Radiation-Induced Cerebral Microbleeds in Pediatric Patients With Brain Tumors Treated With Proton Radiation Therapy.
Proton beam radiation therapy (PBT) has been increasingly used to treat pediatric brain tumors; however, limited information exists regarding radiation-induced cerebral microbleeds (CMBs) among these patients. The purpose of this study was to evaluate the incidence, risk factors, and imaging appearance of CMBs in pediatric patients with brain tumors treated with PBT. A retrospective study was performed of 100 pediatric patients with primary brain tumors treated with PBT. CMBs were diagnosed by examination of serial magnetic resonance imaging scans, including susceptibility-weighted imaging. Radiation therapy plans were analyzed to determine doses to individual CMBs. Clinical records were used to determine risk factors associated with the development of CMBs in these patients. The mean age at time of PBT was 8.1 years. The median follow-up duration was 57 months. The median time to development of CMBs was 8 months (mean, 11 months; range, 3-28 months). The percentage of patients with CMBs was 43%, 66%, 80%, 81%, 83%, and 81% at 1 year, 2 years, 3 years, 4 years, 5 years, and >5 years from completion of proton radiation therapy. Most of the CMBs (87%) were found in areas of brain exposed to ≥30 Gy. Risk factors included maximum radiation therapy dose (P = .001), percentage and volume of brain exposed to ≥30 Gy (P = .0004, P = .0005), and patient age at time of PBT (P = .0004). Chemotherapy was not a significant risk factor (P = .35). No CMBs required surgical intervention. CMBs develop in a high percentage of pediatric patients with brain tumors treated with proton radiation therapy within the first few years after treatment. Significant risk factors for development of CMBs include younger age at time of PBT, higher maximum radiation therapy dose, and higher percentage and volume of brain exposed to ≥30 Gy. These findings demonstrate similarities with CMBs that develop in pediatric patients with brain tumor treated with photon radiation therapy.


Extended-depth-of-focus wavefront design from pseudo-umbilical space curves.
Designing extended-depth-of-focus wavefronts is required in multiple optical applications. Caustic location and structure analysis offer a powerful tool for designing such wavefronts. An intrinsic limitation of designing extended-depth-of-focus wavefronts is that any smooth surface, with a non-constant mean curvature, unavoidably introduces a separation between caustic sheets, which is proportional to the ratio of change of the mean curvature along a curve embedded in the wavefront. We present a method to obtain extended-depth-of-focus wavefronts where the mean curvature variation ratio is reduced thanks to using a long circle-involute space curve effectively filling the wavefront surface. Additionally, we present a variant of the method in which the wavefront is modified within a small tubular neighborhood of the circle involute in order to partially meet the umbilical condition along that tubular region. Finally, we provide some numerical results showing the potential of our method in an application example.


Design of a Web interface for anatomical images.
Interactive documents for use with the World Wide Web have been developed for viewing multi-dimensional radiographic and visual images of human anatomy, derived from the Visible Human Project. Emphasis has been placed on user-controlled features and selections. The purpose was to develop an interface which was independent of host operating system and browser software which would allow viewing of information by multiple users. The interfaces were implemented using HyperText Markup Language (HTML) forms, C programming language and Perl scripting language. Images were pre-processed using ANALYZE and stored on a Web server in CompuServe GIF format. Viewing options were included in the document design, such as interactive thresholding and two-dimensional slice direction. The interface is an example of what may be achieved using the World Wide Web. Key applications envisaged for such software include education, research and accessing of information through internal databases and simultaneous sharing of images by remote computers by health personnel for diagnostic purposes.


Asymmetric synthesis of cis-2,5-disubstituted pyrrolidine, the core scaffold of β3-AR agonists.
A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.


Monitoring Insulin-Aggregated Structures in the Presence of Epigallocatechin-3-gallate and Melatonin by Molecular Dynamics Simulations.
In the present work we illustrate the results of classical molecular dynamics simulations of model systems composed of six insulin molecules in water in the presence and in the absence of either epigallocatechin-3-gallate or melatonin molecules. For each model system, we performed three independent simulations (replicas) to study the aggregate formation dynamics and insulin interaction with epigallocatechin-3-gallate and melatonin. We find that melatonin is less stably close to insulin with respect to epigallocatechin-3-gallate, which interacts more stably with insulin molecules and mainly with insulin's chain B hydrophobic residues. We observe that the shape of the insulin-aggregated structures in the three model systems is different and depends on whether epigallocatechin-3-gallate is present or not. Simulations show that in the absence of epigallocatechin-3-gallate, insulin molecules tend to form linear aggregates, while in the presence of epigallocatechin-3-gallate, aggregates display a globular shape, less prone to form fibril structures.


Hair cell-type dependent expression of basolateral ion channels shapes response dynamics in the frog utricle.
The dynamics of vestibular afferent responses are thought to be strongly influenced by presynaptic properties. In this paper, by performing whole-cell perforated-patch experiments in the frog utricle, we characterized voltage-dependent currents and voltage responses to current steps and 0.3-100 Hz sinusoids. Current expression and voltage responses are strongly related to hair cell type. In particular, voltage responses of extrastriolar type eB (low pass, -3 dB corner at 52.5 ± 12.8 Hz) and striolar type F cells (resonant, tuned at 60 ± 46 Hz) agree with the dynamics (tonic and phasic, respectively) of the afferent fibers they contact. On the other hand, hair cell release (measured with single-sine membrane ΔCm measurements) was linearly related to Ca in both cell types, and therefore did not appear to contribute to dynamics differences. As a tool for quantifying the relative contribution of basolateral currents and other presynaptic factors to afferent dynamics, the recorded current, voltage and release data were used to build a NEURON model of the average extrastriolar type eB and striolar type F hair cell. The model contained all recorded conductances, a basic mechanosensitive hair bundle and a ribbon synapse sustained by stochastic voltage-dependent Ca channels, and could reproduce the recorded hair cell voltage responses. Simulated release obtained from eB-type and F-type models display significant differences in dynamics, supporting the idea that basolateral currents are able to contribute to afferent dynamics; however, release in type eB and F cell models does not reproduce tonic and phasic dynamics, mainly because of an excessive phase lag present in both cell types. This suggests the presence in vestibular hair cells of an additional, phase-advancing mechanism, in cascade with voltage modulation.


Gender, Race and Disease Etiology Predict De Novo Malignancy Risk After Liver Transplantation: Insights for Future Individualized Cancer Screening Guidance.
Malignancy after liver transplant (LT) is a leading cause of mortality, but data is limited. The aim of this study was to identify patients at higher risk for de novo malignancies after LT in a large multicenter database. The Scientific Registry of Transplant Recipients database comprising all 108 412 LT recipients across the United States between 1987 and March 2015 was analyzed with a median follow-up of 6.95 years. Potential risk factors for malignancies after LT were assessed using Cox regression analysis for the outcome of time to first malignancy. Mean age 51.9 ± 10.8 years, 64.6% male, 74.5% white, and 15.8% with previous malignancy. Malignancies during follow-up were 4,483 (41.3%) skin, 1519 (14.0%) hematologic, and 4842 (44.7%) solid organ. The 10-year probability of de novo malignancy was 11.5% (11.3-11.8%). On multivariable analysis, age by decade (hazard ratio [HR], 1.52; P < 0.001), male sex (HR, 1.28; P < 0.001), white race (compared with other races: HR, 1.45-2.04; P < 0.001), multiorgan transplant (HR, 1.35; P < 0.001), previous malignancy (HR, 1.34; P < 0.001), and alcoholic liver disease, autoimmune, nonalcoholic steatohepatitis (HR, 1.35; P < 0.001), and primary sclerosing cholangitis pre-LT (compared with hepatitis C virus, P < 0.001) were associated with higher risk of post-LT malignancy, but type of immunosuppression was not (P = NS). This large data set demonstrates the effects of ethnicity/race and etiologies of liver disease, particularly nonalcoholic steatohepatitis as additional risk factors for cancer after LT. Patients with these high-risk characteristics should be more regularly and diligently screened.


Intermediate clinical outcome of Bryan Cervical Disc replacement for degenerative disk disease and its effect on adjacent segment disks.
The purpose of this study was to determine the intermediate clinical and radiographic outcomes of Bryan Cervical Disc (Medtronic Sofamor Danek, Inc, Memphis, Tennessee) replacement for the treatment of cervical degenerative disk disease and its effect on adjacent levels. Between November 2004 and December 2007, thirty-four patients (38 disks) underwent Bryan Cervical Disc replacement in the authors' hospital. The authors retrospectively analyzed the records of 32 patients who completed follow-up. Outcome data were collected preoperatively; at 3, 12, 24 months postoperatively; and at last follow-up, which ranged from 32 to 69 months (average, 49.4 months). Clinical outcome, radiographic outcome, adjacent segment degeneration, complications, and reoperations were evaluated. The SF-36 physical component, SF-36 mental component, Neck Disability Index, Japanese Orthopaedic Association score, and neck/arm pain visual analog pain scale scores were all improved significantly at each postoperative time point compared with preoperative values (P<.05), but no statistically significant differences were noted between postoperative time points (P>.05). The postoperative flexion-extension range of motion of the operative site and adjacent segments were not significantly different from the preoperative values (P>.05) and were approximately the same for each postoperative time point (P>.05). A new degeneration scoring system demonstrated that approximately 23% of the adjacent levels displayed mild degeneration at last follow-up. However, degeneration did not affect the clinical outcomes. Prosthesis-related complications were rare, and no reoperations were performed. Bryan Cervical Disc replacement achieves satisfactory mid-term clinical and radiographic outcomes. The authors observed the progression of adjacent segment degeneration postoperatively, although no degradation of clinical outcomes occurred.


[Inhibition of NF-kappaB through IkappaBalpha transfection affects invasion of human lung cancer cell line A549].
Recent studies have shown that activation of nuclear factor-kappaB(NF-kappaB) can regulate the invasion and metastasis of cancer cells. The present study was to investigate inhibition of NF-kappaB activity on invasion of human lung cancer cell line A549 and the possible mechanism. The recombinant plasmid pcDNA3.1(+)/IkappaBalpha, expressing the alpha isoform (IkappaBalpha) of the NF-kappaB inhibitor, was constructed. A549 cells were cultured in vitro and divided into non-transfection group, pcDNA3.1(+) transfected group and pcDNA3.1(+)/IkappaBalpha transfected group. The expression of IkappaBalpha was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The activity of NF-kappaB was determined by electrophoretic mobility shift assay (EMSA). Invasion of A549 cells was assessed by transwell chamber assay. The expression of MMP-2 and MMP-9 was detected by RT-PCR and gelatin zymography. Plasmid pcDNA3.1(+)/IkappaBalpha was successfully constructed and expressed in A549 cells. The activity of NF-kappaB, the number of invasive cells, the activity of MMP-2 and MMP-9 of A549 cells in pcDNA3.1(+)/IkappaBalpha transfected group were significantly lower than those in non-transfection group and pcDNA3.1(+) transfected group (all P<0.05). Transfection of IkappaBalpha can inhibit NF-kappaB activity, thus inhibit cell invasion of A549, which may be through the down-regulation of MMP-2 and MMP-9 expressions.


In-silico evidence of ADAM metalloproteinase pathology in cancer signaling networks.
Lack of effective targeted therapies often contributes to poor clinical outcomes of aggressive malignancies associated with drug resistance, angiogenesis and metastasis. Literature mining portrays the major role of ADAM17 in cancer and inflammatory diseases. However, it is quite challenging to design a candidate drug for targeting ADAM17 due to its structural similarity with the catalytic domain of the matrix metalloproteases (MMPs). The present study reports the protein-protein interaction analysis of ADAM17, along with the molecular docking and MD simulation studies for the screened compounds. Our analysis confirms the association of ADAM17 with numerous oncogenes that facilitates cancer progression and inflammation, especially the members of the Notch, receptor tyrosine kinase (RTK) and TNFα pathways. The outcome provides evidence that the prevalent protease ADAM17 could attribute to cancer signaling regulation though the shedding of various inflammatory and oncogenic molecules. We have also exploited the analogues of the existing inhibitors, with an aim at discovering a potent molecule, which could be repurposed as a drug against ADAM17 inflicted cancer progression. Upon stringent screening, we delineated our choice into two specific compounds (I6 and I9; analogues of IK862, a type of y-lactam hydroxamates), possessing the lowest binding energy (-9.1 Kcal/mol), stable MD-simulation studies and superior pharmacodynamic properties. The current information illustrates the avenue to persuade further research on targeting ADAM17 with small molecular compounds (I6 and I9) in cancer therapeutics.Communicated by Ramaswamy H. Sarma.


The significance of widening of the presacral space at contrast radiography in inflammatory bowel disease.
The width of the presacral space was measured prospectively at various levels in 100 persons without organic colonic or rectal disease who had barium enema X-ray examinations. A standard technique was employed. The most consistent measurement was obtained at the level opposite the S3-S4 disc space; readings varied between 2 mm and 16 mm. Using 16 mm as the upper limit of normal, and a similar technique of barium enema examination, the width of the presacral space at the S3-S4 disc level was measured in 66 patients with inflammatory bowel disease (ulcerative colitis--49; Crohn's colitis--17). The width did not correlate with the severity of the disease process as indicated by sigmoidoscopic examination in proximity in time to the radiological examination. There was a relationship between increased width of the presacral space and the duration of the disease process.


Intraperitoneal injection of technetium-99m sulfur colloid in visualization of a peritoneo-vaginalis connection.
Ten minutes after an intraperitoneal infusion of Tc-99m sulfur colloid, a gamma camera was used to obtain anterior abdominal views. This visualized a peritoneoscrotal communication in an 80-yr-old patient. He had developed extensive edema of the genitals and lower limbs after about 6 wk of continuous ambulatory peritoneal dialysis. At operation the communication was confirmed and closed. A repeat test verified the success of operation.


Surgical drains can be safely avoided in lateral neck dissections for papillary thyroid cancer.
Drains are widely used in lateral neck dissections (LNDs). Our objective was to compare outcomes of LNDs for papillary thyroid cancer (PTC) with and without drains. One hundred sixty-five LNDs in 129 patients operated on from July 2001 to October 2008 were analyzed retrospectively. LNDs were divided according to the number of excised lymph nodes as follows: group A < median and group B > median. Further categorization was based on the use of a drain. Main outcome measures were wound complications requiring intervention. One hundred two LNDs were performed with a drain and 63 without. The overall rate of wound complications was 3%. There was no significant difference in complication rate between the drain and the non-drain group (group A: 1.8% vs 0; group B: 2.2% vs 7.9%, respectively). Significant seromas/hematomas are rare complications of LNDs. Patients who undergo LND for PTC without a drain show no significantly increased rate of these complications.


Aluminum does not accumulate in teenagers and adults on prolonged parenteral nutrition containing free amino acids.
Prolonged total parenteral nutrition (TPN) with solutions containing hydrolyzed casein has been associated with aluminum accumulation in patients with bone disease. We investigated the effects of free amino acids in TPN solution on plasma, urine, and bone aluminum in six patients, five of whom had symptoms of bone disease or documented demineralization. No evidence of aluminum accumulation was found. TPN with free amino acids, containing 42 micrograms aluminum per liter or less, does not lead to aluminum loading in adolescents or adults.


Cardioprotective role of H₃R agonist imetit on isoproterenol-induced hemodynamic changes and oxidative stress in rats.
The cardioprotective role of histamine H3 receptor (H3R) agonist imetit (IMT) in isoproterenol (ISO)-induced alterations of hemodynamic and oxidative stress was investigated in Wistar rats. In this study, rats were treated with IMT (5 and 10 mg/kg, per orally [p.o.]), carvedilol (10 mg/kg, p.o.) and ISO control group (normal saline) for 7 d, with concurrent subcutaneous administration of ISO (85 mg/kg) at 24 h interval on last two consecutive days whereas control group was administered with vehicle only. ISO significantly attenuated cardiac antioxidant enzymes superoxide dismutase, catalase and increased plasma cardiac injury biomarkers creatine kinase-MB, alanine transaminase and aspartate transaminase. ISO also altered cardiac activity as evidenced by decrease in blood pressure (34.60%) and increase in heart rate (11.40%). The damage due to oxidative stress was revealed by histopathology alterations such as myocyte necrosis, myofibrillar degeneration and pyknotic nucleus. However, pre-treatment with IMT demonstrated restoration of hemodynamic alterations along with significant preservation of antioxidants and myocyte injury-specific marker enzymes. Furthermore, protective effect of IMT was reconfirmed by the histopathological salvage of myocardium. Results of the present study demonstrated the cardioprotective potential of IMT, as evidenced by favorable improvement in ISO-induced hemodynamic, plasma cardiac biomarkers and tissue antioxidant status along with maintenance of integrity of myocardium.


FilterNet: A Many-to-Many Deep Learning Architecture for Time Series Classification.
In this paper, we present and benchmark FilterNet, a flexible deep learning architecture for time series classification tasks, such as activity recognition via multichannel sensor data. It adapts popular convolutional neural network (CNN) and long short-term memory (LSTM) motifs which have excelled in activity recognition benchmarks, implementing them in a many-to-many architecture to markedly improve frame-by-frame accuracy, event segmentation accuracy, model size, and computational efficiency. We propose several model variants, evaluate them alongside other published models using the Opportunity benchmark dataset, demonstrate the effect of model ensembling and of altering key parameters, and quantify the quality of the models' segmentation of discrete events. We also offer recommendations for use and suggest potential model extensions. FilterNet advances the state of the art in all measured accuracy and speed metrics when applied to the benchmarked dataset, and it can be extensively customized for other applications.


Differential gene regulation by the SRC family of coactivators.
SRCs (steroid receptor coactivators) are required for nuclear receptor-mediated transcription and are also implicated in the transcription initiation by other transcription factors, such as STATs and NFkappaB. Despite phenotypic manifestations in gene knockout mice for SRC-1, GRIP1, and AIB1 of the SRC (Steroid Receptor Coactivator) family indicating their differential roles in animal physiology, there is no clear evidence, at the molecular level, to support a functional specificity for these proteins. We demonstrated in this report that two species of SRC coactivators, either as AIB1:GRIP1 or as AIB1:SRC-1 are recruited, possibly through heterodimerization, on the promoter of genes that contain a classical hormone responsive element (HRE). In contrast, on non-HRE-containing gene promoters, on which steroid receptors bind indirectly, either GRIP1 or SRC-1 is recruited as a monomer, depending on the cellular abundance of the protein. Typically, non-HRE-containing genes are early genes activated by steroid receptors, whereas HRE-containing genes are activated later. Our results also showed that SRC proteins contribute to the temporal regulation of gene transcription. In addition, our experiments revealed a positive correlation between AIB1/c-myc overexpression in ER+ breast carcinoma samples, suggesting a possible mechanism for AIB1 in breast cancer carcinogenesis.


Linking Changes to Intraspecific Trait Diversity to Community Functional Diversity and Biomass in Response to Snow and Nitrogen Addition Within an Inner Mongolian Grassland.
In recent years, both the intraspecific and interspecific functional diversity (FD) of plant communities have been studied with new approaches to improve an understanding about the mechanisms underlying plant species coexistence. Yet, little is known about how global change drivers will impact intraspecific FD and trait overlap among species, and in particular how this may scale to impacts on community level FD and ecosystem functioning. To address this uncertainty, we assessed the direct and indirect responses of specific leaf area (SLA) among both dominant annual and subordinate perennial species to the independent and interactive effects of nitrogen and snow addition within the Inner Mongnolian steppe. More specifically, we investigated the consequences for these responses on plant community FD, trait overlap and biomass. Nitrogen addition increased the biomass of the dominant annual species and as a result increased total community biomass. This occurred despite concurrent decreases in the biomass of subordinate perennial species. Nitrogen addition also increased intraspecific FD and trait overlap of both annual species and perennial species, and consequently increased the degree of trait overlap in SLA at the community level. However, snow addition did not significantly impact intraspecific FD and trait overlap of SLA for perennial species, but increased intraspecific FD and trait overlap of annual species, of which scaled to changes in community level FD. We found that the responses of the dominant annual species to nitrogen and snow additions were generally more sensitive than the subordinate perennial species within the inner Mongolian grassland communities of our study. As a consequence of this sensitivity, the responses of the dominant species largely drove impacts to community FD, trait overlap and community biomass. In total, our study demonstrates that the responses of dominant species in a community to environmental change may drive the initial trajectories of change to community FD and functioning.


Boosting the zinc storage of a small-molecule organic cathode by a desalinization strategy.
Organic materials offer great potential as electrodes for batteries due to their high theoretical capacity, flexible structural design, and easily accessible materials. However, one significant drawback of organic electrode materials is their tendency to dissolve in the electrolyte. Resazurin sodium salt (RSS) has demonstrated remarkable charge/discharge performance characterized by a voltage plateau and high capacity when utilized as a cathode in aqueous zinc-ion batteries (AZIBs). Unfortunately, the solubility of RSS as a sodium salt continues to pose challenges in AZIBs. In this study, we introduce an RSS-containing organic compound, triresazurin-triazine (TRT), with a porous structure prepared by a desalinization method from the RSS and 2,4,6-trichloro-1,3,5-triazine (TCT). This process retained active groups (carbonyl and nitroxide radical) while generating a highly conjugated structure, which not only inhibits the dissolution in the electrolyte, but also improves the electrical conductivity, enabling TRT to have excellent electrochemical properties. When evaluated as a cathode for AZIBs, TRT exhibits a high reversible capacity of 180 mA h g-1, exceptional rate performance (78 mA h g-1 under 2 A g-1), and excellent cycling stability with 65 mA h g-1 at 500 mA g-1 after 1000 cycles.


PROCORAD's international intercomparisons highlight the evolution of techniques used to determine uranium in urine.
Inter-laboratory tests are a means of assessing the analytical coherence of medical laboratories. In radiotoxicology, this kind of exercise makes it possible to keep up with laboratory know-how and with the evolution and relative performances of analytical techniques. The intercomparison exercises organised by PROCORAD (Association for the Promotion of Quality Controls in Radiotoxicological Bioassays) provide an opportunity to compare and contrast radiochemistry and metrology for the in vitro analysis of urine and faeces. For uranium compounds, the development of new techniques such as inductively coupled plasma-mass spectrometry (ICP-MS), alpha spectrometry, and laser spectrofluorimetry makes it possible to compare the effectiveness of these protocols with respect to radiation protection monitoring, both in routine and special situations. Detection limits, flexibility, repeatability, reproducibility and isotopic quantification are the criteria considered in this study. The authors present the evolution of performances for the analysis of uranium in urine over the years. However, the goal of the laboratories taking part in these annual exercises is not only to check the accuracy of their results but also to have analytical discussions and the opportunity to exchange experiences that will enrich the group's general competence.


Paint-remover hazard.
The in-home use of paint removers containing methylene chloride results in the absorption of this solvent, which is metabolized to carbon monoxide. Exposure for two to three hours can result in the elevation of carboxyhemoglobin (COHb) to levels that stress the cardiovascular system. The metabolic formation of COHb continues following the paint-remover exposure, doubling the duration of the cardiovascular stress produced by a comparable COHb level after exposure to CO. Patients with diseased cardiovascular systems may not be able to tolerate this unexpected stress.


A Model of Social Media Effects in Public Health Communication Campaigns: Systematic Review.
Social media platforms are frequently used in health communication campaigns. Common understandings of campaign effects posit a sequential and linear series of steps from exposure to behavior change, commonly known as the hierarchy of effects model (HOE). These concepts need to be reevaluated in the age of social media, which are interactional and communal. This review aims to update the traditional HOE for health communication campaigns in the context of social media, including identifying indicators of effectiveness and how these are conceptualized to lead to health-related outcomes. We conducted a systematic review of studies following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines reporting on the use of social media as part of health communication campaigns, extracting campaign information such as objectives, platforms used, and measures of campaign performance. We used these data, combined with our understanding of the HOE, to develop an updated conceptual model of social media campaign effects. We identified 99 eligible studies reporting on 93 campaigns, published between 2012 and 2022. The campaigns were conducted in over 20 countries, but nearly half (n=42) were conducted in the United States. Campaigns targeted a variety of health issues and predominantly used Facebook, Twitter, Instagram, and YouTube. Most campaigns (n=81) set objectives targeting awareness or individual behavior change. Process measures (n=68; eg, reach and impressions) and engagement measures (n=73; eg, likes and retweets) were reported most frequently, while two-fifths (n=42) did not report any outcomes beyond engagement, such as changes in knowledge, behavior, or social norms. Most campaigns (n=55) collected measures that did not allow them to determine if the campaign objective had been met; that is, they were process evaluations only. Based on our review, our updated model suggests that campaign exposure can lead to individual behavior change and improved health outcomes, either through a direct or indirect pathway. Indirect pathways include exposure through social and policy changes. "Engagement" is positioned as critical to success, replacing awareness in the traditional HOE, and all types of engagement are treated as equal and good. No consideration is being given to potential negative engagement, such as the distribution of misinformation. Additionally, the process is no longer linear and sequential, with circular pathways evident, such as engagement not only influencing behavior change but also generating additional exposure to campaign messages. Our review has highlighted a change in conventional understandings of how campaigns can influence health outcomes in the age of social media. The updated model we propose provides social media campaigners with a starting point to develop and tailor campaign messages and allows evaluators to identify critical assumptions to test, including the role and value of "engagement." PROSPERO CRD42021287257; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=287257.


The effects of some physico-chemical factors and pharmaceutical excipients on the bioavailability of nitrofurantoin oily and aqueous suspensions in rats.
The effects of some physico-chemical factors and various excipients, i.e., sucrose, aluminum stearate, hydrogenated castor oil, Cab-o-sil, and lecithin, either alone or in combination, from suspensions in fractionated coconut oil and distilled water have been investigated. In vitro drug release studies were performed according to the flask-stirrer method. In addition to adsorption and solubility studies, determination of partition coefficients and rheological measurements have been carried out. The experimental design was based on an 8x8 latin square using rats as the test animals. The results of the study showed that the rate and extent of absorption of nitrofurantoin are decreased significantly by the use of an oil' rather than an aqueous vehicle. In vitro drug release data showed some correlation with in vivo parameters, and also with the apparent viscosity of the vehicles. However, no correlation was detectable between in vivo parameters and the apparent viscosity of the vehicles.


Abdominal pressure during laparoscopy: effects of fentanyl.
In patients breathing spontaneously during anaesthesia, expiration is active and opioids enhance this effect. The mechanical consequences are not well characterized. We studied 14 patients undergoing laparoscopy for minor gynaecological procedures, anaesthetized with isoflurane in nitrous oxide, and breathing spontaneously through a laryngeal mask airway. We made direct recordings of intra-abdominal pressure and respiratory flow before and after giving fentanyl 25 microg i.v. Satisfactory records were obtained in 11 patients. Before fentanyl, the abdominal pressure changes were small and had an inconsistent pattern, increasing in inspiration in seven patients and during expiration in five. After fentanyl, an increase in pressure during inspiration was seen in only two patients, and the intra-abdominal pressure during expiration was increased. The mean value of maximum abdominal pressure (which always occurred during expiration) increased from 17 (SD 5) cm H2O before to 25 (9) cm H2O after fentanyl (P<0.01). Direct measurements support previous findings that opioids stimulate active phasic expiratory activity and can cause large increases in abdominal pressure.


Flat band carrier confinement in magic-angle twisted bilayer graphene.
Magic-angle twisted bilayer graphene has emerged as a powerful platform for studying strongly correlated electron physics, owing to its almost dispersionless low-energy bands and the ability to tune the band filling by electrostatic gating. Techniques to control the twist angle between graphene layers have led to rapid experimental progress but improving sample quality is essential for separating the delicate correlated electron physics from disorder effects. Owing to the 2D nature of the system and the relatively low carrier density, the samples are highly susceptible to small doping inhomogeneity which can drastically modify the local potential landscape. This potential disorder is distinct from the twist angle variation which has been studied elsewhere. Here, by using low temperature scanning tunneling spectroscopy and planar tunneling junction measurements, we demonstrate that flat bands in twisted bilayer graphene can amplify small doping inhomogeneity that surprisingly leads to carrier confinement, which in graphene could previously only be realized in the presence of a strong magnetic field.


CpG oligonucleotides and Astragalus polysaccharides are effective adjuvants in cultures of avian bone-marrow-derived dendritic cells.
1. The potential use of CpG oligodeoxynucleotides and/or Astragalus polysaccharide (APS) as adjuvants for the culture of chicken bone-marrow-derived dendritic cells (chBM-DCs) was investigated. 2. Chicken dendritic cells (DCs) were isolated and cultured in the presence of recombinant chicken granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4. The chBM-DC displayed typical DC morphology and expressed DC surface markers (MHC-II and CD11c). 3. Cultured chBM-DC showed effective T-cell activation in vitro, based on a mixed lymphocyte response (MLR). Flow cytometry analysis showed an increased proportion of cells expressing CD40 and CD80 in the APS-stimulated culture, compared to the control culture. In the MLR, the APS- and CpG-stimulated chBM-DC could activate T-cells more than control chBM-DC. Real-time PCR assays showed that CpG can activate the TLR21 and an inflammatory response, while APS just reduced the expression of IRF-3. 4. The results demonstrated that in vitro the adjuvant CpG can stimulate chBM-DC to mature by activation of the TLR-signalling pathway, whereas the adjuvant APS stimulates maturation of chBM-DC in vitro to a lesser degree and by another mechanism.


Dedifferentiated chordoma with a sarcomatous component: an overlooked diagnosis.
A 60 year old male presented with unremitting complaints of acute urinary retention and constipation. Computerized Tomography of the abdomen and pelvis confirmed a sacral mass. The biopsy diagnosed dedifferentiated sacral chordoma; an extremely rare entity, seldom reported and frequently misdiagnosed. We present a unique case report after an extensive review of retrospective literature on dedifferentiated chordomas.


Genetic characterization and phylogenetic analysis of echinostomes.
We conducted this study to identify species and determine the phylogenetic relationships using ribosomal DNA (rDNA) sequences [partial sequences of 28S rDNA and second internal transcribed spacer (IT52)] of echinostomes collected from free-grazing ducks in Phitsanulok Province, Thailand. Four adult echinostomes were morphologically identified as Echinostoma revolutum, 4 as Hypoderaeulm conoideurn and 2 unidentified. Sequences of other species/isolates of echinostomes retrieved from the GenBank database were employed to compare and construct the phylogenetic tree. Three major lineages were found, namely, genus Echinostoma, genus Echinoparyphiulm and genus Hypoderaeulm. One of the unidentified echinostome specimen was 99% identical to and clustered with genus Echinoparyphiurm, whereas the other was located in the "revolutum" roup, but was closely related to the geographical isolates from America rather than from Thailand. This study indicates that 28S rDNA and 1T52 regions are suitable molecular markers for genetic characterization and phylogenetic analysis of echinostomes.


Leflunomide in active rheumatoid arthritis: a prospective study in daily practice.
We prospectively studied the efficacy, incidence of adverse drug reactions and withdrawal from leflunomide in an outpatient population with rheumatoid arthritis in a setting of care-as-usual. In this prospective case series study, a standard dataset was collected from outpatient medical records, including patient and disease characteristics, data on leflunomide use and adverse drug reactions. During the study period 136 rheumatoid arthritis patients started leflunomide. Median (range) follow-up duration was 317 (11-911) days. Sixty-five percent of patients experienced at least one adverse drug reaction related to leflunomide. During follow-up 76 patients (56%) withdrew from leflunomide treatment, mainly because of adverse drug reactions (29%) or lack of efficacy (13%). The overall incidence density for withdrawal from leflunomide was 56.2 per 100 patient years. Complete data for calculating efficacy using a validated disease activity score on 28 joints (DAS(28)) was available for 48, 36, and 35% of patients at 2, 6, and 12 months follow-up, respectively. Within a 12-month period after start of leflunomide treatment 76% of the evaluable patients were classified as moderate or good responders according to the DAS(28) response criteria. In the setting of care-as-usual rheumatoid arthritis patients starting leflunomide frequently experienced adverse drug reactions. More than half of the patients withdrew from leflunomide treatment within 1 year of starting leflunomide treatment, mainly because of adverse drug reactions.


The Timing and Magnitude of Improvements in Depression, Anxiety, Disability, and Pain Intensity During an Internet-delivered Program for Chronic Pain.
Numerous studies have found that pain management programs are an effective treatment option for people with chronic pain. However, little is known about when people experience improvements during these programs and why they are effective. Using a secondary analysis, the current study examined the timing and magnitude of symptom change during an 8-week internet-delivered psychological pain management program for people with chronic pain. The change in 4 outcomes was examined: depression (n = 881), anxiety (n = 561), disability (n = 484), and pain intensity (n = 484). The largest improvements in depression, anxiety, and disability were reported during the first half of treatment (ie, 4 weeks), whereas the largest reductions in pain intensity were reported during the second half of treatment. Half the participants had experienced a clinically meaningful improvement in depression or anxiety, and a third of participants had reported such an improvement in disability by midtreatment (ie, 5 weeks after baseline). In a subgroup analysis (n = 397), this pattern of change in depression and anxiety symptoms did not differ based on the level of therapist guidance. This study highlights the importance of the first few weeks of psychological pain management programs and encourages future work to examine how the mechanisms underpinning rapid change may be harnessed to optimize care for people with chronic pain. PERSPECTIVE: This study found that depression, anxiety, and disability improved rapidly during the first half of an 8-week internet-delivered pain management program, and most of the prepost change had occurred by midtreatment. This work highlights the therapeutic potential of the first few treatment sessions and prompts future research into a rapid responding.


The many faces of the anti-COVID immune response.
The novel 2019 strain of coronavirus is a source of profound morbidity and mortality worldwide. Compared with recent viral outbreaks, COVID-19 infection has a relatively high mortality rate, the reasons for which are not entirely clear. Furthermore, treatment options for COVID-19 infection are currently limited. In this Perspective, we explore the contributions of the innate and adaptive immune systems to both viral control as well as toxicity during COVID-19 infections and offer suggestions to both understand and therapeutically modulate anti-COVID immunity.


Distinction between dipolar and inductive effects in modulating the conductance of gramicidin channels.
The ion permeability of transmembrane channels formed by the linear gramicidins is altered by amino acid sequence substitutions. We have previously shown that the polarity of the side chain at position one is important in modulating a channel's conductance and ion selectivity [Russel et al. (1986) Biophys. J. 49, 673-686]. Changes in polarity could alter ion permeability by (through-space) ion-dipole interactions or by (through-bond) inductive electron shifts. We have addressed this question by investigating the permeability characteristics of channels formed by gramicidins where the NH2-terminal amino acid is either phenylalanine or one of a series of substituted phenylalanines: p-hydroxy-, p-methoxy-, o-fluoro-, m-fluoro-, or p-fluorophenylalanine. The electron-donating or -withdrawing nature, as quantified by the Hammett constant, ranges from -0.37 to +0.34 for these side chains. Channels formed by these gramicidins show a more than 2.5-fold variation in their Na+ conductance, but the conductance variations do not rank in the order of the Hammett constants of the side chains. Inductive effects cannot therefore be of primary importance in the modulation of the gramicidin single-channel conductance by these side chains. The results support previous suggestions that electrostatic interactions between side chain dipoles and permeating ions can modify the energy profile for ion movement through the gramicidin channel and thus alter the conductance.


Improvements in the cell-free production of functional antibodies using cell extract from protease-deficient Escherichia coli mutant.
Expression of a functional antibody fragment (Fab) using an Escherichia coli cell-free expression system has been reported previously [Jiang et al., FEBS Lett., 514, 290-294 (2002)]. The low yield of the synthesized antibody, however, limits the usefulness of the cell-free expression system, partly due to the degradation of product by endogenous proteases from the E. coli extract. To determine which proteases are responsible for the degradation, we compared the expression of a 6D9 Fab fragment under conditions whereby several protease inhibitors were added into the cell-free system. The addition of serine protease inhibitor increased the amount of the Fab fragment, indicating that serine proteases caused the antibody degradation. Therefore, several serine protease-deficient mutants of E. coli BW25113 were constructed by targeted homologous recombination. The use of extract from a double protease-deficient mutant (DeltadegP-ompT) significantly increased the amount and antigen-binding activities of an anti-HSA scFv and a 6D9 Fab fragment. These results suggest that the DegP- and OmpT-deleted mutant is a useful source of S30 extract for the production or screening of antibodies using the cell-free expression system.


Are muscle fibers denervated in myotonic dystrophy?
An underlying neurogenic abnormality has recently been postulated in the muscular dystrophies. To test this hypothesis, we applied a widely accepted criterion of denervation-ie, and increase in extrajunctional acetyicholine (ACh) receptor sites--to muscles biopsy specimens from nine patients with myotonic dystrophy and three with amyotrophic lateral scierosis (ALS). The ACh receptor sites were determined by means of iodine 125-labeled alpha-bungarotoxin binding, measured by scintillation counting and autoradiography. None of the myotonic dystrophy muscles showed increased extrajunctiona ACh receptor sites, even in the smallest fibers. By contrast, muscle biopsy specimens from patients with ALS showed notably increased extrajunctional ACh receptor sites, especially in the small fibers. Our findings do not support the hypothesis of a neurogenic defect in myotonic dystrophy.


Effect of cetyltrimethylammonium chloride on various Escherichia coli strains and their inactivation kinetics by ozone and monochloramine.
Cethyltrimethylammonium chloride (CTMA) is one of the most used quaternary ammonium compounds (QACs) in consumer products. CTMA and other QACs are only partially eliminated in municipal wastewater treatment and they can interact with bacteria in biological processes. Currently, there is only limited information on the antimicrobial efficiency of CTMA in matrices other than standard growth media and if and how CTMA influences conventional chemical disinfection. The results obtained in this study showed that the susceptibility of E. coli to CTMA was significantly enhanced in phosphate-buffered saline, lake water and wastewater compared to broth. In broth, a minimum inhibitory concentration (MIC) of CTMA of 20 mgL-1 was observed for E. coli, whereas a 4-log inactivation occurred for CTMA concentrations of about 4 mgL-1 in buffered ultra-purified water, a lake water and wastewater effluent. The impacts of the pre-exposure and the presence of CTMA on inactivation by ozone and monochloramine were tested with three different E. coli strains: AG100 with the efflux pump acrAB intact, AG100A with it deleted and AG100tet with it overexpressed. Pre-exposure of E. coli AG100 to CTMA led to an increased susceptibility for ozone with second-order inactivation rate constants (∼ 106 M-1s-1) increasing by a factor of about 1.5. An opposite trend was observed for monochloramine with second-order inactivation rate constants (∼ 103 M-1s-1) decreasing by a factor of about 2. For E. coli AG100tet, the second-order inactivation rate constant decreased by a factor of almost 2 and increased by a factor of about 1.5 for ozone and monochloramine, respectively, relative to the strain AG100. The simultaneous presence of CTMA and ozone enhanced the second-order inactivation rate constants for CTMA concentrations of 2.5 mgL-1 by a factor of about 3. For monochloramine also an enhancement of the inactivation was observed, which was at least additive but might also be synergistic. Enhancement by factors from about 2 to 4.5 were observed for CTMA concentrations > 2.5 mgL-1.


Patterns of prescription opioid dispensing among Red River Métis in Manitoba, Canada: a retrospective longitudinal cross-sectional study.
Amid rising concern about opioid use across Canada, Métis leaders in Manitoba are seeking information on prescription opioid dispensing in Red River Métis populations to assist with planning and implementing appropriate evidence-based harm-reduction strategies in their communities. We examined patterns of prescription opioid dispensing among Red River Métis and compared them to those among other residents of Manitoba. We conducted a population-based retrospective cross-sectional study for fiscal years 2006/07-2018/19 using administrative data from the Manitoba Population Research Data Repository and a study designed in partnership with researchers from the Manitoba Métis Federation. We compared age- and sex-adjusted rates of prescription opioid dispensing and mean morphine equivalents (MEQ) between Red River Métis and all other Manitobans aged 10 years or older, in accordance with Indigenous data sovereignty principles. To better understand what was driving any differences in patterns of prescription opioid dispensing between the 2 groups, we stratified the groups by age, sex, urbanicity, number of comorbidities, income quintile and opioid type, and compared patterns in MEQ/person. The 2018/19 cohort included 76 755 Red River Métis and 1 117 854 other Manitobans. Other Manitobans were more likely than Red River Métis to be in higher income quintiles and to live in urban areas, and were less likely to have been diagnosed with a mood or anxiety disorder or a substance use disorder in the previous 5 years. The rate of prescription opioid dispensing and the opioid-associated MEQ/person were consistently higher among Red River Métis than among other Manitobans in each study year (p < 0.001). The rate of prescription opioid dispensing declined and the MEQ/person rose among other Manitobans over the study period but did not change among Red River Métis. The rate of prescription opioid dispensing and the potency of prescribed opioids were higher among Red River Métis in Manitoba than among other Manitobans. Further investigation into the different dispensing patterns between the 2 groups and the potential opioid-related harms they may herald is warranted.


Maximal oxygen uptake relative to plasma volume expansion.
Controversy exists as to whether plasma volume (PV) expansion has the potential to increase maximal oxygen uptake (VO2max). In the present study, VO2max and exercise time to fatigue were measured in nine untrained men when plasma volume (PV) was normal and then again on the next day following two levels of PV expansion. Resting PV was expanded (via intravenous infusion of a 6% dextran solution) by 282 +/- 16 ml (i.e., PVX-1) and then by 624 +/- 26 ml (i.e., PVX-2). PVX-1 increased stroke volume (CO2 rebreathing) during submaximal exercise by 15% (P less than 0.05) above normal levels. VO2max following PVX-1 was increased 4% (P less than 0.05; 3.78 to 3.92 l/min) despite a 4% reduction in hemoglobin concentration. Exercise time to fatigue was also increased (P less than 0.05). PVX-2 resulted in an 11% (P less than 0.05) reduction in hemoglobin concentration during maximal exercise and a return of VO2max and exercise time to normal levels. In summary, we have observed in untrained men that 200-300 ml of PV expansion increases SV, measured during submaximal exercise, yet causes only a small amount of hemodilution. As a result, VO2max is increased slightly and performance is improved. Further PV expansion to levels 500-600 ml above normal results in an excessive hemodilution and a subsequent decline in VO2max and performance to normal levels. There is an optimal PV for eliciting VO2max in untrained men which appears to be approximately 200-300 ml above their normal levels.


Engineering humanized antibody framework sequences for optimal site-specific conjugation of cytotoxins.
The prevailing techniques used to generate antibody-drug conjugates (ADCs) involve random conjugation of the linker-drug to multiple lysines or cysteines in the antibody. Engineering natural and non-natural amino acids into an antibody has been demonstrated to be an effective strategy to produce homogeneous ADC products with defined drug-to-antibody ratios. We recently reported an efficient residue-specific conjugation technology (RESPECT) where thiol-reactive payloads can be efficiently conjugated to a native unpaired cysteine in position 80 (C80) of rabbit light chains. Deimmunizing the rabbit variable domains through humanization is necessary to reduce the risk of anti-drug antibody responses in patients. However, we found that first-generation humanized RESPECT ADCs showed high levels of aggregation and low conjugation efficiency. We correlated these negative properties to the phenylalanine at position 83 present in most human variable kappa frameworks. When position 83 was substituted with selected amino acids, conjugation was restored and aggregation was reduced to levels similar to the chimeric ADC. This engineering strategy allows for development of second-generation humanized RESPECT ADCs with desirable biopharmaceutical properties.


[Effects of levonorgestrel-releasing intrauterine system on pain and recurrence associated with endometriosis and adenomyosis].
To observe the effects of levonorgestrel-releasing intrauterine system (LNG-IUS) in treatment of pain associated with endometriosis (EM) and adenomyosis (AM), and in prevention of disease recurrence. Thirty-three cases of moderate to severe EM or AM patients received insertion of LNG-IUS immediately after conservative operation, or after recurrence of simple pain, and were self controlled respectively before and after insertion of LNG-IUS. The visual analogue scale (VAS) was compared, and the change of the lesion and the uterine size, as well as the serum steroid and CA(125) were observed. The side-effects, such as bleeding pattern were recorded. The bleeding period was compared between the cases injected with or without gonadotropin-releasing hormone agonist (GnRHa) before insertion of LNG-IUS. Baseline and follow-up VASs of EM were 8.09 +/- 0.21 and 1.64 +/- 1.12 (P = 0.042), of AM were 8.41 +/- 1.59 and 3.99 +/- 3.87 (P = 0.068), respectively. During nearly 2 years' follow-up, moderate dysmenorrhea recurred in only 1 case who was hyper-estrogenism at that time. Generally, irregular bleeding and spotting period were longer in this LNG-IUS treated group than those reported in literatures in which LNG-IUS was used for contraception. Persistent prolonged spotting was seen in most of the patients during 1 year follow-up. Average bleeding days in one month during the first 6 months after insertion of LNG-IUS were both around 18 days, whether using GnRHa or not. LNG-IUS greatly reduces pain associated with EM and AM, and delays disease recurrence. Irregular bleeding and spotting is the main side effects. Administration of GnRHa in advance does not improve the bleeding symptoms.


Expression of EPL1 from Trichoderma atroviride in Arabidopsis Confers Resistance to Bacterial and Fungal Pathogens.
During plant interaction with beneficial microorganisms, fungi secrete a battery of elicitors that trigger plant defenses against pathogenic microorganisms. Among the elicitor molecules secreted by Trichoderma are cerato-platanin proteins, such as EPL1, from Trichoderma atroviride. In this study, Arabidopsis thaliana plants that express the TaEPL1 gene were challenged with phytopathogens to evaluate whether expression of EPL1 confers increased resistance to the bacterial pathogen Pseudomonas syringae and the necrotrophic fungus Botrytis cinerea. Infection assays showed that Arabidopsis EPL1-2, EPL1-3, EPL1-4 expressing lines were more resistant to both pathogens in comparison to WT plants. After Pseudomonas syringae infection, there were reduced disease symptoms (e.g., small chlorotic spots) and low bacterial titers in the three 35S::TaEPL1 expression lines. Similarly; 35S::TaEPL1 expression lines were more resistant to Botrytis cinerea infection, showing smaller lesion size in comparison to WT. Interestingly, an increase in ROS levels was detected in 35S::TaEPL1 expression lines when compared to WT. A higher expression of SA- and JA-response genes occurred in the 35S::TaEPL1 lines, which could explain the resistance of these EPL1 expression lines to both pathogens. We propose that EPL1 is an excellent elicitor, which can be used to generate crops with improved resistance to broad-spectrum diseases.


[Compartment syndrome can also be seen in the forearm].
Chronic compartment syndrome is a challenge for the clinician and symptomatic similar to neuropathies, tenosynovitis, stress fractures and referred pain from lumbar cervicalis. Thus, chronic compartment syndrome of the upper extremities is probably an underdiagnosed condition. In patients with stress-induced pain in the upper limbs, chronic compartment syndrome should be considered - particularly in young patients with high physical activity. Despite limited literature, the effect of surgical treatment is promising.


An in vivo reporter assay for sRNA-directed gene control in Gram-positive bacteria: identifying a novel sRNA target in Staphylococcus aureus.
Bacterial small regulatory RNAs (sRNAs) play a major role in the regulation of various cellular functions. Most sRNAs interact with mRNA targets via an antisense mechanism, modifying their translation and/or degradation. Despite considerable progresses in discovering sRNAs in Gram-positive bacteria, their functions, for the most part, are unknown. This is mainly due to difficulties in identifying their targets. To aid in the identification of sRNA targets in Gram-positive bacteria, we set up an in vivo method for fast analysis of sRNA-mediated post-transcriptional control at the 5΄ regions of target mRNAs. The technology is based on the co-expression of an sRNA and a 5΄ sequence of an mRNA target fused to a green fluorescent protein (GFP) reporter. The system was challenged on Staphylococcus aureus, an opportunistic Gram-positive pathogen. We analyzed several established sRNA-mRNA interactions, and in addition, we identified the ecb mRNA as a novel target for SprX2 sRNA. Using our in vivo system in combination with in vitro experiments, we demonstrated that SprX2 uses an antisense mechanism to prevent ecb mRNA translation initiation. Furthermore, we used our reporter assay to validate sRNA regulations in other Gram-positive organisms, Bacillus subtilis and Listeria monocytogenes. Overall, our method is broadly applicable to challenge the predicted sRNA-mRNA interactions in Gram-positive bacteria.


Immunological hallmarks of stromal cells in the tumour microenvironment.
A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.


Long-term effects of lip repair on dentofacial morphology in patients with unilateral cleft lip and palate.
Lateral cephalograms from the growth archive of the Sri Lankan Cleft Lip and Palate Project were analyzed in a cohort design to study the long-term effects of lip repair on dentofacial morphology in patients with unilateral cleft lip and palate. A total of 71 patients were recruited, including 23 adult patients with nonsyndromic unilateral cleft lip and palate without surgical repair and 48 adult patients with nonsyndromic unilateral cleft lip and palate who had lip repair, but without management of alveolus or anterior vomer. The design utilized exact matching on ethnicity and statistical control for gender and age. The data support the hypothesis that lip repair primarily produces a bone-bending effect on the anterior maxillary alveolus (alveolar molding), accompanied by controlled uprighting of maxillary incisors, and secondarily produces a bone-remodeling effect (bone resorption) in the base of the anterior maxillary alveolus. When analyzed by the age at lip repair and the surgeon who performed lip repair, early lip repair produced a greater bone-remodeling effect than did late lip repair, and variation in the surgeon who performed lip repair had an insignificant impact on dentofacial morphology after adjusting for covariates.


Efficacy and safety of SOX chemotherapy with or without surgery in AFP-producing advanced gastric cancer.
The present study investigated the clinical efficacy of S-1 plus oxaliplatin (SOX) regimen, with or without surgery in α-fetoprotein-producing gastric cancer (APGC) with liver metastasis. A total of 24 patients with APGC treated at the Liaocheng People's Hospital between January 2011 and December 2013 were retrospectively reviewed. Clinical efficacy and patient safety were compared between the two groups. The median progression-free survival (PFS) and overall survival (OS) in the SOX group were 6.5 [95% confidence interval (CI), 4.6-8.4] and 13.5 (95% CI, 8.1-18.9) months, respectively. The corresponding indicators in the SOX and surgery group were 7.0 (95% CI, 5.7-8.3) and 14 (95% CI, 11.0-17.1) months, respectively. There was no significant difference in PFS and OS between the two groups (P=0.703 and 0.710, respectively). The adverse effects of leucopenia, neutropenia, anemia and diarrhea occurred in ~10% of patients in the SOX group and in 14.3% (2/14), 7.14% (1/14), 14.3% (2/14) and 7.14% (1/14), respectively, in the surgery group. No significant difference was identified between groups in terms of overall incidence of adverse effects (P=0.17). However, severe adverse events, including gastroplegia, pancreatic fistula, pulmonary infection and refractory ascites, occurred only in the SOX plus surgery group [incidence rate for severe adverse events, 7.14% (1/14); P<0.001 between groups]. In conclusion, SOX chemotherapy is safe and effective in patients with APGC and liver metastasis. However, the addition of surgery to SOX chemotherapy may not improve the disease control rate and may increase the adverse effects.


In vivo recording of nerve conduction velocity of spinal CNS fibers in the mouse.
Anesthetic and surgical procedures and an electrophysiological method were developed for recording nerve conduction velocity (NCV) of CNS fibers in the murine spinal cord. Under intravenous anesthesia and artificial ventilation the lumbar spinal cord segments L1 to L4 and dorsal roots L3 to L5 on the left side were exposed by laminectomy. After stimulation of the dorsal root L4, a compound action potential (CAP) was recorded at the ipsilateral left fasciculus gracilis at the spinal cord level L1. The latency from stimulation to the CAP together with the measured distance between the electrodes was used for the determination of the NCV. NCV of the fastest fibers in the fasciculus gracilis was observed to be approximately 28 m/s. Reversible decrease of the NCV was measured, in vivo, under general hypothermia. The technique described serves for in vivo electrophysiological investigations of spinal central fibers in wildtype and mutant mice.


Summary: NAON's Best Practice Guideline, Total Hip Replacement (Arthroplasty).
This article summarizes the Best Practice Guideline for Total Hip Replacement (Arthroplasty) recently released by the National Association of Orthopaedic Nurses (NAON). The summary highlights the process of content development utilizing a systematic literature review and resulting recommendations for nursing care strategies throughout the patient care continuum. The authors of the Best Practice Guideline are expert nurses working in Joint Commission Disease Specific Certified clinical settings. The Summary concludes reminding readers of the purpose and focus of the guideline to enhance clinician knowledge and to improve patient care pathways and, ultimately, patient outcomes.


Psychotropic drug use among older people in general practice: discrepancies between opinion and practice.
The use of psychotropic drugs has increased over recent years in France. GPs are the first prescribers, especially for older patients. To analyse discrepancies between GPs' opinions and practice when prescribing psychotropic drugs to older patients. Postal surveys sent to GPs all over mainland France. Cross-sectional postal study. A questionnaire collected data on characteristics of GPs' practices, their opinions about psychotropic drug consumption in older people, and a full description of their last older patient receiving a psychotropic drug and seen last by the GP on that particular day. A total of 350 participating GPs saw 2498 patients aged > or =65 years. Among these patients, the prevalence of psychotropic use was 32.1% (803/2498) for anxiolytics/hypnotics, and 17.5% for antidepressants (438/2498). A total of 91% of GPs agreed that it was possible to reduce or stop psychotropic drugs for these patients. Characteristics of 339 patients taking psychotropic drug were reported: 85.8% (291/339) received at least one anxiolytic/hypnotic and 56.9% (193/339) received at least one antidepressant; there were prescribed for more than 1 year in 68.4% (199/291) and 43.5% (84/193) of the cases respectively. GPs stated that it was possible to reduce or stop anxiolytic/hypnotic drugs for only 27% (79/291) of these patients. Barriers to doing this were patients' refusal (79%), and the absence of any local offer of psychotherapy (73%) or alternative therapy (70%). A mismatch exists between GPs' intent (91%) and practice (27%) regarding reduction of psychotropic prescription in individuals aged > or =65 years. The barriers encountered should be examined further to help physicians improve management of psychotropic prescription.


Breaking Barriers to an AIDS Model with Macaque-Tropic HIV-1 Derivatives.
The development of an animal model of human immunodeficiency virus type 1 (HIV-1)/AIDS that is suitable for preclinical testing of antiretroviral therapy, vaccines, curative strategies, and studies of pathogenesis has been hampered by the human-specific tropism of HIV-1. Although simian immunodeficiency virus (SIV) or HIV-1/SIV chimeric viruses (SHIVs)-rhesus macaque models are excellent surrogates for AIDS research, the genetic differences between SIV or SHIV and HIV-1 limit their utility as model systems. The identification of innate retro viral restriction factors has increased our understanding about blockades to HIV-1 replication in macaques and provided a guide for the construction of macaque-tropic HIV-1 clones. However, while these viruses replicate in macaque cells in vitro, they are easily controlled and have not caused AIDS in host animals, indicating that we may not fully understand the restrictive barriers of innate immunity. In this review, we discuss recent findings regarding HIV-1 restriction factors, particularly as they apply to cross-species transmission of primate lentiviruses and the development of a macaque model of HIV-1/AIDS.


Analysis of genetically independent phenotypes identifies shared genetic factors associated with chronic musculoskeletal pain conditions.
Chronic musculoskeletal pain affects all aspects of human life. However, mechanisms of its genetic control remain poorly understood. Genetic studies of pain are complicated by the high complexity and heterogeneity of pain phenotypes. Here, we apply principal component analysis to reduce phenotype heterogeneity of chronic musculoskeletal pain at four locations: the back, neck/shoulder, hip, and knee. Using matrices of genetic covariances, we constructed four genetically independent phenotypes (GIPs) with the leading GIP (GIP1) explaining 78.4% of the genetic variance of the analyzed conditions, and GIP2-4 explain progressively less. We identified and replicated five GIP1-associated loci and one GIP2-associated locus and prioritized the most likely causal genes. For GIP1, we showed enrichment with multiple nervous system-related terms and genetic correlations with anthropometric, sociodemographic, psychiatric/personality traits and osteoarthritis. We suggest that GIP1 represents a biopsychological component of chronic musculoskeletal pain, related to physiological and psychological aspects and reflecting pain perception and processing.


Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs.
The allospecifc T cell population responding to a transplanted organ consists of both naive and memory lymphocytes. Although it is established that naive T cells are activated by antigen within the organized structures of secondary lymphoid organs (the spleen, lymph nodes, and mucosal lymphoid tissues), it is not clear whether memory T cell activation and propagation depend on homing to these organs. To answer this question, we investigated whether allospecific naive or memory T cells can mediate acute cardiac allograft rejection in mutant mice that lack all of their secondary lymphoid tissues. The results of our experiments demonstrated that antigen-experienced memory T cells have two advantages over naive T cells: (i) memory T cells mount a vigorous immune response that leads to allograft rejection independent of secondary lymphoid organs; and (ii) memory T cells generate more memory T cells without homing to secondary lymphoid organs. These unique properties of memory T cells were further confirmed by showing that memory-like T cells that arise from the homeostatic proliferation of naive T cells in the absence of antigenic stimulation are suboptimal at rejecting allografts and do not generate memory T cells in mice devoid of secondary lymphoid tissues.


First Record of Toxorhynchites moctezuma in Sinaloa, Mexico: Notes about its Morphology.
Mosquito larvae were collected in the urban area of the city of Culiacan, Sinaloa, in September of 2020. The immature stages were placed in emergence containers and fed with Aedes aegypti larvae. The adults that emerged from the immature stages were mounted on insect pins and characterized based on their morphology. The species corresponded morphologically to Toxorhynchites moctezuma, making this the first report of the species for the state of Sinaloa, Mexico. Similarities and morphological variations are discussed with previous analysis for this species.


[Milk of calcium bile syndrome in children. 2 cases].
Milk of calcium cholecystitis is a rare entity in children. Two cases are reported here, each in a boy aged respectively 4 and 13. The symptoms were limited to abdominal pain with or without vomiting. Plain X-ray of the abdomen showed the usual milk of calcium picture, with calcified deposits within the gallbladder and an obstructing stone at the site of the gallbladder neck or the cystic duct. Surgery consisted simply of cholecystectomy with preoperative cholangiogram. Neither biochemical analysis of the gallbladder contents, nor the pathological examination of the gallbladder wall helped in determining the pathogenesis of the disease. Only four other cases of milk of calcium cholecystitis in children have been found by the authors in the literature, where a number of adult cases have been described.


Assessment of tolerance to the effects of methamphetamine on daytime and nighttime activity evaluated with actigraphy in rhesus monkeys.
Methamphetamine is one of the most largely consumed illicit drugs, and its use is associated with abuse liability and several adverse health effects, such as sleep impairment. Importantly, sleep quality can influence addiction treatment outcomes. Evidence suggests that tolerance can develop to the sleep-disrupting effects of stimulant drugs. The aim of the present study was to investigate the development of tolerance to the actigraphy-based sleep-disrupting and stimulant effects of methamphetamine self-administration in rhesus monkeys. Methamphetamine (0.03 mg/kg/inf, i.v.) self-administration was carried out following three different protocols: 14 consecutive days of self-administration, 5 days/week for 3 weeks, with a 2-day interval between 5-day blocks of self-administration, and 3 days/week for 3 weeks, with a 4-day interval between 3-day blocks of self-administration. Daytime activity and activity-based sleep measures were evaluated with Actiwatch monitors a week before (baseline parameters) and throughout each protocol. Methamphetamine self-administration markedly disrupted sleep-like measures and increased daytime activity. Tolerance developed to those effects with repeated methamphetamine intake exceeding five consecutive days. Inclusion of washout periods (2 or 4 days) between blocks of methamphetamine self-administration attenuated the development of tolerance, with longer breaks from methamphetamine intake being more effective in maintaining the sleep-disrupting and stimulant effects of methamphetamine. Tolerance can develop to the stimulant and sleep-disrupting effects of methamphetamine self-administration. Interruption of drug intake extends the effects of methamphetamine on sleep-like measures and daytime activity.


Implementing competency recommendations into pre-registration nursing curricula: effects upon levels of confidence in clinical skills.
The competency based pre-registration nursing curriculum was introduced to address concerns about levels of confidence and competence in skills of newly qualified Project 2000 educated nurses [Department of Health, 1999. Making a Difference: Strengthening the Nursing, Midwifery and Health Visiting Contribution to Health and Healthcare. The Stationary Office, London]. This study sought to examine whether the implementation of the competency recommendations has led to improvements in the confidence of nursing students in their clinical skills. A self-administered questionnaire examining ratings of confidence in areas of nursing practice and core competencies as specified by the Nursing and Midwifery Council (NMC) [UKCC, 2001. Requirements for Pre-registration Nursing Programmes. UKCC, London] was administered to 139 final year adult nursing students who were studying with the Project 2000 or competency curriculum. The response rate was 53%, results indicating that the students studying the competency curriculum have higher levels of confidence in all areas of their practice targeted by the competency recommendations than students studying in the Project 2000 curriculum. The positive effect that the competency recommendations had upon levels of confidence in nursing practice, and the implications of such changes to curricula are discussed.


Lack of Diversity in Personal Health Record Evaluations with Older Adult Participants: A Systematic Review of Literature.
Older adults are not adopting personal health records (PHRs) at the same rates as other adult populations. Disparities in adoption rates are also reported in older adult subgroups. The variability in adoption may be because PHRs are not designed to meet older adult users. We analyzed PHR evaluation studies to examine the characteristics and perspectives of older adult study participants to identify their self-reported needs. We searched Medline, CINAHL, PsycINFO, and Embase for PHR evaluation studies that involved older adult participants. 1017 abstracts were identified, and 179 publications went through full text review. 10 publications met inclusion criteria. These publications described studies conducted in 3 countries, and evaluated 7 PHRs. Homogeneity was found in the study populations and participant opinions of the systems. Many PHR evaluations do not include diverse older adult participants. This may lead to consistency in outcomes, but it also may create gaps in identifying user needs. Additional studies, specifically targeting diverse older adult participants, are needed to gain a more comprehensive understanding of the opinions of older adults on PHRs and how these systems could benefit older adult healthcare consumers. The body of research shows that older adults are highly satisfied using PHRs. These outcomes may be generalizable because most PHR evaluation studies do not include diverse older adult participants. This lack of participant diversity may be contributing to the disparities observed in PHR adoption rates.


Clinical thrombotic manifestations in SLE patients with and without antiphospholipid antibodies: a 5-year follow-up.
To analyze the association of antiphospholipid antibodies (aPL) with the development of clinical thrombotic manifestations and to characterize the efficacy of anti-thrombotic therapies used. 272 systemic lupus erythematosus (SLE) patients participated in the study. Patient files and a cumulative database were used to collect patients' medical histories. Anti-cardiolipin (aCL), anti-beta2-glycoprotein I (abeta2GPI) antibodies, and lupus anticoagulant (LAC) were measured according to international recommendations. New thrombotic events were registered during follow-up. The patients were prospectively studied for 5 years, of whom 107 were aPL negative (aPL- group). Criteria for antiphospholipid syndrome (APS) were fulfilled by 84 of 165 aPL-positive patients (APS+ group) indicating that SLE patients with aPL have around 50% risk to develop thrombotic complications. The aPL+ group (n = 81) consisted of aPL+ but APS- patients. LAC was the most common aPL (n = 27, 32.1%) in patients with APS. The cumulative presence of aPL further increased the prevalence of thrombotic events. During the follow-up period, aPL developed in 8 of 107 patients (7.5%) from the aPL- group, of whom 3 (2.8%) presented with thrombotic complications. Other types of aPL developed in 7 of 165 (4.2%) aPL+ patients within 5 years. New thrombotic events occurred in 3.7% of aPL+ (n = 3) and 8.3% (n = 7) of the APS group. During follow-up, 52 of 81 aPL+ patients received primary prophylaxis, and 1 (1.9%) had transient ischemic attack (TIA). In the non-treatment group, 2 (6.9%) had stroke. Seventy-nine of 84 of the APS patients received secondary prophylaxis, and myocardial infarction occurred in 2 patients (on cumarine therapy maintaining an international normalized ratio around 2.5-3.0), and 5 suffered a stroke/TIA (1 on aspirin and 4 on aspirin + cumarine). The findings emphasize the importance of determining both aCL and abeta2GPI antibodies and LAC in SLE patients and the need for adequate anticoagulant therapy.


Sporozoite-induced Plasmodium cynomolgi infections in captive born Macaca fascicularis.
Capability of captive born cynomolgus monkeys to substitute for rhesus in the Plasmodium cynomolgi radical curative antimalarial drug development model was examined. Eighteen monkeys divided into 3 groups were given standard or high doses of sporozoites intravenously. One group of 4 received 0.8 - 1.6 X 10(6) and a second group of 8 received 0.3 - 1.0 X 10(7) sporozoites. The third group of 6 was splenectomized and then received 3.0 - 4.0 X 10(6). The 2 groups of intact monkeys developed a persistent low level parasitemia; however, gametocyte production was poor. The splenectomized group developed a persistent parasitemia with a higher mean, which more closely resembled rhesus parasitemias. A high, post-patent leukocytosis consisting primarily of lymphocytes was observed in this group. Good gametocyte production resulted in the splenectomized group and oocysts were produced from all lots of Anopheles dirus which fed on them. Following clearance of blood forms, relapse potential was demonstrated in the 2 splenectomized monkeys tested. In this study the splenectomized captive born cynomolgus appeared to be capable of supplementing rhesus as an antimalarial drug testing model.


Pattern of soft tissue injuries to the oro-facial region in Nigerian children attending a teaching hospital.
This study was designed to determine the aetiological factors and pattern of oro-facial soft tissue injuries among children in a suburban Nigerian population. The problems encountered in the management of the patients are also highlighted. Obafemi Awolowo University Teaching Hospitals' Complex, Ile-Ife, Osun State Nigeria. This prospective study was carried out in children aged < or = 15 years who presented with oro-facial soft tissue injuries between July 1996 and December 1997. Data was collected from a clinical examination of the child and a questionnaire completed by the parent or carer. During the study period, 174 children were managed for oro-facial soft tissue injuries, an incidence of 1.1%, out of a total of 15 582 child admissions. A male preponderance was found (1 : 0.74). The mean age +/- SD was 7.3 +/- 4.2 years and the range was 9 months-15 years. Falls were the most common aetiology followed by road traffic accident. The forehead was the most frequently injured site. A mortality of 3.4% was found. Although animal bites and burns accounted for only 13.8% of all injuries, all the deaths were a result of these aetiologies. Road traffic accidents and burn victims had the longest hospital stay. Although falls and road traffic accidents are frequent causes of oro-facial soft tissue injuries, less common causes, like burns and dog bites are more likely to result in death.


Benzylguanine thiol self-assembled monolayers for the immobilization of SNAP-tag proteins on microcontact-printed surface structures.
The site-selective, oriented, covalent immobilization of proteins on surfaces is an important issue in the establishment of microarrays, biosensors, biocatalysts, and cell assays. Here we describe the preparation of self-assembled monolayers consisting of benzylguanine thiols (BGT) to which SNAP-tag fusion proteins can be covalently linked. The SNAP-tag, a modified O(6)-alkylguanine-DNA alkyltransferase (AGT), reacts with the headgroup of BGT and becomes covalently bound upon the release of guanine. Bacterially produced recombinant His-tag-SNAP-tag-GFP was used to demonstrate the site-specific immobilization on BGT surface patterns created by microcontact printing (microCP). With this versatile method, any SNAP-tag protein can be coupled to a surface.


Quantification of polyphenolics and their antioxidant capacity in fresh plums.
Total phenolics, total flavonoids, and antioxidant capacity of 11 cultivars of fresh plums were determined using spectrophotometric methods. Identification and quantification of individual polyphenolics were performed using reversed-phase high-performance liquid chromatography equipped with a diode array detector. The total phenolic contents of various cultivars widely varied from 125.0 to 372.6 mg/100 g expressed as gallic acid equivalents. The level of total flavonoids in fresh plums ranged between 64.8 and 257.5 mg/100 g expressed as catechin equivalents. Antioxidant capacity, expressed as vitamin C equivalent antioxidant capacity (VCEAC), ranged from 204.9 to 567.0 mg/100 g with an average of 290.9 mg/100 g of fresh weight. Cv. Beltsville Elite B70197 showed the highest amounts of total phenolics and total flavonoids and the highest VCEAC. A positive relationship (correlation coefficient r (2)() = 0.977) was presented between total phenolics and VCEAC, suggesting polyphenolics would play an important role in free radical scavenging. The level of IC(50) value of superoxide radical anion scavenging activity of the plum cultivars ranged from 13.4 to 45.7 mg of VCEAC/100 g. Neochlorogenic acid was the predominant polyphenolic among fresh plums tested. Flavonols found in plum were commonly quercetin derivatives. Rutin was the most predominant flavonol in plums. Various anthocyanins containing cyanidin aglycon and peonidin aglycon were commonly found in all plums except for cv. Mirabellier and NY 101.


Bcl-2 inhibits gut epithelial apoptosis induced by acute lung injury in mice but has no effect on survival.
Gut epithelial apoptosis is increased in human studies and animal models of noninfectious inflammation and sepsis. Elevated intestinal cell death appears to be physiologically significant in sepsis. Previous studies demonstrate that overexpression of the antiapoptotic protein Bcl-2 in the gut epithelium of transgenic mice is associated with improved survival from Pseudomonas aeruginosa pneumonia and cecal ligation and puncture. The functional significance of elevated gut apoptosis in noninfectious inflammation has not been examined. We hypothesized that intestinal apoptosis would be detrimental to survival in noninfectious critical illness. To address this issue, acute lung injury (ALI) was induced with intratracheal injection of lipopolysaccharide (LPS, 800 microg) in wild-type (WT) FVB/N mice and transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Guts were harvested at 12, 24, 48, and 72 h and assessed for apoptosis by both hematoxylin and eosin and active caspase-3 staining in 100 contiguous crypts. ALI increased gut epithelial apoptosis 12 h after LPS instillation compared with shams (P < 0.01), whereas overexpression of Bcl-2 decreased intestinal apoptosis compared with WT animals with ALI when assayed by active caspase-3 (P < 0.05). Plasma levels of tumor necrosis factor alpha, interleukin (IL)-6, and IL-10 were similar between WT and transgenic animals with ALI, both of which had elevated IL-10 levels at 12 h and elevated IL-6 levels at 24 h compared with sham animals. In a separate experiment, transgenic and WT animals with ALI were followed for mortality to determine whether gut overexpression of Bcl-2 conferred a survival advantage. Survival at 10 days was 73% in WT animals (n = 33) and 65% in Bcl-2 animals (n = 23, P = ns). These results indicate that while gut epithelial apoptosis is elevated in multiple models of critical illness, prevention of intestinal cell death by overexpression of Bcl-2 is associated with a disparate survival effect between sepsis and noninfectious inflammation.


[The presentation of small-cell lung cancer with metastatic carcinomatous encephalitis in a non-Hodgkin's lymphoma patient].
Carcinomatous encephalitis or milary cerebral metastases characterized by signs of diffuse encephalopathy is a rare form of brain metastases. Tiny tumor nodules are seen throughout the cortical and subcortical gray matter. We report the case of a patient with a history of non-Hodgkin lymphoma who developed carcinomatous encephalitis probably secondary to small-cell lung cancer. This case is discussed in light of findings of 16 cases of carcinomatous encephalitis reported in the literature. We discuss clinical, radiological, histological, pathophysiological characteristics and the survival of this form. The frequency of carcinomatous encephalitis is underestimated because clinical expression is non specific. Brain magnetic resonance imaging must be performed in all patients presenting encephalopathy without an obvious cause.


Stacking in lipid vesicle-tubulin mixtures is an artifact of negative staining.
Multilamellar stacking seen in negatively stained lipid vesicle-tubulin mixtures has been attributed to lipid-protein interactions (Caron, J. M., and R. D. Berlin, 1979, J. Cell Biol. 81:665-671). We show that this stacking is produced by the phosphotungstic acid used for staining, independent of the presence of tubulin in the sample. The morphology of negatively stained single bilayer vesicles obtained from dimyristoyl phosphatidylcholine or egg lecithin is specifically dependent upon the choice of metal stain. Uranyl oxalate maintains the appearance of unilamellar vesicles. After staining with sodium tungstate, the lipids form a network of multilayered lamellae with a periodicity of approximately 55 A. Phosphotungstic acid produces stacks of flattened vesicles with a period of approximately 115 A as well as broader multilamellar structures having a 55 A repeat. The stain-determined morphology is not markedly altered by sample concentration, incubation time, or temperature, or by the presence of tubulin.


Cataract- and lens-specific upregulation of ARK receptor tyrosine kinase in Emory mouse cataract.
The Emory mouse is a well-characterized model for age-onset cataract. The purpose of the present study was to identify differentially expressed genes between pre- and postcataract Emory mouse lenses. Eyes were extracted from Emory mice at 3 weeks (precataract) and 7.5 months (postcataract) of age, and lenses were dissected. Lens RNA was compared for gene expression differences by RT-PCR differential display, and transcripts exhibiting altered levels of gene expression were cloned and identified by sequencing. The levels of two transcripts were further evaluated by RT-PCR in 3-week- and 7.5-month-old lenses and the remainder of the eye. The same transcripts were also measured in lenses from three non-Emory mouse strains (FVB/N, 129Sv, and CD1) ages 4 weeks to 11.5 months. Three transcripts were identified as exhibiting altered levels of gene expression between 3-week- and 7.5-month-old Emory mouse lenses. These encoded alphaA-crystallin (decreased), betaA3/A1-crystallin (decreased), and adhesion-related kinase (ARK) receptor tyrosine kinase (increased). Decreased alphaA-crystallin and increased ARK expression were not detected in lenses isolated from three non-Emory mouse strains of similar age. Increased expression of ARK was not detected between 3-week- and 7.5-month-old Emory mouse eye nonlens tissues. The present data confirm that expression of the alphaA-crystallin gene is decreased in cataract in the Emory mouse lens relative to age-matched control lenses and they provide evidence for cataract- and lens-specific upregulation of the ARK receptor tyrosine kinase in the Emory mouse.


2-Ketogluconate Kinase from Cupriavidus necator H16: Purification, Characterization, and Exploration of Its Substrate Specificity.
We have cloned, overexpressed, purified, and characterized a 2-ketogluconate kinase (2-dehydrogluconokinase, EC 220.127.116.11) from Cupriavidus necator (Ralstonia eutropha) H16. Exploration of its substrate specificity revealed that three ketoacids (2-keto-3-deoxy-d-gluconate, 2-keto-d-gulonate, and 2-keto-3-deoxy-d-gulonate) with structures close to the natural substrate (2-keto-d-gluconate) were successfully phosphorylated at an efficiency lower than or comparable to 2-ketogluconate, as depicted by the measured kinetic constant values. Eleven aldo and keto monosaccharides of different chain lengths and stereochemistries were also assayed but not found to be substrates. 2-ketogluconate-6-phosphate was synthesized at a preparative scale and was fully characterized for the first time.


Technique, indications, and clinical use of ambulatory 24-hour gastric pH monitoring in a surgical practice.
Prolonged pH monitoring is used increasingly to assess alterations of gastric luminal pH caused by gastroduodenal secretory and motor abnormalities. The clinical value of gastric pH monitoring, however, has been debated. We obtained normal values for 24-hour ambulatory gastric pH monitoring in 50 healthy volunteers and evaluated its clinical use by monitoring pH in 285 consecutive patients with nonspecific foregut symptoms and duodenal ulcers (n = 33), gastric ulcers (n = 21), antral gastritis (n = 123), or no mucosal injury (n = 108). Patients with duodenal ulcer had a shift of their recorded pH values to a more acidic range, particularly during the night (p < 0.01). Multiple regression analysis showed that an increased percentage of time pH was less than 1.2 during the night indicates gastric acid hypersecretion. In contrast, patients with gastric ulcer or antral gastritis had an increased frequency of alkaline peaks and percentage of time spent at a pH greater than 3 (p < 0.01). The presence of excessive duodenogastric reflux was identified in 39% of these patients as compared with 7% with no gastric mucosal injury (p < 0.01). Delayed gastric emptying was suggested by prolonged postprandial alkalinization of the gastric pH record in 25% of the patients. Radionuclide gastric emptying studies confirmed this in 85% of these patients. Gastric pH monitoring allows evaluation of gastric secretory state fluctuation in gastric pH environment, duodenogastric reflux, and gastric emptying under physiologic conditions during a complete circadian cycle and has potential to be one of the most inclusive initial tests of gastroduodenal function.


[COVID-19 emergency operations center: experience of the Rio de Janeiro municipality, BrazilCentro de operaciones de emergencia en respuesta a la COVID-19: la experiencia del municipio de Rio de Janeiro].
The present report describes the implementation of an emergency operations center to coordinate the response to the COVID-19 pandemic in the municipality of Rio de Janeiro, Brazil. Following the public health emergency management framework proposed by the World Health Organization (WHO), this temporary center (COE COVID-19 RIO) started operating in January 2021. The report is organized along five themes: legal framework; structure, planning, and procedures; institutional articulation; health information for decision-making; and risk communication. Major advances obtained with the initiative include improvements in governance for the management of COVID-19, increase in the synergy among sectors and institutions, improved information sharing in relation to COVID-19 prevention and control measures, innovation in epidemiologic analyses, and gains in transparency and decision-making opportunities. In conclusion, even if conceived at an advanced stage of the pandemic in the municipality of Rio de Janeiro, the COE COVID-19 RIO has played a relevant role in shaping the city's responses to the pandemic. Also, despite its temporary character, the experience will leave a lasting legacy for the management of future public health emergencies in the municipality of Rio de Janeiro.


Interleukin-6 -634G>C genetic polymorphism is associated with prognosis following surgery for advanced thoracic esophageal squamous cell carcinoma.
Systemic and/or local interleukin-6 (IL-6) reportedly plays an active role in the progression and prognosis of thoracic esophageal squamous cell carcinoma (TESCC). We assessed the associations between IL-6 and IL-6 receptor (IL-6R) genetic polymorphisms, tumoral IL-6 expression and survival rates following surgery. The study participants were 63 Japanese patients treated between 2003 and 2008 for T2-T4 advanced TESCC using curative esophagectomy without neoadjuvant treatment. We investigated IL-6 -634G>C (rs1800796) and IL-6R 48892A>C (rs8192284, Asp358Ala) genetic polymorphisms using DNA from peripheral blood samples. In addition, tumoral IL-6 expression was investigated immunohistochemically in resected specimens, and serum IL-6 was measured using a human IL-6 immunoassay. There was a significant difference in survival between patients with the IL-6 -634G/G+G/C genotype and those with the C/C genotype, such that their 5-year overall survival rates were 42 and 72%, respectively. By contrast, the IL-6R 48892A /C genotype and tumoral IL-6 expression had no significant effect on survival among patients. Univariate and multivariate analyses revealed that IL-6 -634G>C polymorphism was an independent prognostic factor with a hazard ratio of 3. IL-6 -634G>C genetic polymorphism may be a predictive prognostic factor in patients receiving esophagectomy for TESCC.


AVERAGE TREATMENT EFFECTS IN THE PRESENCE OF UNKNOWN INTERFERENCE.
We investigate large-sample properties of treatment effect estimators under unknown interference in randomized experiments. The inferential target is a generalization of the average treatment effect estimand that marginalizes over potential spillover effects. We show that estimators commonly used to estimate treatment effects under no interference are consistent for the generalized estimand for several common experimental designs under limited but otherwise arbitrary and unknown interference. The rates of convergence depend on the rate at which the amount of interference grows and the degree to which it aligns with dependencies in treatment assignment. Importantly for practitioners, the results imply that if one erroneously assumes that units do not interfere in a setting with limited, or even moderate, interference, standard estimators are nevertheless likely to be close to an average treatment effect if the sample is sufficiently large. Conventional confidence statements may, however, not be accurate.


[Unusual clinical manifestation of Lyme disease--report of 2 cases].
Unusual clinical manifestation of Lyme borreliosis in two children has been presented. We discuss patient from Borrelia-endemic area who presented with persistent headache, weakness and fever. The second patient experienced acute flu-like signs with associated neck pain and stiffness (probable diagnosis). After two weeks lasting antibiotic therapy (ceftriaxone, ampicillin) nonspecific symptoms and signs decreased.


Stimuli-Responsive Systems in Optical Humidity-Detection Devices.
The use of electronic devices to measure Relative Humidity (RH) is widespread. However, under certain circumstances, for example when explosive gases are present, a spark-free method should be used. Here we suggest the use of stimuli-responsive materials, like gelatin and interpenetrated polymers, to detect RH with an optical method. These materials are hydrophilic. When water vapor is absorbed by the films the molecules attach to the films molecular network. The result is that the film thickness increases and their refractive index changes. To detect the change of these two parameters an optical method based on diffraction gratings is employed. Surface diffraction gratings are recorded on the films. Then gratings are placed in an optical configuration that is immersed in a climatic chamber. A light beam is sent to the grating where it is diffracted. Several light orders appear. Due to the absorption of water molecules the films swell and grating surface modulation changes. This implies that the diffracted orders intensity changes. A calibrating plot relating intensity as a function of RH is obtained.


[Formulas for the steel balls used for healing wounds].
The author presents and compares the formulas for steel balls or Mars balls (Globuli Martiales) as they are produced in Nancy, Molsheim and in the monastery of Grande-Chartreuse (Isère).