in patients with SLE or lupus and in healthy individuals given the potential role of cytotoxic CD8(+) T cells in the pathogenesis of lupus. We used flow cytometry to measure the expression of 2B4 on IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells as well as the frequency of these cell populations in the peripheral blood of healthy individuals and patients with SLE. Also, 2B4-mediated cytotoxicity was quantitated in IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells using target cells with CD48 antigen. We found that IL-7Rα(high) EM CD8(+) T cells had higher levels of 2B4 expression compared with IL-7Rα(low) EM CD8(+) T cells. Triggering 2B4 enhanced the cytotoxic function of IL-7Rα(low) EM CD8(+) T cells against target cells. We also noticed that patients with SLE had an increased frequency of IL-7Rα(low) EM CD8(+) T cells that correlated with disease manifestation. Our findings show that SLE patients have increased IL-7Rα(low) EM CD8(+) T cells, possibly contributing to tissue damage through 2B4-mediated cytotoxicity.


National Academy of Neuropsychology/Division 40 of the American Psychological Association Practice Survey of Clinical Neuropsychology in the United States. Part II: Reimbursement experiences, practice economics, billing practices, and incomes.
Leaders of the National Academy of Neuropsychology and Division 40 (Clinical Neuropsychology) of the American Psychological Association determined that current information on the professional practice of clinical neuropsychology within the United States was needed. These two organizations co-sponsored a national survey of U.S. clinical neuropsychologists that was conducted in September 2000. The primary goal of the survey was to gather information on such topics as: practitioner and practice characteristics, economic variables (e.g., experience with major third party payors, such as Medicare and managed care), practice expenses, billing methods, experiences with Current Procedural Terminology (CPT) codes, time spent on various clinical tasks, use of assistants, and income. In this second of two articles describing the survey results, reimbursement experiences, practice economics, billing practices, and incomes are highlighted. Survey results indicate that neuropsychologists frequently have difficulty gaining access to membership on managed care panels. For those who gain access, managed care companies often limit provision of services; this is quite often perceived as negatively affecting quality of patient care. It is very common for neuropsychologists to feel obligated to provide more services to managed care and Medicare patients than are allowed to be billed to the insurance carrier; these hours are typically "written off." Numerous CPT codes are used to bill the same clinical service. Awareness of Medicare practice and billing expectations is variable among practitioners, as is awareness of public aid/Medicaid billing status. Professional income is influenced by years of licensed practice, practice setting, gender, types and amounts of non-clinical professional activities, and types and amounts of reimbursement sources within one's clinical practice. Income of neuropsychologists has only a minimal relationship to percentage of clinical practice per week. Within the context of prior surveys, neuropsychologists are engaging in more clinical hours per week and, nevertheless, compared to data from 1993, are reporting decreased income. These and other findings are presented and discussed.


Airline pilot cosmic radiation and circadian disruption exposure assessment from logbooks and company records.
US commercial airline pilots, like all flight crew, are at increased risk for specific cancers, but the relation of these outcomes to specific air cabin exposures is unclear. Flight time or block (airborne plus taxi) time often substitutes for assessment of exposure to cosmic radiation. Our objectives were to develop methods to estimate exposures to cosmic radiation and circadian disruption for a study of chromosome aberrations in pilots and to describe workplace exposures for these pilots. Exposures were estimated for cosmic ionizing radiation and circadian disruption between August 1963 and March 2003 for 83 male pilots from a major US airline. Estimates were based on 523 387 individual flight segments in company records and pilot logbooks as well as summary records of hours flown from other sources. Exposure was estimated by calculation or imputation for all but 0.02% of the individual flight segments' block time. Exposures were estimated from questionnaire data for a comparison group of 51 male university faculty. Pilots flew a median of 7126 flight segments and 14 959 block hours for 27.8 years. In the final study year, a hypothetical pilot incurred an estimated median effective dose of 1.92 mSv (absorbed dose, 0.85 mGy) from cosmic radiation and crossed 362 time zones. This study pilot was possibly exposed to a moderate or large solar particle event a median of 6 times or once every 3.7 years of work. Work at the study airline and military flying were the two highest sources of pilot exposure for all metrics. An index of work during the standard sleep interval (SSI travel) also suggested potential chronic sleep disturbance in some pilots. For study airline flights, median segment radiation doses, time zones crossed, and SSI travel increased markedly from the 1990s to 2003 (P(trend) < 0.0001). Dose metrics were moderately correlated with records-based duration metrics (Spearman's r = 0.61-0.69). The methods developed provided an exposure profile of this group of US airline pilots, many of whom have been exposed to increasing cosmic radiation and circadian disruption from the 1990s through 2003. This assessment is likely to decrease exposure misclassification in health studies.


Etiological spectrum of pancytopenia based on bone marrow examination in children.
To determine the spectrum of pancytopenia with its frequency, common clinical presentation and etiology on the basis of bone marrow examination in children from 2 months to 15 years. Observational study. Department of Paediatrics, Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro, from October 2005 to March 2007. All patients aged 2 months to 15 years having pancytopenia were included. Patients beyond this age limits, already diagnosed cases of aplastic anemia and leukemia, clinical suspicion of genetic or constitutional pancytopenia, history of blood transfusion in recent past, and those not willing for either admission or bone marrow examination were excluded. History, physical and systemic examination and hematological parameters at presentation were recorded. Hematological profile included hemoglobin, total and differential leucocyte count, platelet count, reticulocyte count, peripheral smear and bone marrow aspiration/biopsy. During the study period, out of the 7000 admissions in paediatric ward, 250 patients had pancytopenia on their peripheral blood smear (3.57%). Out of those, 230 patients were finally studied. Cause of pancytopenia was identified in 220 cases on the basis of bone marrow and other supportive investigations, while 10 cases remained undiagnosed. Most common was aplastic anemia (23.9%), megaloblastic anemia (13.04%), leukemia (13.05%), enteric fever (10.8%), malaria (8.69%) and sepsis (8.69%). Common clinical presentations were pallor, fever, petechial hemorrhages, visceromegaly and bleeding from nose and gastrointestinal tract. Pancytopenia is a common occurrence in paediatric patients. Though acute leukemia and bone marrow failure were the usual causes of pancytopenia, infections and megaloblastic anemia are easily treatable and reversible.


Early-type hypersensitivity-associated airway inflammation and eosinophilia induced by Dermatophagoides farinae in sensitized mice.
In a murine ear-swelling model, we demonstrated a unique hypersensitivity response and defined it as early-type hypersensitivity (ETH). ETH was characterized by increased vasopermeability and edematous change that occurred within 1 h at the site of Ag challenge. In this study, intranasal challenge with Dermatophagoides farinae (Df) on Df-sensitized BALB/c mice induced an ETH response in the lungs. The lung ETH was manifested by an increase in wet lung weight, production of TNF-alpha in bronchoalveolar lavage fluids, and hyperemia and edematous change around vessels of small airways 1 h after Ag provocation. The challenged animals subsequently developed airway inflammation, beginning with a neutrophilic infiltrate which was followed by lymphocytes and eosinophils. The Df-induced eosinophilia was Ag-specific and maximal at 48 h after challenge. At this time, the trachea from sensitized mice also exhibited hyperreactivity to carbachol. Pretreatment with anti-CD4+ mAb significantly decreased the recruitment of eosinophils in bronchoalveolar lavage fluids. An enhanced expression of pulmonary endothelial vascular cell adhesion molecule-1 was noted as early as 6 h after challenge. Anti-Df Abs of IgG class, but not IgE class, were detected in Df-immunized mice at the time of challenge. Furthermore, Df challenge induced a stronger eosinophil response in BALB/c mice (H-2d) than in B10.BR (H-2k) mice. B10.BR mice also did not exhibit pulmonary edema or ETH of ear swelling 1 h after challenge. These data suggest that an ETH-associated 1 h pulmonary edematous change was induced by intranasal challenge of Df in Df-sensitized mice, and that the ETH might contribute to the development of subsequent pulmonary inflammation and eosinophilia.


Polymorphic serum prealbumin (Pa) of pig, identified as and alpha1-protease inhibitor.
Pig serum proteins were analysed by horizontal polyacrylamide gel electrophoresis, with a discontinuous buffer system (pH 9.0). A 12% acrylamide concentration in the separation gel was used. Each of the two paralbumin (Pa) alleles gave rise to two closely migrating fractions. The polymorphic Pa was identified as an alpha1-protease inhibitor as the Pa fractions inhibited the esterolytic activity of both bovine trypsin and chymotrypsin. Therefore, it has been proposed that the locus symbol for this prealbumin be changed to Pi-1. The protease inhibitory spectra and electrophoretic mobility of the Pa (Pi-1) fractions suggested that this protein was probably the same as the pig serum alpha1-protease inhibitor described in some earlier studies and that it corresponds to human serum alpha 1-protease inhibitor (Pi).


Factors affecting filamentation in Candida albicans: changes in respiratory activity of Candida albicans during filamentation.
Glucose metabolism and respiration of Candida albicans were compared under conditions which permitted either maximal filamentous or maximal yeast growth. Changes in metabolism were monitored by comparing the quantities of ethanol produced, CO2 evolved, and oxygen consumed. Filamenting cultures produced more ethanol and less CO2 than yeasts, with oxygen consumption in the former concomitantly slower than that of the latter. Studies involving cofactors and inhibitors associated with electron transport imply that a transfer of electrons away from flavoprotein is required for maintenance of yeast morphology. Conditions consistent with a buildup of reduced flavoprotein, however, favored filament formation. These changes were expressed metabolically as a shift from an aerobic to a fermentative metabolism. The results presented are consistent with hypotheses correlating filament production with changes in carbohydrate metabolism and an interruption of electron transfer within the cell.