Hepatic IL-17 responses in human and murine primary biliary cirrhosis.
The emergence of new regulatory and pro-inflammatory immune cell subsets and cytokines dictates the need to re-examine the role of these subsets in various diseases involving the immune system. IL-17 has been recently identified as a key cytokine involved in numerous autoimmune processes. However, its role in liver autoimmune diseases remains unclear. Primary biliary cirrhosis (PBC) is characterized histologically by autoreactive CD4 and CD8 T cells surrounding damaged bile ducts. CD4(+) T cells are a major source of IL-17, which compose a distinct T helper subset (Th17). Thus we set out to determine the role of IL-17 in both human and a murine model of PBC in a liver-targeted manner. Our data demonstrate an increase in the frequency of IL-17(+) lymphocytic infiltration in liver tissues from PBC patients and those with other liver dysfunctions as compared to healthy livers. IL-2 receptor alpha knockout mice, a recently identified murine model of human PBC, also demonstrate marked aggregations of IL-17-positive cells within portal tracts and increased frequencies of Th17 cells in the liver compared to the periphery. Interestingly, CD4(+) T cells from livers of normal C57BL/6J mice also secreted higher levels of IL-17 relative to those from spleens, indicating a preferential induction of Th17 cells in liver tissues. Importantly, C57BL/6J cocultures of splenic CD4(+) T cells and liver non-parenchymal cells increased IL-17 production approximately 10-fold compared to T cells alone, suggesting a role of the liver microenvironment in Th17 induction in cases of liver autoimmunity and other liver inflammatory diseases.


[Free amino acids in the synthesis of peptides. Effect of inorganic compounds on the solubility of amino acids in aprotic solvents].
In order to increase the solubility of free amino acids so that they could be used in peptide synthesis, a system consisting of dimethylformamide, an inorganic additive, and pyridine was suggested. Compounds BF3, AlCl3, SnCl2, SiCl4, ZnCl2, SbCl3, CaCl2, BaI2, CdI2, and NaI can serve as the additives. Acylation of amino acids in such a solution (pH 5.2-5.3) with pentafluorophenyl esters of N alpha-protected amino acids gave N alpha-protected di- and tripeptides in a yield of more than 90%.


Ocular manifestations of leprosy in a noninstitutionalized community in the United States.
Our goal was to delineate the epidemiologic and clinical patterns of ocular leprosy in an outpatient setting in the United States. Examinations were performed in 61 consecutive outpatients seen in a Midwestern leprosy clinic. Forty-three male and 18 female patients were examined. The patients' origins included Southeast Asia (24 patients [39%]), Latin America (23 patients [38%]), India (nine patients [15%]), Europe or North America (two patients [3%]), Africa (two patients [3%]), and the Middle East (one patient [2%]). Thirty-nine percent of patients were classified as having polar lepromatous leprosy; 18%, borderline lepromatous leprosy; 3%, borderline borderline leprosy; 36%, borderline tuberculoid leprosy; 2%, polar tuberculoid leprosy; and 2%, indeterminate leprosy. Ninety-six percent of patients had a best-corrected visual acuity of 20/40 or better. Ocular findings included madarosis (28 patients [46%]), subconjunctival fibrosis (18 patients [30%]), punctate epithelial keratopathy (17 patients [28%]), posterior subcapsular cataract (10 patients [16%]), corneal hypesthesia (10 patients [16%]), lagophthalmos (seven patients [11%]), corneal pannus (six patients [10%]), entropion (five patients [8%]), prominent or beaded corneal nerves (four patients [7%]), iridocyclitis (four patients [7%]), focal avascular keratitis (three patients [5%]), scleritis (three patients [5%]), interstitial keratitis (two patients [3%]), iris pearls (two patients [3%]), and ocular clofazimine crystals (two patients [3%]). Madarosis, corneal hypesthesia, and posterior subcapsular cataracts were significantly associated with disease duration (P < .05). We report herein a relatively low frequency of visual impairment attributable to leprosy in our series compared with that seen among institutionalized leprous patients. However, since 48% of subjects had one or more sight-threatening complications as a result of their disease, a program of regular ophthalmic follow-up is strongly advocated for all patients with leprosy.


Nervous systems in 3D: a comparison of Caridean, anomuran, and brachyuran zoea-I (Decapoda).
Using serial semi-thin sections and digital 3D-reconstructions we studied the nervous systems of zoea-I larvae in three decapod species, Hippolyte inermis (Leach, 1815), Porcellana platycheles (Pennant, 1777), and Pachygrapsus marmoratus (Fabricius, 1787). These taxa represent three decapod lineages, that is, Caridea, Anomura, and Brachyura, each characterized by specific zoea-I morphology. Special attention was paid to development of ganglia, neuropil composition, and segmental nerves. In all zoeae studied, the overall elements, for example, the segmental ganglia, their neuropils and most of the nerves of the adult decapod nervous system are present. Ongoing differentiation processes are observable as well, most obvious in segments with well-developed limbs the ganglia are in a more advanced stage of differentiation and more voluminous compared to segments with only limb buds or without externally visible limb anlagen. Intra- and interspecific comparisons indicate that neuromere differentiation thus deviates from a simple anterior-posterior gradient as, for example, posterior thoracic neuromeres are less developed than those of the pleon. In addition, the differences in the progress of the development of ganglia between the studied taxa can best be attributed to heterochronic mechanisms. Taxon and stage-specific morphologies indicate that neuronal architecture reflects both, morphogenesis to the adult stage and specific larval adaptions, and provides sets of characters relevant to understanding the corresponding phylogeny.


Associations of motor co-ordination and attention with motor-perceptual development in 3-year-old preterm and full-term children who needed neonatal intensive care.
Children who have needed neonatal intensive care (NIC) are considered to be at risk for deficits such as developmental co-ordination disorder and attention-deficit/hyperactivity disorder. By assessing motor-perceptual development, motor co-ordination and attention already at 3 years of age, it might be possible to identify such deficits earlier than they are today. To investigate the motor-perceptual development in a group of 202 NIC children but had no major impairments, to describe associations of deficits in co-ordination and attention with motor-perceptual delays, and to estimate the prevalence of NIC children with combined deficits together with a motor-perceptual delay. Co-ordination and attention in children born very preterm (n = 57), moderately preterm (n = 75) and full-term (n = 70) were observed according to a model for Combined Assessment of Motor Performance and Behaviour while they were assessed using a developmental scale, Motor-Perceptual Development, 0-7 years, MPU. In two out of 14 MPU areas, a larger proportion of very preterm than of moderately preterm and full-term children had marked developmental delay. Overall, the proportion of NIC children having a motor-perceptual delay increased with increasing incoordination and especially increasing lack of attention. Twenty-one (11%) of the NIC children had different motor-perceptual delays combined with pronounced incoordination and pronounced lack of attention. Deficits in co-ordination and attention were associated with motor-perceptual delays in areas important for daily living and development of academic skills. Therefore, to find children at risk for developmental co-ordination disorder and attention-deficit/hyperactivity disorder, assessments of co-ordination and attention should be added to assessments of motor-perceptual development in 3-year-old NIC children.


Dietary lignin, and insoluble fiber, enhance uterine cancer but did not influence mammary cancer induced by N-methyl-N-nitrosourea in rats.
Previous investigations suggested potential breast cancer-preventive properties of dietary fiber from cabbage. The purpose of the present investigation was to determine whether lignin, a component of cabbage fiber, would protect against mammary carcinogenesis by N-methyl-N-nitrosourea (MNU) in Sprague-Dawley rats. A six-week study was conducted using diets containing 0.5-5% dietary wood lignin (a readily available, purified source). These diets were well tolerated by the rats, and a carcinogenesis study using 5 mg MNU/100 g body wt i.v. at 50 days of age was conducted, with the 2.5% lignin diet fed from 6 through 8 weeks of age followed by 5% lignin diet until 20 weeks after MNU. Dietary lignin and MNU treatment increased food consumption (p < 0.05), and body weight was slightly reduced at 10 and 20 weeks after MNU in the MNU-5% lignin diet group (p < 0.05). Serum estradiol was not altered by dietary lignin or MNU treatment, but uterine weights were highest in the MNU-control diet group 4 and 12 weeks after MNU. Expression of creatine kinase B, and estrogen-responsive gene, was lower in eh uteri of the MNU-lignin diet group than in other groups at 20 weeks. Mammary carcinogenesis was not altered by dietary lignin. However, uterine endometrial adenocarcinoma was observed only in the MNU-lignin diet group (4 carcinomas/40 effective rats) (p < 0.05).


Impaired Awareness of Hypoglycemia in Type 1 Diabetes: A Report of An NIDDK Workshop in October 2021.
Hypoglycemia remains a limiting factor in the optimal treatment of type 1 diabetes. Repeated episodes of hypoglycemia result in impaired awareness of subsequent hypoglycemic events, inducing a vicious feed-forward cycle and increasing the risk of morbidity and mortality. Why this occurs and how to manage the problem in clinical practice remain uncertain. To address the obstacles and barriers that have hindered progress in this clinically important area, the National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on 14-15 October 2021. This perspective offers a summary of this outstanding meeting, which brought clinical and basic scientists from the fields of diabetes, neuroscience, psychology, psychiatry, and imaging together, on how to best advance the field of impaired awareness of hypoglycemia and hypoglycemia in general in patients with diabetes.


Clinical and molecular genetics of Usher syndrome.
Usher syndrome is an autosomal-recessive disorder manifested by hearing impairment, retinitis pigmentosa (RP), and variable vestibular deficit. Recent progress in the characterization of the genetics of Usher syndrome has shown that this disorder is phenotypically and genetically complex. This progress impacts the approach of the clinicians in the study of patients who may potentially have Usher syndrome. There are three major phenotypic classes: Usher I, II, and III. Usher I is distinguished from Usher II by having a more severe audiologic involvement and by the presence of vestibular areflexia. Usher III has a progressive hearing loss with variable vestibular involvement. A minimum of three genes have been identified as being responsible for Usher I; two have been identified as being responsible for Usher II. It is not yet clear whether other manifestations such as progressive hearing loss, associated mental retardation, or other physical anomalies are associated with the known Usher genes or whether they represent as yet undiscovered genetic disorders. As progress towards the identification of the Usher genes is made, the clinician will gradually gain new and effective diagnostic procedures for the identification and delineation of the Usher syndromes.


FIST: a sensory domain for diverse signal transduction pathways in prokaryotes and ubiquitin signaling in eukaryotes.
Sensory domains that are conserved among Bacteria, Archaea and Eucarya are important detectors of common signals detected by living cells. Due to their high sequence divergence, sensory domains are difficult to identify. We systematically look for novel sensory domains using sensitive profile-based searches initiated with regions of signal transduction proteins where no known domains can be identified by current domain models. Using profile searches followed by multiple sequence alignment, structure prediction and domain architecture analysis, we have identified a novel sensory domain termed FIST, which is present in signal transduction proteins from Bacteria, Archaea and Eucarya. Chromosomal proximity of FIST-encoding genes to those coding for proteins involved in amino acid metabolism and transport suggest that FIST domains bind small ligands, such as amino acids.


Fluorescence enhancement of oligodeoxynucleotides modified with green fluorescent protein chromophore mimics upon triplex formation.
Green fluorescent protein (GFP)-based molecular-rotor chromophores were attached to the 5-positions of deoxyuridines, and subsequently, incorporated into the middle positions of oligodeoxynucleotides. These oligonucleotides were designed to form triplex DNA in order to encapsulate the GFP chromophores, mimicking GFP structures. Upon triplex formation, the embedded GFP chromophores exhibited fluorescence enhancement, suggesting the potential application of these fluorescent probes for the detection of nucleic acids.


Catalyst deep neural networks (Cat-DNNs) in singlet fission property prediction.
Many current deep neural network (DNN) models only focus on straightforward optimization over the given database. However, most numerical fitting procedures depart from physical laws. By introducing the concept of "catalysis" from physical chemistry, we propose that the physical correlations among molecular properties could spontaneously act as a catalyst in the DNNs, which increases the accuracy, and more importantly, guides the DNNs in the right way. These Catalysis-DNNs (Cat-DNNs) could precisely predict both the ground and excited-state properties, especially the molecules' screening with singlet fission character. We show that traditional machine learning metrics are not suitable for evaluating model accuracy in physical-chemical tasks and issue new physical errors. We believe that the agile transfer of fundamental physics or chemistry domain knowledge, like the catalyst, could significantly benefit both the architecture and application of artificial intelligence technology in the future.


Cyclophilin D promotes tubular cell damage and the development of interstitial fibrosis in the obstructed kidney.
Cyclophilin D (CypD) is an important component in mitochondrial-dependent tubular cell death in acute kidney injury. However, it is not known whether CypD contributes to tubular cell damage in chronic interstitial fibrosis. We investigated this question in the unilateral ureter obstruction (UUO) model of renal interstitial fibrosis. Groups of CypD-/- and wild type (WT) mice were killed 7 or 12 days after UUO surgery. The significant tubular cell apoptosis seen in WT UUO was significantly reduced in CypD-/- UUO based on TUNEL and cleaved caspase 3 staining. Other markers of tubular cell damage; loss of E-cadherin and AQP1 expression, were also reduced in the CypD-/- UUO kidney. This reduced tubular damage was associated with less inflammation and a partial protection against loss of peritubular capillaries. The prominent accumulation of α-SMA+ myofibroblasts and interstitial collagen deposition seen in WT UUO was significantly reduced in CypD-/- UUO on day 12, but not day 7. Activation of several pro-fibrotic signalling pathways (p38 MAPK, JNK and Smad3) was unaltered in CypD-/- UUO, arguing that CypD acts independently to promote renal fibrosis. CypD deletion in cultured tubular cells attenuated oxidative stress-induced pro-inflammatory, pro-fibrotic and apoptotic responses; however, responses to angiotensin II and LPS were unaffected. In contrast, CypD deletion in cultured renal fibroblasts did not affect PDGF-induced proliferation or TGF-β1-induced collagen I expression, suggesting no direct role of CypD in the fibroblast response. In conclusion, we have identified a role for CypD in chronic tubular cell damage and in the development of renal interstitial fibrosis.


Monoclonal antibodies specific for African swine fever virus proteins.
We have obtained 60 stable hybridomas which produced immunoglobulins that recognized 12 proteins from African swine fever virus particles and African swine fever virus-infected cells. Most of the monoclonal antibodies were specific for the three major structural proteins p150, p72, and p12. The specificity of some monoclonal antibodies for the structural proteins p150 and p37 and the nonstructural proteins p220 and p60 indicated that proteins p150 and p220 are antigenically related to proteins p37 and p60. The association of some viral antigens to specific subcellular components was determined by immunofluorescence and analysis of the binding of monoclonal antibodies to infected cells. A host protein (p24) seemed to be associated with the virus particles.


Longitudinal course of cognitive impairment in patients with atopic dermatitis.
Atopic dermatitis (AD) is a common inflammatory skin disease. Cognitive dysfunction was recently demonstrated to be increased in adults and children with AD. However, little is known about the longitudinal course of cognitive impairment in AD and its relationship with pruritus. To investigate the longitudinal course and predictors of cognitive impairment in AD a prospective dermatology practice-based study was performed using questionnaires and evaluation by a dermatologist (n = 210). Patients with ≥ 2 visits were included (mean follow-up time: 318 days). Cognitive function was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function 8-item Short-Form. At baseline, 20.85% of patients had PROMIS T scores ≤ 45, indicating cognitive impairment (CI). Among patients with CI at baseline, 34.09% had persistent CI, 47.72% had a fluctuating course, and 18.18% had sustained improvement of cognitive function. In repeated-measures regression models, cognitive function scores declined overtime in patients with worse AD severity [SCORing Atopic Dermatitis (SCORAD): p = 0.01, Atopic Dermatitis Severity Index: p = 0.001], increased itch (p = 0.01), skin pain (p = 0.001), and sleep disturbance (p = 0.001). In multivariable logistic regression models, persistent CI was associated with female gender and depressive symptoms [moderate-to-severe Patient Health Questionnaire-9 score (PHQ9)]. Latent class analysis identified two classes of cognitive dysfunction: normal cognition (77.23%), moderate dysfunction (16.21%) and severe impairment (6.55%). Black/African-American race (p = 0.02), moderate-to-severe SCORAD (p = 0.03), dermatology life quality index (p < 0.0001), PHQ9 (p < 0.0001), itch (p = 0.02) and skin pain (p < 0.0001) were more likely to experience moderate dysfunction or severe cognitive impairment. AD is associated with a heterogeneous longitudinal course of cognitive function in adults, with some patients experiencing persistent CI over time.


Identification of SYWKQCAFNAVSCFamide: a broadly conserved crustacean C-type allatostatin-like peptide with both neuromodulatory and cardioactive properties.
The allatostatins comprise three structurally distinct peptide families that regulate juvenile hormone production by the insect corpora allata. A-type family members contain the C-terminal motif -YXFGLamide and have been found in species from numerous arthropod taxa. Members of the B-type family exhibit a -WX(6)Wamide C-terminus and, like the A-type peptides, appear to be broadly conserved within the Arthropoda. By contrast, members of the C-type family, typified by the unblocked C-terminus -PISCF, a pyroglutamine blocked N-terminus, and a disulfide bridge between two internal Cys residues, have only been found in holometabolous insects, i.e. lepidopterans and dipterans. Here, using transcriptomics, we have identified SYWKQCAFNAVSCFamide (disulfide bridging predicted between the two Cys residues), a known honeybee and water flea C-type-like peptide, from the American lobster Homarus americanus (infraorder Astacidea). Using matrix assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FTMS), a mass corresponding to that of SYWKQCAFNAVSCFamide was detected in the H. americanus brain, supporting the existence of this peptide and its theorized structure. Furthermore, SYWKQCAFNAVSCFamide was detected by MALDI-FTMS in neural tissues from five additional astacideans as well as 19 members of four other decapod infraorders (i.e. Achelata, Anomura, Brachyura and Thalassinidea), suggesting that it is a broadly conserved decapod peptide. In H. americanus, SYWKQCAFNAVSCFamide is capable of modulating the output of both the pyloric circuit of the stomatogastric nervous system and the heart. This is the first demonstration of bioactivity for this peptide in any species.


Influence of organic promoter gradient on the MoS2 growth dynamics.
Chemical vapor deposition has been demonstrated to be the most efficient, versatile and reliable technique for the synthesis of monolayers of transition metal dichalcogenides. The use of organic promoters during the growth process was a turning point in order to increase the monolayer lateral size or to obtain complete coverage of the growth substrate. In this work we clarify the influence of the promoter gradient on the growth dynamics of MoS2. In particular, we place a sacrificial substrate covered with a promoter (a low sublimation-temperature perylene-based compound) downstream with respect to the growth substrate in order to maximize its gradient on the growth substrate through upstream diffusion. We demonstrate that the morphology and the number of layers of MoS2 are drastically affected by the distance of the growth substrate from the promoter sacrificial substrate. The farthermost area from the promoter substrate presents micrometric MoS2 triangular monolayers and large low hierarchy dendritic multi-layer structures. On the contrary the closest area reveals an almost continuous polycrystalline MoS2 monolayer, with bilayer terraces, with a lateral dimension up to hundreds of micrometers.


Towards Equitable Health Care Access: Community Participatory Research Exploring Unmet Health Care Needs of Homeless Individuals.
Community and health services often overlook health care needs of persons experiencing homelessness, which leads to deterioration in health and increased utilization of emergency services. Since homeless people are underrepresented in health service research, little is known about their unmet health care needs, particularly in smaller cities where resources are limited. This community-based participatory research explored the experiences of small-city homeless service users (HSUs) with unmet health care needs and community service providers (CSPs) who work with them to determine barriers to health care access affecting them. Structured interviews were conducted with 65 HSUs and 15 CSPs in interior British Columbia, Canada. These interviews were audio-recorded, and the retrieved data were analyzed thematically. The three themes uncovered included: a lack of access to health care and risk of stigma, a lack of trust and fear of discrimination, and a need for community navigation and social support. The findings indicate that HSUs do not receive equitable care and face challenges in accessing appropriate and timely foot care, which contributes to increased foot-related emergency visits, loss of trust in the health care system, and disabilities due to worsening foot conditions. Various social determinants of health also impact HSUs, such as low socioeconomic status, lack of housing, decreased social support, unhealthy behaviors, and inequitable access to health services. By collaborating with HSUs, community and health services need to develop innovative outreach programs that provide better community resources as the first step toward equitable access to health care.


Umbrella and Systematic Review Methodology to Support the 2018 Physical Activity Guidelines Advisory Committee.
In 2016, the 2018 Physical Activity Guidelines Advisory Committee, a group of experts in exercise science and health, began an extensive review of the literature to inform the second edition of the Physical Activity Guidelines for Americans. The purpose of this paper is to describe the evidence-based methodology used to review, evaluate, and synthesize published, peer-reviewed physical activity research. The protocol-driven methodology was designed to maximize transparency, minimize bias, and ensure relevant, timely, and high-quality systematic reviews. Training protocols, quality control procedures, search strategies, assessment instruments, abstraction guides and forms, and reporting templates were developed. A systematic approach was used to select the evidence for the 2018 Physical Activity Guidelines Advisory Committee Scientific Report that included umbrella reviews and systematic reviews. Within 16 months, 38 searches were conducted; and 20,838 titles, 4913 abstracts, and 2139 full texts were triaged. Of those, 1130 articles were abstracted to answer 38 research questions. To inform population-based physical activity guidelines, this systematic process facilitated a vast review of the literature on physical activity and health in a short period of time. This flexible, yet rigorous and transparent process included a clear and detailed methodology with a focus on training and quality control.


Primary adenocarcinoma of the fallopian tube: a case report.
We report a case of a 75-year-old postmenopausal woman with primary fallopian tube carcinoma confined to the left fallopian tube in Stage IA-2, who is alive without evidence of disease three years after total abdominal hysterectomy, bilateral salpingo-oophorectomy, total omentectomy, pelvic and paraaortic lymph node dissection were performed. Histopathological examination revealed a poorly differentiated (grade 3) papillary serous adenocarcinoma of the left fallopian tube. Adjuvant irradiation was given. Primary fallopian cancer should be suspected by clinicians even if the presenting symptoms are atypical and the primary treatment remains surgical resection followed by adjuvant chemotherapy or radiation. Appropriate therapy for each stage of the disease should be defined and new studies are needed to better depict the clinical course and prognostic factors.


Combining cognitive bias modification training with motivational support in alcohol dependent outpatients: study protocol for a randomised controlled trial.
Addiction research has hypothesised that automatic and reflective cognitive processes play an important role in the onset and maintenance of alcohol (ab)use, wherein automatic reactions to drug-related cues steer the drug user towards consuming before reflective processes can get over and steer towards a different behavioural response. These automatic processes include the tendency to attend and approach alcohol cues. These biases may be trained away from alcohol via computerised cognitive bias modification (CBM). The present protocol describes the design of a double-blind randomised controlled trial (RCT) testing the effectiveness of attentional bias and approach bias re-training with a 2×2 factorial design, alongside a brief motivational support (MS) program. Participants (n = 120) are adult alcohol dependent outpatients, recruited from a public health service for addiction in Italy, who have been abstinent for at least two months, and with a main diagnosis of alcohol dependence disorder. Participants are randomly assigned to one of four experimental conditions and complete 11 sessions of training after a baseline assessment. The MS takes place before each training session. Post-intervention and three-month follow-up assessments examine the change in clinical outcome variables and attentional and approach biases (measured with the Visual Probe Task and the Approach-Avoidance Task, respectively). Alcohol approach-avoidance implicit memory associations (measured with the Brief Implicit Association Test) are also evaluated at pre- and post-intervention to explore generalisation effects. Primary outcome measure is relapse rate at follow-up. Secondary outcome measures include change in cognitive biases, in alcohol-related implicit memory associations, and in the clinical variables assessed. An exploratory analysis is also planned to detect interaction effects between the CBM modules and possible moderators (interference control capacity, gender, age, number of previous detoxifications) and mediators (change in cognitive bias) of the primary outcome measure. This RCT is the first to test the effectiveness of a combined CBM intervention alongside motivational support in alcohol-dependent outpatients. The results of this study can be extremely valuable for future research in the optimisation of CBM treatment for alcohol addiction. Current Controlled Trials ISRCTN01005959 (registration date: 24 October 2013).


A perceptually tuned watermarking scheme for color images.
Transparency and robustness are two conflicting requirements demanded by digital image watermarking for copyright protection and many other purposes. A feasible way to simultaneously satisfy the two conflicting requirements is to embed high-strength watermark signals in the host signals that can accommodate the distortion due to watermark insertion as part of perceptual redundancy. The search of distortion-tolerable host signals for watermark insertion and the determination of watermark strength are hence crucial to the realization of a transparent yet robust watermark. This paper presents a color image watermarking scheme that hides watermark signals in most distortion-tolerable signals within three color channels of the host image without resulting in perceivable distortion. The distortion-tolerable host signals or the signals that possess high perceptual redundancy are sought in the wavelet domain for watermark insertion. A visual model based on the CIEDE2000 color difference equation is used to measure the perceptual redundancy inherent in each wavelet coefficient of the host image. By means of quantization index modulation, binary watermark signals are embedded in qualified wavelet coefficients. To reinforce the robustness, the watermark signals are repeated and permuted before embedding, and restored by the majority-vote decision making process in watermark extraction. Original images are not required in watermark extraction. Only a small amount of information including locations of qualified coefficients and the data associated with coefficient quantization is needed for watermark extraction. Experimental results show that the embedded watermark is transparent and quite robust in face of various attacks such as cropping, low-pass filtering, scaling, media filtering, white-noise addition as well as the JPEG and JPEG2000 coding at high compression ratios.


Antiproliferative and pro-apoptotic activity of novel phenolic derivatives of resveratrol.
Gloriosaols A-C, isolated from Yucca gloriosa (Agavaceae), are novel phenolic compounds structurally related to resveratrol. In the present study, we show that gloriosaols possess antiproliferative and pro-apoptotic activity on tumor cells of different histogenetic origin and that their cell growth inhibition potential is higher than that of resveratrol. Despite the close similarities in their structure, gloriosaols A-C exhibited different antiproliferative potency, as the EC(50) ascending order is: gloriosaol C, gloriosaol A, gloriosaol B. Further mechanisms of gloriosaol C cytotoxicity were elucidated in detail in U937 cells, the most sensitive of the cell lines tested. The effect of gloriosaol C on cell growth turned out to be strongly dependent upon the concentration. Gloriosaol C doses lower than the EC(50) value (8 mu-icroM) blocked the cell cycle in G(0)/G(1), with a concurrent decrease in the number of cells in the G(2)/M phases of the cell cycle. At higher doses, this arrest overlaps with the occurrence of apoptosis and necrosis. In the 10-25 microM range of doses, gloriosaol C caused cell death mainly by apoptosis, as measured by hypodiploidia induction, phosphatidyl serine externalization and disruption of mitochondrial transmembrane potential. A switch in the mode of death from apoptosis to necrosis occurred at doses of gloriosaol C higher than 30 microM. Gloriosaol C was found to induce production of reactive species dose-dependently, but also to counteract their elevation in stressed cells. Thus, the different fate of cells, that is cell cycle arrest or cell death, in response to different doses of gloriosaol C might be related to the extent of induced oxidative stress.


Molecular evidence for the existence of two species of Marteilia in Europe.
Marteilia refringens is one of the most significant pathogens of bivalve molluscs. Previous sequencing of the small subunit ribosomal RNA gene of M. refringens isolates derived from the infected mussels (Mytilus edulis and Mytilus galloprovinciallis) and the oyster (Ostrea edulis) in Europe did not reveal genetic polymorphisms despite indications from epizootiological data that distinct types may exist. We investigated the existence of polymorphisms in the internal transcribed spacer region of the ribosomal RNA genes. The sequences of this region proved to be clearly dimorphic among Marteilia from five sampling sites. The distribution of the two genetic types, named "O" and "M", appeared to be linked to the host species, oysters and mussels, respectively. We therefore support the recognition of two species of Marteilia in Europe and propose that the "O" type corresponds to M. refringens and the "M" type to M. maurini.


Reactivation of hepatitis B two years after rituximab therapy in a renal transplant patient with recurrent focal segmental glomerulosclerosis: a note of caution.
We report on the reactivation of hepatitis B in a renal transplant patient who had been treated with rituximab for recurrent focal segmental glomerulosclerosis two and a half yr previously. He lost his anti-hepatitis B surface antigens and anti-hepatitis B core antigen antibodies and developed hepatitis B virus (HBV)-DNA positive hepatitis. Hepatitis C, which had been successfully treated by alpha interferon 10 yr before, remained quiescent. We suggest regular controls of HBV-DNA, anti-HBV antibodies and transaminases for prolonged periods in patients with status post-hepatitis B treated with rituximab. Prophylactic therapy with lamivudine and/or hepatitis B hyperimmune globulin may be considered in patients with a decrease in anti-HBV antibodies.


Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells.
Thrombospondin 1 (TSP1) inhibits angiogenesis and modulates endothelial cell adhesion, motility, and growth. The antiproliferative activity of TSP1 is mimicked by synthetic peptides derived from the type I repeats of TSP1 that antagonize fibroblast growth factor 2 and activate latent transforming growth factor beta. These TSP1 analogues induced programmed cell death in bovine aortic endothelial cells based on morphological changes, assessment of DNA fragmentation, and internucleosomal DNA cleavage. Intact TSP1 also induced DNA fragmentation. The endothelial cell response was specific because no DNA fragmentation was induced in MDA-MB-435S breast carcinoma cells, although TSP1 and the peptide conjugates inhibited the growth of both cell types. Apoptosis did not depend on activation of latent transforming growth factor beta because peptides lacking the activating sequence RFK were active. Apoptosis was not sensitive to inhibitors of ceramide generation but was inhibited by the phosphatase inhibitor vanadate. Induction of DNA fragmentation by the peptides was decreased when endothelial cell cultures reached confluence. Growth of the cells on a fibronectin substrate also suppressed induction of apoptosis by TSP1 or the peptides. Differential sensitivities to kinase inhibitors suggest that apoptosis and inhibition of proliferation are mediated by distinct signal transduction pathways. These results demonstrate that induction of apoptosis by the TSP1 analogues is not a general cytotoxic effect and is conditional on a lack of strong survival-promoting signals, such as those provided by a fibronectin matrix. The antitumor activity of TSP1 may therefore result from an increased sensitivity to apoptosis in endothelial cells adjacent to a provisional matrix during formation of vascular beds in tumors expressing TSP1.


A rapid real-time PCR assay for determination of hepatitis C virus genotypes 1, 2 and 3a.
The genotypes of hepatitis C virus (HCV) in serum of patients have been described as independent predictors of success of antiviral therapy. Therefore, different antiviral regimens have been proposed depending on the infecting HCV genotype. HCV strain is usually determined by polymerase chain reaction (PCR) amplification of genome followed by sequencing or by line-probe assays. We report a new one step real-time PCR assay for genotyping of HCV strains that are prevalent in patients in Norway. HCV types 1, 2 and 3a were genotyped unambiguously in 37 patient serum samples with 100% correlation to genotyping by nucleotide sequence analysis and line-probe assays. Genotyping could also be confirmed against an HCV genotype panel from the National Institute for Biological Standards and Control. This assay does not require manipulation of amplified PCR products, it involves very little hands on and analysis time. This assay can be used for rapid genotyping of HCV-RNA in infected patients to aid physicians decide suitability of patients for treatment and subsequent length of treatment.


Histoplasmomas of uncommon size.
Histoplasma capsulatum infection demonstrates a broad spectrum of acute and chronic clinical manifestations. Unlike the acute reaction to proliferating organisms, the chronic complications are often the result of excessive or prolonged host response with a paucity of organisms. Lung nodules (histoplasmomas) may be noted decades after initial infection and present a challenging clinical problem, as they can be difficult to distinguish from malignancy or tuberculomas. Typically, histoplasmomas are small (<1 cm), asymptomatic, and may be stable in size or slowly enlarge over time. Here we report three patients with unusually large, or giant, histoplasmomas (>3 cm) and describe their extreme phenotype. Importantly, two of the patients presented with subacute symptomatic disease, a presentation that is very atypical for histoplasmoma. The term "buckshot" calcification has been used to describe dozens of small (2-4 mm) calcified nodules, so it may be appropriate to label masses that exceed 3 cm as "cannonball" histoplasmoma.


The serotonin transporter promoter polymorphism moderates the continuity of behavioral inhibition in early childhood.
Persistently elevated behavioral inhibition (BI) in children is a marker of vulnerability to psychopathology. However, little research has considered the joint influences of caregiver and child factors that may moderate the continuity of BI in early childhood, particularly genetic variants that may serve as markers of biological plasticity, such as the serotonin transporter linked polymorphic region (5-HTTLPR). We explored this issue in 371 preschoolers and their caregivers, examining whether parent characteristics (i.e., overinvolvement or anxiety disorder) and child 5-HTTLPR influenced the continuity of BI between ages 3 and 5. Measures were observational ratings of child BI, observational and questionnaire measures of parenting, and parent interviews for anxiety disorder history, and children were genotyped for the 5-HTTLPR. Parent factors did not moderate the association between age 3 and age 5 BI; however, child BI at age 3 interacted with children's 5-HTTLPR variants to predict age 5 BI, such that children with at least one copy of the short allele exhibited less continuity of BI over time relative to children without this putative plasticity variant. Findings are consistent with previous work indicating the 5-HTTLPR short variant increases plasticity to contextual influences, thereby serving to decrease the continuity of BI in early childhood.


Thalassaemia is paradoxically associated with a reduced risk of in-hospital complications and mortality in COVID-19: Data from an international registry.
Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.


Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics.
Reports of neuroleptic malignant syndrome (NMS) induced by second-generation antipsychotic drugs highlight a propensity for atypical clinical presentations. To systematically compare the clinical profile of NMS induced by first- (1G-NMS) and second-generation antipsychotic drugs (2G-NMS). The Australian Adverse Drug Reaction Advisory Committee (ADRAC) database was searched to identify individuals with NMS reported between April 1994 and September 2010. The clinical characteristics of 208 people with NMS induced by monotherapy with first- or second-generation antipsychotic drugs, as well as presenting features of NMS, were compared. The individuals with 2G-NMS were younger and more likely to have a psychotic disorder diagnosis. The features of NMS in the two groups were very similar, except that people with 2G-NMS were less likely to present with rigidity or extrapyramidal signs compared with those with 1G-NMS. This difference was due to the lower rates of rigidity in those with clozapine-induced NMS. Mortality was considerably lower for those with 2G-NMS (3.0%) compared with 1G-NMS (16.3%), and the former were more likely to have received supportive treatment. The clinical profile of 2G-NMS is largely similar to 1G-NMS, with clozapine-induced NMS being differentiated by the relative lack of rigidity as a feature. Mortality is lower for 2G-NMS.


Ramatroban as a Novel Immunotherapy for COVID-19.
SARS-CoV-2 virus suppresses host innate and adaptive immune responses, thereby allowing the virus to proliferate, and cause multiorgan failure, especially in the elderly. Respiratory viruses stimulate cyclooxygenase-2 (COX-2) to generate prostanoids including Prostaglandin D2 (PGD2) and thromboxane A2. Furthermore, PGD2 concentrations in the airways increase with aging. PGD2 action mediated via DP2 receptors suppresses both innate and adaptive immune responses, by inhibiting interferon-λ and stimulation of myeloid monocyte-derived suppressor cells respectively. PGD2 and thromboxane A2 actions via the TP receptors activate platelets leading to a prothrombotic state. Ramatroban, a small-molecule antagonist of DP2 and TP receptors, reverses viremia-associated proinflammatory, immunosuppressive5 and prothrombotic processes which are similar to those induced by SARS-Cov-2. Ramatroban, used for the treatment of allergic rhinitis in Japan for the past 20 years has an excellent safety profile. Therefore, Ramatroban merits investigation as a novel immunotherapy for the treatment of COVID-19 disease.


Production of interferon-alpha induced by dsRNA in human peripheral blood mononuclear cell cultures: role of priming by dsRNA-induced interferons-gamma and -beta.
Poly(I):poly(C) (rIn.rCn), mismatched poly(I):poly(C) [rIn.r(C12U)n], and poly(I):poly(C) poly-lysine carboxymethylcellulose [poly(ICLC)] were studied for their capacity to induce interferon-alpha (IFN-alpha) in human peripheral blood mononuclear cell (MNC) cultures and in their subpopulations. In MNC, poly(I):poly(C) and mismatched poly(I):poly(C) induced IFN-alpha in a dose-dependent manner, whereas poly(ICLC) was unable to do so in concentrations that ranged from 1 to 160 micrograms/ml. In contrast, all three molecules were incapable of inducing IFN-alpha when added into either purified monocyte or lymphocyte cultures. The capacity of poly(I):poly(C) to induce IFN-alpha was reestablished only in monocyte cultures when, prior to the stimulation, the cells were exposed for at least 2 h to supernatants from poly(I):poly(C)-stimulated lymphocyte cultures. IFN-beta and IFN-gamma were found in those supernatants and the ability of each dsRNA to induce IFN-alpha correlated with its ability to induce IFN-gamma. Further studies using recombinant human IFN-gamma and IFN-beta and their specific antibodies corroborated an important role of these molecules for the induction of IFN-alpha with dsRNA. Because each IFN type is produced by different cells, our studies show that complex cell-to-cell interactions via other IFNs have to take place in peripheral blood mononuclear cells (MNC) cultures before IFN-alpha can be induced by dsRNA.


Spectrum of injuries from glacial sports.
Glacial sports continue to be a popular form of wilderness activity, but no published studies have commented on this type of sport or focused on the injury patterns of glacial accidents. The objectives of this study were to investigate the types and frequency of injuries associated with a glacial-crevasse or ice-field fall. The trauma registry data and radiology record system of a pediatric and adult level 1 trauma center were evaluated from January 1997 through August 2003. All admissions with injuries caused by a glacial-crevasse or ice-field fall were reviewed. During the 5 1/2-year period we identified 12 patients, of whom 9 (75%) were male. The average age was 30.2 years with an age range of 9 to 57 years. Six patients fell into glacial crevasses, and the other 6 slid down an ice field of a glacier. Leading diagnoses were head injury (44.6%), thorax injury (20.1%), and lower extremity injury (18.4%). Serious injuries were observed in 66.6% of the patients with a Glasgow Coma Scale of 3 to 8. A wide spectrum of injuries is associated with glacial accidents. They range from common extremity injuries with fracture or joint instability and peripheral frostbite to potentially life-threatening nonorthopedic trauma, which requires intensive clinical and radiological work-up. Injury prevention strategies should focus on wearing helmets to reduce head injuries and adequate clothing to forestall or prevent hypothermia, for these are the most severe and life-threatening injuries.


Effect of particle size on the biodistribution of lipid nanocapsules: comparison between nuclear and fluorescence imaging and counting.
In vivo biodistribution of nanoparticles depends on several physicochemical parameters such as size. After intravenous injection of 25, 50 and 100 nm lipid nanocapsules (LNC) in nude mice bearing HEK293(β3) tumour xenografts, biodistribution was evaluated by γ-scintigraphy and by γ-counting. The small LNC 25 nm disappeared faster than the larger LNC 50 and 100 nm from the blood circulation due to faster elimination and wider tissue distribution. At 24h, biodistribution profiles of all these LNC were similar. Low LNC quantities were found in this weak EPR (enhanced permeability and retention) tumour regardless the particle size. Co-injected 50 nm fluorescent DiD-LNC and (99m)Tc-LNC allowed direct comparison of biodistribution as evaluated by the two methods. Optical imaging underestimated LNC quantity especially in dark-colored organs that were observed to capture extensive quantities of the particles by γ-counting (i.e. liver, spleen, and kidney).


Bacterioplankton: a sink for carbon in a coastal marine plankton community.
Recent determinations of high production rates (up to 30 percent of primary production in surface waters) implicate free-living marine bacterioplankton as a link in a "microbial loop" that supplements phytoplankton as food for herbivores. An enclosed water column of 300 cubic meters was used to test the microbial loop hypothesis by following the fate of carbon-14-labeled bacterioplankton for over 50 days. Only 2 percent of the label initially fixed from carbon-14-labeled glucose by bacteria was present in larger organisms after 13 days, at which time about 20 percent of the total label added remained in the particulate fraction. Most of the label appeared to pass directly from particles smaller than 1 micrometer (heterotrophic bacterioplankton and some bacteriovores) to respired labeled carbon dioxide or to regenerated dissolved organic carbon-14. Secondary (and, by implication, primary) production by organisms smaller than 1 micrometer may not be an important food source in marine food chains. Bacterioplankton can be a sink for carbon in planktonic food webs and may serve principally as agents of nutrient regeneration rather than as food.


Tolerance to bromodeoxyuridine in a thymidine-requiring strain of Bacillus subtilis.
Mutations which allow tolerance to 5-bromo-2'-deoxyuridine (BUdR) in a thymidine (TdR)-requiring strain of Bacillus subtilis have been examined. Differences in sensitivity to BUdR existed between isogenic strains harbouring the mutations. Those mutations originally isolated as BUdR-tolerant also bestowed tolerance to 5-bromouracil and vice versa. The strain exhibiting the greatest tolerance to BUdR maintained a normal rate of replication in the presence of BUdR whereas the parent strain did not, but the tolerant strain incorporated less analogue into DNA than the parent strain. The basis of the tolerance mutation appeared to lie at the point of uptake of the analogue into the cell as the tolerant mutant preferentially took up TdR over BUdR into whole cells. DNA polymerase activity measured in vitro did not distinguish between TdR and BUdR in either the parent or the mutant strain and although TdR kinase activity showed a preference for TdR over BUdR as a substrate, the extent of discrimination was similar in both strains.


DDX5 (p68) orchestrates β-catenin, RelA and SP1 mediated MGMT gene expression in human colon cancer cells: Implication in TMZ chemoresistance.
DDX5 (p68) upregulation has been linked with various cancers of different origins, especially Colon Adenocarcinomas. Similarly, across cancers, MGMT has been identified as the major contributor of chemoresistance against DNA alkylating agents like Temozolomide (TMZ). TMZ is an emerging potent chemotherapeutic agent across cancers under the arena of drug repurposing. Recent studies have established that patients with open MGMT promoters are prone to be innately resistant or acquire resistance against TMZ compared to its closed conformation. However, not much is known about the transcriptional regulation of MGMT gene in the context of colon cancer. This necessitates studying MGMT gene regulation which directly impacts the cellular potential to develop chemoresistance against alkylating agents. Our study aims to uncover an unidentified mechanism of DDX5-mediated MGMT gene regulation. Experimentally, we found that both mRNA and protein expression levels of MGMT were elevated in response to p68 overexpression in multiple human colon cancer cell lines and vice-versa. Since p68 cannot directly interact with the MGMT promoter, transcription factors viz., β-catenin, RelA (p65) and SP1 were also studied as reported contributors. Through co-immunoprecipitation and GST-pull-down studies, p68 was established as an interacting partner of SP1 in addition to β-catenin and NF-κB (p50-p65). Mechanistically, luciferase reporter and chromatin-immunoprecipitation assays demonstrated that p68 interacts with the MGMT promoter via TCF4-LEF, RelA and SP1 sites to enhance its transcription. To the best of our knowledge, this is the first report of p68 as a transcriptional co-activator of MGMT promoter and our study identifies p68 as a novel and master regulator of MGMT gene expression.


Tissue factor expression by monocytes: regulation and pathophysiological roles.
The expression of tissue factor (TF) by monocytes/macrophages leads to thrombin generation and contributes to their physiological and pathophysiological roles in wound repair, disseminated intravascular coagulation linked to sepsis, postoperative thrombosis, unstable angina, atherosclerosis, chronic inflammation and cancer. Regulation of TF expression in monocytes is controlled by the transcription factors NF-kappaB and AP-1. In whole blood, the activation of the transcription factors is mediated through the phospholipase A2 pathway. Platelets play a crucial role in the expression of TF activity in monocytes, and granulocytes are mandatory in provoking the platelet effect in a P-selectin-dependent reaction. Although all induced or constitutive TF is expressed on the surface of monocytes, its catalytic activity is only about 10% compared to the activity of lysed cells. This phenomenon has been attributed to the increased availability of anionic phospholipid (phosphatidylserine) after cell lysis. At the surface of viable cells, the transmembrane phospholipid distribution and its regulation may be important for the expression of the catalytic activity of the complex of TF and activated factor VII. Phosphatidylserine pathophysiologically exposed at the outer surface of monocytes may, similar to that for platelet membranes, provide a strong stimulus for thrombin generation.


Increasing utilization of computed tomography in the pediatric emergency department, 2000-2006.
The objective of this study is to characterize changes in computed tomography (CT) utilization in the pediatric emergency department (ED) over a 6-year period. CT scans ordered on pediatric (ages 0 to 17 years) ED patients from July 2000 to July 2006 were analyzed in five groups: head, cervical spine, chest, abdomen, and miscellaneous. Pediatric ED patient volume and triage acuity scores were determined. There were 6,073 CT scans performed on 4,138 pediatric patients in the ED during the study period. During this same period, 78,932 pediatric patients were evaluated in the ED. From 2000 to 2006, pediatric ED patient volume increased by 2%, while triage acuity remained stable. During this same period, head CT increased by 23%, cervical spine CT by 366%, chest CT by 435%, abdominal CT by 49%, and miscellaneous CT by 96%. Increases in CT utilization were most pronounced in adolescents ages 13 to 17 years. Increases in CT utilization in this age group met or exceeded increases seen in the adult population. In children less than 13 years of age, increases were substantially smaller. Pediatric ED CT utilization particularly in the adolescent population has increased at a rate far exceeding the growth in ED patient volume, mimicking the adult trend. This increase has occurred despite considerable discussion in the medical literature about the radiation risks of CT in the pediatric population and may reflect increased availability of CT, improvements in CT diagnostic capabilities, and increased desire on the part of physicians and patients for diagnostic certainty. Whether this increased utilization results in improved patient outcomes is uncertain and deserves further study.


Dissemination and Adoption of Comparative Effectiveness Research Findings When Findings Challenge Current Practices.
Insufficient evidence regarding the effectiveness of medical treatments has been identified as a key source of inefficiency in the U.S. healthcare system. Variation in the use of diagnostic tests and treatments for patients with similar symptoms or conditions has been attributed to clinical uncertainty, since the published scientific evidence base does not provide adequate information to determine which treatments are most effective for patients with specific clinical needs. The federal government has made a dramatic investment in comparative effectiveness research (CER), with the expectation that CER will influence clinical practice and improve the efficiency of healthcare delivery. To do this, CER must provide information that supports fundamental changes in healthcare delivery and informs the choice of diagnostic and treatment strategies. This article summarizes findings from a qualitative analysis of the factors that impede the translation of CER into clinical practice and those that facilitate it. A case-study methodology is used to explore the extent to which these factors led to changes in clinical practice following five recent key CER studies. The enabling factors and barriers to translation for each study are discussed, the root causes for the failure of translation common to the studies are synthesized, and policy options that may optimize the impact of future CER-particularly CER funded through the American Recovery and Reinvestment Act of 2009-are proposed.


Patient Satisfaction With a Comprehensive Medication Review Provided by a Community Pharmacist.
Background: The comprehensive medication review (CMR) is one of the most commonly delivered medication therapy management services, and it is a required service to be provided to Medicare Part D beneficiaries. Despite the large body of evidence available on medication therapy management benefits, and the growing value placed on it by payers, there has been little research assessing patient satisfaction with these services. Objectives: The primary objective of this study was to determine patient satisfaction with a face-to-face or telephonic CMR provided by a chain community pharmacist. The study secondarily assessed patients' perceived value of the service while also collecting demographic information. Methods: A Likert-type satisfaction survey was distributed to patients on completion of a face-to-face or telephonic CMR in either Outcomes or Mirixa by members of a clinical team (7 clinical pharmacists and 4 residents) within a chain community pharmacy. Participants were asked to return the survey in a self-addressed stamped envelope within 1 week of the CMR. Results: The response rate for the survey was 33% (31 of 95 surveys returned). The study found that approximately 70% (21 of 31) strongly agreed with being overall satisfied with the CMR. Conclusion: This research study provided insight to patients' perceptions of a CMR provided by a community pharmacist. Patient views of the CMR were positive, with patients finding CMR delivery in a community pharmacy valuable. Further investigation of specific interventions and approaches during a medication review could help identify ways to increase patient satisfaction.


Effects of age and aerobic fitness on myocardial lipid content.
Aging and sedentary lifestyles lead to cardiac atrophy, ventricular stiffening, and impaired diastolic function. Both conditions are marked by increased adiposity, which can lead to ectopic fat deposition in nonadipocyte tissues including the myocardium. The effect of excess intramyocardial fat on cardiac function in nonobese individuals is unknown. Cardiac lipid content was measured by magnetic resonance spectroscopy in 153 healthy nonobese subjects with varying fitness levels quantified by peak oxygen uptake during treadmill exercise. Cardiac function (echo) and left ventricular (LV) filling pressures (right heart catheterization) were measured under varying preloads. LV stiffness was calculated from a curve fit of the diastolic portion of the pressure-volume curve. The strongest clinical predictors of lipid content were body mass index (β=+0.03; 95% confidence interval, 0.001-0.06) and peak oxygen uptake (β=-0.02; 95% confidence interval, -0.03 to -0.009; R(2)=0.14; P<0.001). Subjects in the highest quintile had smaller LV end-diastolic volumes (68±13 versus 58±12 mL/m(2); P<0.01) and decreased peak early mitral annular and increased peak late mitral inflow velocities. There were no differences in LV stiffness, but a leftward shift in the pressure-volume curve suggested a less distensible ventricle with increasing myocardial lipid levels. After adjusting for age, fitness, and body mass index, echocardiographic and morphometric differences among groups were attenuated and no longer significant. Body mass index and fitness levels are the strongest predictors of myocardial lipid content in nonobese humans. Cardiac lipid content is associated with decreased ventricular distensibility, and it may provide a causal mechanism linking changes in LV function related to age and fitness.


Antigen presentation dynamics shape the antibody response to variants like SARS-CoV-2 Omicron after multiple vaccinations with the original strain.
The Omicron variant of SARS-CoV-2 is not effectively neutralized by most antibodies elicited by two doses of mRNA vaccines, but a third dose increases anti-Omicron neutralizing antibodies. We reveal mechanisms underlying this observation by combining computational modeling with data from vaccinated humans. After the first dose, limited antigen availability in germinal centers (GCs) results in a response dominated by B cells that target immunodominant epitopes that are mutated in an Omicron-like variant. After the second dose, these memory cells expand and differentiate into plasma cells that secrete antibodies that are thus ineffective for such variants. However, these pre-existing antigen-specific antibodies transport antigen efficiently to secondary GCs. They also partially mask immunodominant epitopes. Enhanced antigen availability and epitope masking in secondary GCs together result in generation of memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies.


Is There a Link between COVID-19 and Periodontal Disease? A Narrative Review.
The coronavirus disease 2019 (COVID-19) pandemic greatly affected human well-being, social behavior, global economy, and healthcare systems. Everyday clinical practice in dentistry has been adjusted to the increased hazards of aerosol production by routine dental procedures. The objective of this study was to assess the existing literature to determine possible mechanisms of a relationship between COVID-19 and periodontitis, as well as describe findings from relevant epidemiological studies.Scarce data exist in the literature that directly addresses the relationship between the two diseases. However, several data describe the role of the oral cavity and periodontal tissues as portals of entry of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and the contribution of cytokines known to be produced in periodontal disease to severe forms of COVID-19. It is also suggested from the current literature that periodontal disease, shown to be associated with systemic diseases such as diabetes mellitus, cardiovascular and respiratory diseases, shares common risk factors with-especially-severe forms of COVID-19.Further clinical studies are required to establish the relationship between these diseases. Oral hygiene performance and intact periodontal tissues can assist in mitigating the pandemic, and it is suggested that dental practitioners can contribute to identifying at-risk patients.


Prevention of Oxidative Stress by α-Ketoglutarate via Activation of CAR Signaling and Modulation of the Expression of Key Antioxidant-Associated Targets in Vivo and in Vitro.
α-Ketoglutarate (AKG) can act as an antioxidant both in vitro and in vivo. However, the mechanisms of the protective effects of AKG are still not well understood. We evaluated the effects of AKG supplementation on the regulation of the constitutive-androstane-receptor (CAR) pathway in porcine intestinal cells and piglets exposed to H2O2. Our data showed that AKG treatment significantly increased not only the intra- and extracellular levels of AKG (26.9 ± 1.31 μmol/g protein, 1064.4 ± 39.80 μmol/L medium) but also those of Asp (29.3 ± 0.21 μmol/g, 4.20 ± 0.11 μmol/L), Gln (24.82 ± 1.50 μmol/g, 1087.80 ± 16.10 μmol/L), and Glu (91.90 ± 3.6 μmol/g, 19.76 ± 1.00 μmol/L). There was approximately a 4-fold increase in α-ketoglutarate dehydrogenase mRNA levels in enterocytes and a simultaneous reduction in ROS levels ( P < 0.05). Moreover, AKG treatment increased the activities of the antioxidant enzymes and the efficiency of cellular respiration ( P < 0.05). AKG also regulated the mRNA levels of the target genes involved in antioxidant responses and xenobiotic detoxification in enterocytes. Increases in the protein levels of SOD1, SOD2, CAR, RXRα, and UCP2 and marked reductions in the expression levels of Nrf2 and Keap1 proteins ( P < 0.05) were observed after AKG administration in the H2O2-induced piglets. Our results indicated that AKG may protect against oxidative stress by activating CAR signaling and modulating the expression of key antioxidant-related targets, which improves cellular respiration and antioxidant capacity. The in vivo and in vitro effects of AKG suggest that it may prove to be useful in the reduction of oxidative stress in animal and human trials and subsequent prevention of gastrointestinal pathologies.


Rheumatic heart disease: current status of diagnosis and therapy.
Rheumatic heart disease (RHD) is the only preventable cardiovascular disease which causes significant morbidity and mortality particularly in low- and middle-income countries. Early clinical diagnosis is key, the updated Jones criteria increases the likelihood of diagnosis in endemic settings, including the echo diagnosis of sub-clinical carditis, polyarthralgia and monoarthritis as well as amended thresholds of minor criteria. The mainstay of rheumatic heart valve disease (RHVD) is a thorough clinical and echocardiographic investigation while severe disease is managed with medical, interventional and surgical treatment. In this report we detail some of the more recent epidemiological findings and focus on the diagnostic and interventional elements of the specific valve lesions. Finally, we discuss some of the recent efforts to improve medical and surgical management for this disease. As we are already more than a year from the historic 2018 World Heart Organization Resolution against Rheumatic Fever and Rheumatic Heart Disease, we advocate strongly for renewed efforts to prioritize this disease across the endemic regions of the world.


A nanophotonic interferometer.
The transmission of light through sub-wavelength apertures (zero-mode waveguides, ZMW) in metal films is well-explored. It introduces both an amplitude modulation as well as a phase shift to the oscillating electromagnetic field. We propose a nanophotonic interferometer by bringing two ZMW (∼100 nm diameter) in proximity and monitoring the distribution of transmitted light in the back-focal plane of collecting microscope objective (1.3 N.A.). We demonstrate that both an asymmetry induced by the binding of a quantum dot in one of the two ZMW, as well as an asymmetry in ZMW diameter yield qualitatively similar transmission patterns. We find that the complex pattern can be quantified through a scalar measure of asymmetry along the symmetry axis of the aperture pair. In a combined experimental and computational exploration of detectors with differing ZMW diameters, we find that the scalar asymmetry is a monotonous function of the diameter difference of the two apertures, and that the scalar asymmetry measure is higher if the sample is slightly displaced from the focal plane of the collecting microscope objective. An optimization of the detector geometry determined that the maximum response is achieved at an aperture separation that is comparable to the wavelength on the exit side of the sensor. For small separations of apertures, on the order of a quarter of the wavelength and less, the signal is strongly polarization dependent, while for larger separations, on the order of the wavelength or larger, the signal becomes essentially polarization-independent.


Molecular techniques in hematopathology.
Molecular techniques have already earned a place in the management of hematologic disorders. The requests of clinical hematologists to Pathology include, besides the diagnosis, any additional information useful for prognosis and therapeutic choices, as well as expertise and technologies to follow-up patients. To fulfill these commitments, pathologists have been resorting to classical morphology, cytochemistry, immunocytochemistry, and have only recently come to include molecular genetic techniques. Most of the molecular methods of practical utility are based on the analysis of DNA. The DNA methodologies of routine applicability mainly include Southern blotting and polymerase chain reaction (PCR). Southern blotting recognizes major DNA rearrangements, whereas PCR-based methods allow to recognize both gross chromosomal modifications and fine gene alterations, including point mutations. PCR techniques may also be used for partially degraded DNA from formalin-fixed paraffin-embedded tissues. Here we will draw a brief overview of the role of molecular genetic techniques in the pathology practice for the diagnosis, prognosis and follow-up of neoplastic diseases, using examples from our experience.


Contemporary activities of Toxicologic Pathology Societies.
Educational activities and training opportunities in toxicologic pathology are major goals of 9 formally established Toxicologic Pathology Societies and the International Academy of Toxicologic Pathology. Some Toxicologic Pathology Societies have examination-based certification programs while others accept certification or registration by veterinary pathology organizations including the American College of Veterinary Pathologists, the European College of Veterinary Pathologists. We summarize here the membership numbers and current activities of formally established Toxicologic Pathology Socities.


Printed paper sensors for serum lactate dehydrogenase using pullulan-based inks to immobilize reagents.
In this study, a paper-based point-of-care (POC) colorimetric biosensor was developed for the detection of lactate dehydrogenase in serum using a nonporous, oxygen impermeable reversibly gelling polysaccharide material based on pullulan. The pullulan could be printed onto paper surfaces along with all required assay reagents, providing a means for high-stability immobilization of all reagents on paper. Serum containing lactate dehydrogenase (LDH) was directly spotted on to the pullulan-coated bioactive paper and provided quantitative colorimetric data that was comparable to that obtained with a conventional plate-reader method. The paper strip was found to be highly stable and could be stored at 4 °C for at least 10 weeks with no loss in performance, as compared to a complete loss in performance within 1 day when the reagents were printed without the stabilizing polysaccharide. The ease of fabrication coupled with the high stability of the printed reagents provides a facile platform for easily manufactured POC sensors.


Imaging Josephson vortices on the surface superconductor Si(111)-(√7×√3)-In using a scanning tunneling microscope.
We have studied the superconducting Si(111)-(√7×√3)-In surface using a ³He-based low-temperature scanning tunneling microscope. Zero-bias conductance images taken over a large surface area reveal that vortices are trapped at atomic steps after magnetic fields are applied. The crossover behavior from Pearl to Josephson vortices is clearly identified from their elongated shapes along the steps and significant recovery of superconductivity within the cores. Our numerical calculations combined with experiments clarify that these characteristic features are determined by the relative strength of the interterrace Josephson coupling at the atomic step.


[Antigenic makeup of the protective fractions of S. typhimurium].
The authors present the results of chemical and immunochemical study of 4 protective fractions (Grasset's antigens, hydroxylamine vaccines, surface antigens, and Boivin's antigens) isolated from the virulent S. typhimurium strain, and of suppressor revertant obtained from streptomycin-dependent mutant of the initial strain. Despite some differences in their chemical and antigenic composition, Grasset's antigens, surface antigens fraction, and hydroxylamine vaccine contained the main cell protective substances and could be used (after further study) as vaccines for enteral immunization. On the basis of the results of chemical analysis and the study of Boivin's antigens antigenic structure it is supposed that O-antigen was changed in the revertant strain.


Reduced motility related protein-1 (MRP-1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer.
Motility related protein-1 (MRP-1) is a transmembrane glycoprotein that is identical to the CD9 antigen. In previous studies, we showed that various types of cultured tumor cells transfected with MRP-1/CD9 cDNA have low motility and diminished metastatic potential to the lung. More recently we used immunohistochemical procedures, immunoblotting, and reverse transcription-PCR to demonstrate that the level of MRP-1/CD9 expression was inversely related to the clinical stage of a given carcinoma of the breast. In addition, we found that the primary tumors of almost 50% of the patients had higher MRP-1/CD9 levels than their respective metastatic lymph nodes. In consideration of these findings, we have now applied reverse transcription-PCR to determine MRP-1/CD9 gene expression in lung cancer. We analyzed tumor tissues of 109 patients: 49 tumors were stage I; 15 were stage II; and 45 were stage III. We found that 67 patients had MRP-1/CD9-positive tumors, and that gene expression was reduced in the tumors of the remaining 42 individuals. The overall rate of survival was strikingly higher among patients with positive tumors than in those whose tumors had reduced gene expression (62.3 versus 34.9%; P < 0.001). This also pertained to patients with adenocarcinomas of the lung (55.4 versus 26.0%; P < 0.001). Multivariate analysis with the Cox regression model indicated that MRP-1/CD9 positivity correlated better with overall survival rate than did other variables, except lymph node status. Our data suggest that low MRP-1/CD9 expression by tumors of the lung may be associated with poor prognosis. It is conceivable that testing for MRP-1/CD9 may identify node-negative lung cancer patients and patients with adenocarcinomas who are at high risk for early disease recurrence.


Pre-eclampsia: fitting together the placental, immune and cardiovascular pieces.
The success of pregnancy is a result of countless ongoing interactions between the placenta and the maternal immune and cardiovascular systems. Pre-eclampsia is a serious pregnancy complication that arises from multiple potential aberrations in these systems. The pathophysiology of pre-eclampsia is established in the first trimester of pregnancy, when a range of deficiencies in placentation affect the key process of spiral artery remodelling. As pregnancy progresses to the third trimester, inadequate spiral artery remodelling along with multiple haemodynamic, placental and maternal factors converge to activate the maternal immune and cardiovascular systems, events which may in part result from increased shedding of placental debris. As we understand more about the pathophysiology of pre-eclampsia, it is becoming clear that the development of early- and late-onset pre-eclampsia, as well as intrauterine growth restriction (IUGR), does not necessarily arise from the same underlying pathology.


Prognostic importance of tumor angiogenesis in breast carcinoma with adjuvant chemotherapy.
Tumor angiogenesis is believed to be related to prognostic factors involved in tumor development and metastasis. Using immunohistochemical methods, we evaluated tumor angiogenesis in 42 early invasive breast cancer patients (T1-2, NO-1-2, M0). Four patients received tamoxifen, 25 patients received CAF or CA, and 15 patients received CMF as adjuvant therapy. The median follow-up was 47 (range 24-119) months. Ten patients (43.5%) in the node-positive group and 2 patients (10.5%) in the node-negative group relapsed (p = 0.019). The mean microvessel count (MVC) was 60.3 3.05 per 200x field (range: 16-95). MVCs of postmenopausal and premenopausal patients were 50.13 +/- 5.74 and 68.64 +/- 4.11, respectively, in the axillary lymph node (ALN)-negative patient group (p = 0.04). Staining was moderate to strong in 13 (68%) ALN-negative and in 17 (74%) ALN-positive patients (p > 0.05), and was also moderate to strong in 82% of premenopausal patients and in 50% of postmenopausal patients (p = 0.037). There was no significant relationship between angiogenesis and p53, nor was angiogenesis significantly associated with the patient ER status and tumor size. No significant correlations were found between OS/DFS and Factor VIII staining or p53 (log rank test, p > 0.05). Of all ALN-negative patients with increased angiogenesis, one patient of the CMF group relapsed, but no recurrence occurred in patients undergoing anthracycline-based chemotherapy (p > 0.05). On the other hand, of all ALN-positive patients with increased angiogenesis, 5/14 patients treated with anthracylcine and 2/2 CMF-treated patients relapsed (p = 0.175). Despite the statistical insignificance, anthracycline-based adjuvant chemotherapy appears to be more effective than CMF as regards relapse prevention particularly in early ALN-positive breast cancer patients with increased angiogenesis. Additional studies are necessary to demonstrate the clinical importance of angiogenesis.


Emergency Department Presentations by Children in Remote Australia: A Population-based Study.
Background. Aboriginal leaders invited us to examine the frequency and reasons for emergency department (ED) presentations by children in remote Western Australia, where Prenatal Alcohol Exposure (PAE) is common. Methods. ED presentations (2007-11 inclusive) were examined for all children born in the Fitzroy Valley in 2002-03. Results. ED data for 127/134 (94.7%) children (95% Aboriginal) showed 1058 presentations over 5-years. Most (81%) had at least 1 presentation (median 9.0, range 1-50). Common presentations included: screening/follow-up/social reasons (16.0%), injury (15.1%), diseases of the ear (14.9%), skin (13.8%), respiratory tract (13.4%), and infectious and parasitic diseases (9.8%). PAE and higher presentations rates were associated. Commonly associated socio-economic factors were household over-crowding, financial and food insecurity. Conclusion. Children in very remote Fitzroy Crossing communities have high rates of preventable ED presentations, especially those with PAE. Support for culturally appropriate preventative programs and improved access to primary health services need to be provided in remote Australia.


Neocortical very fast oscillations (ripples, 80-200 Hz) during seizures: intracellular correlates.
Multi-site field potential and intracellular recordings from various neocortical areas were used to study very fast oscillations or ripples (80-200 Hz) during electrographic seizures in cats under ketamine-xylazine anesthesia. The animals displayed spontaneously occurring and electrically induced seizures comprising spike-wave complexes (2-3 Hz) and fast runs (10-20 Hz). Neocortical ripples had much higher amplitudes during seizures than during the slow oscillation preceding the onset of seizures. A series of experimental data from the present study supports the hypothesis that ripples are implicated in seizure initiation. Ripples were particularly strong at the onset of seizures and halothane, which antagonizes the occurrence of ripples, also blocked seizures. The firing of electrophysiologically defined cellular types was phase-locked with ripples in simultaneously recorded field potentials. This indicates that ripples during paroxysmal events are associated with a coordination of firing in a majority of neocortical neurons. This was confirmed with dual intracellular recordings. Based on the amplitude that neocortical ripples reach during paroxysmal events, we propose a mechanism by which neocortical ripples during normal network activity could actively participate in the initiation of seizures on reaching a certain threshold amplitude. This mechanism involves a vicious feedback loop in which very fast oscillations in field potentials are a reflection of synchronous action potentials, and in turn these oscillations help generate and synchronize action potentials in adjacent neurons through electrical interactions.


Can Native Plants Mitigate Climate-related Forage Dearth for Honey Bees (Hymenoptera: Apidae)?
Extreme weather events, like high temperatures and droughts, are predicted to become common with climate change, and may negatively impact plant growth. How honey bees (Apis mellifera L. [Hymenoptera: Apidae]) will respond to this challenge is unclear, especially when collecting pollen, their primary source of protein, lipids, and micro-nutrients. We explored this response with a data set from multiple research projects that measured pollen collected by honey bees during 2015-2017 in which above-average temperatures and a drought occurred in 2017. We summarized the abundance and diversity of pollen collected from July to September in replicated apiaries kept at commercial soybean and corn farms in Iowa, in the Midwestern USA. The most commonly collected pollen was from clover (Trifolium spp. [Fabales: Fabaceae]), which dramatically declined in absolute and relative abundance in July 2017 during a period of high temperatures and drought. Due to an apparent lack of clover, honey bees switched to the more drought-tolerant native species (e.g., Chamaecrista fasciculata [Michx.] Greene [Fabales: Fabaceae], Dalea purpurea Vent. [Fabales: Fabaceae], Solidago spp. [Asterales: Asteraceae]), and several species of Asteraceae. This was especially noticeable in August 2017 when C. fasciculata dominated (87%) and clover disappeared from bee-collected pollen. We discuss the potential implications of climate-induced forage dearth on honey bee nutritional health. We also compare these results to a growing body of literature on the use of native, perennial flowering plants found in Midwestern prairies for the conservation of beneficial insects. We discuss the potential for drought resistant-native plants to potentially promote resilience to climate change for the non-native, managed honey bee colonies in the United States.


Prevention of childhood injuries. Part II: Recreational injuries.
This is the second of two articles on the prevention of childhood injuries. Here, interventions to reduce death and disability among children from recreational injuries are identified. The major categories of recreational injury are listed, the magnitude of the problem defined, the risk factors described, and selected interventions of the National Committee for Injury Prevention and Control summarized. Recommendations for practice are discussed.


[Changes in the retinotectal system of the tortoise Testudo graeca following enucleation].
Electrophysiological and electron microscopic studies have been made on degeneration in the optic nerve and midbrain tectum after enucleation of the tortoise T. graeca. It was found that intensive degeneration of terminals which follows "dark" type (1/2--1 month after enucleation) corresponds to degeneration of myelinated fibers. Mass degeneration of the "light" type is associated with degeneration of unmyelinated fibers, being observed 1 1/2--2 months after the enucleation. The main bulk of fibers and terminals degenerates at the period of 4--4 1/2 months. Changes in functional characteristics of the evoked potentials (EP) follow morphological ones and consist in an increase of the interval between the stimulus and the peak of EP components, as well as of the decrease of the amplitude of the EP. Within 4--4 1/2 months, both EP components disappear almost simultaneously.


Skeletal Muscle Dysfunction and Exercise Intolerance in Children Treated with Haematopoietic Stem Cell Transplant-A Pilot Feasibility Study.
Haematopoietic stem cell transplant (HSCT) is an intensive therapy for some pediatric hematological illnesses. Survivors are at risk for adverse effects including exercise intolerance. Peripheral tissue dysfunction may contribute to exercise intolerance; therefore, we examined the feasibility of a magnetic resonance spectroscopy (MRS) protocol to evaluate skeletal muscle metabolism in children post-HSCT. We measured demographic characteristics, aerobic exercise capacity (YMCA protocol), and skeletal muscle function in response to exercise (MRS; Siemens 3T MRI) in five children post-allogeneic HSCT and five age/body mass index-matched healthy controls (HCs). The mean age (± standard deviation) of the HSCT group and HC group were 11 ± 1.2 and 12.8 ± 2.4 years, respectively. Children post-HSCT had a lower peak aerobic exercise capacity compared to HCs (27.8 ± 3.4 vs. 40.3 ± 8.1 mL kg-1 min-1, respectively; p = 0.015). Exercise MRS testing protocols were successfully completed by all HSCT and HC participants; however, MRS-derived skeletal muscle metabolism variables were not different between the two groups. In conclusion, the use of exercise protocols in conjunction with MRS to assess peripheral skeletal muscle metabolism was achievable in children post-HSCT. In the future, larger studies should determine if skeletal muscle function is associated with exercise capacity in children post-HSCT.


Migration and children's psychosocial development in China: When and why migration matters.
Migration has affected a large number of children in many settings. Despite growing attention to these children, important gaps remain in our understanding of their psychosocial development, as well as the factors that mediate and moderate the impact of migration on children. The present study examines the influences of migration on children's psychosocial well-being in China using a new nationally representative survey. We compared different groups of children age 3-15, including migrant children, left-behind children, and rural and urban children in nonmigrant families. Results show that rural children left behind by both parents were significantly worse off in psychological and behavioral well-being than rural nonmigrant children. By contrast, rural children left behind by one parent and migrant children were no worse off. The disadvantage of left-behind children was mediated by their caregivers' emotional well-being and parenting practices. Frequent contact with migrant parents, but not receipt of remittances, helped ameliorate the vulnerability of left-behind children. These results add to our understanding of how migration affects child development in general.


Lung fibrosis and lung cancer incidence in beagle dogs that inhaled 238PuO2 or 239PuO2.
Determination of radiation protection guidelines for persons working with plutonium has been complicated by limited human data on the biological behavior and subsequent health effects from internally deposited plutonium. One solution has been the use of animal models to predict likely health effects in humans. To compare the relationships between plutonium inhalation and lung fibrosis and lung cancer, data from life-span studies of beagle dogs given a single exposure to either plutonium-238 dioxide (238PuO2) or plutonium-239 dioxide (239PuO2) were analyzed. Estimates of the cumulative hazard of lung fibrosis and lung cancer after exposure to either were generated. The hazard of lung fibrosis was not consistent with a linear no-threshold model, although the magnitude of the threshold differed by radionuclide. In dogs given 239PuO2, the best model of lung fibrosis incorporated a linear dose-response function; a linear-quadratic dose-response function fit the data better in dogs given 238PuO2. At any given cumulative dose, the lung fibrosis hazard was greater for dogs given 238PuO2. In dogs given 238PuO2, with or without covariates, a quadratic dose-response function for lung cancer hazard fit better than a linear no-threshold model. In dogs given 239PuO2, models of lung cancer with the dose-response function as the sole predictor variable were consistent with a linear no-threshold model; however, a quadratic dose-response function with a cell-killing term fit better. These findings have implications for radiation protection because, while lung cancer hazard was dependent on cumulative dose, regardless of isotope, the lung fibrosis hazard depended on both cumulative dose and isotope.


Long-term clinical and patient-reported outcomes in free flap reconstruction of the weight-bearing heel pad and non-weight-bearing Achilles tendon regions.
The non-weight-bearing (NWB) Achilles tendon and weight-bearing (WB) heel pad regions are technically challenging to reconstruct with distinct functional and aesthetic considerations that have not been previously considered in the literature. This study is the first to characterize the long-term clinical and patient-reported outcomes of these components to better inform patients about the postreconstruction period. A retrospective review of medical records and phone-based survey of adult patients who underwent free flap reconstruction of the heel/ankle with 6-month minimum clinical follow-up was performed. Forty-three patients, with 31 (72.1%) NWB and 12 (27.9%) WB defects, treated from January 1, 2000 to February 28, 2017 were included. Muscle flaps were more common than fasciocutaneous flaps (N = 36 [83.7%] vs. 7 [16.3%]). Flap survival rate was 95.3% and limb salvage rate was 93.0% at median follow-up of 12.0 months (interquartile range [IQR] 6.2, 25.5). Flap ulceration occurred more frequently in the WB region (41.7 vs. 6.5%, p = .0123). The survey response rate was 63.6%. The majority of patients complete daily tasks with no/little impairment (76.2%), walk half a mile or more (85.7%), returned to work (86.6%), and fit shoes "fair" or "well" (71.4%). Most patients were "very satisfied" with heel/ankle function (71.4%) and would "very likely" undergo the same procedure if needed (76.2%). Free flap reconstruction in both the NWB Achilles tendon and WB heel pad has excellent limb salvage and flap survival rates. Patients were satisfied with heel/ankle function, but additional counseling is recommended for variance in appearance and higher ulceration rates in WB defects.


Sequential expression of germ-layer specific molecules in the sea urchin embryo.
Described are two germ-layer specific molecules that appear coincident with the formation of two germ layer cell lineages in the sea urchin embryo. Meso1 is a molecule of 380 kDa that is first detected at the time of primary mesenchyme cell delamination from the wall of the blastula. Endo1 is a molecule of 320 kDa that appears on endoderm cells at the time of archenteron formation a few hours after Meso1 appears. Both antigens are identified by monoclonal antibodies. The appearance of these antigens is described by immunofluorescence microscopy, and quantitative data on their localization has been obtained by ultrastructural immunoelectron microscopy. The synthesis of the molecules has been followed by pulse-chase immunoprecipitation. Meso1 is first expressed in trans Golgi-like saccules, is concentrated in peripheral low electron-dense vesicles, and is found throughout the plasma membrane of the mesenchymal cells and their filopodial extensions. Newly translated Meso1 can first be immunoprecipitated upon differentiation of the mesoderm cell lineage, and pulse-chase studies suggest that the determinant is the result of a post-translational modification. [35S]Methionine pulses early in development followed by a chase to the mesenchyme blastula or prism stage show that at least a portion of the molecule is translated well in advance of the mesenchyme blastula stage. Endo1, in contrast, does not appear to be translated until the onset of gastrulation, just preceding the post-translational expression of the Endo1 determinant. Endo1 is localized to the apical and basolateral cell surfaces of the midgut and hindgut. No label is detected in foregut cells, demonstrating a heterogeneity of cell populations within the endoderm cell lineage corresponding to a difference in morphology. In addition, Endo1 is shown to be the result of new transcription by the embryonic genome. Even though the function of neither molecule is known, together they show the spatial and temporal precision of differentiation that accompanies the formation of germ layers.


Purification and characterization of chick interferon induced by viruses.
Chick interferon (IFN), produced in primary chick embryo (CE) cells stimulated by u.v.-irradiated Newcastle disease virus, was partially purified by two-step chromatography using both controlled pore glass and Blue Sepharose. The specific activity of the IFN increased about 500-fold by this method and the final recovery from starting material was more than 95%. The partially purified IFN was analysed by SDS-PAGE, and two peaks of IFN activity were observed. The molecular weight represented by the sharp peak was estimated to be 18 000 (18K) and a broad peak was found at 20K to 30K. Glycosidase treatment before SDS-PAGE resulted in disappearance of the broad peak and increased the activity of the 18K peak. Anti-CE IFN rabbit serum and a monoclonal antibody against the CE IFN neutralized the antiviral activity of all IFN samples prepared under various conditions.


Remarkably Selective Binding, Behavior Modification, and Switchable Release of (Bipyridine)3Ru(II) vis-à-vis (Phenanthroline)3Ru(II) by Trimeric Cyclophanes in Water.
A recurring dream of molecular recognition is to create receptors that distinguish between closely related targets with sufficient accuracy, especially in water. The more useful the targets, the more valuable the dream becomes. We now present multianionic trimeric cyclophane receptors with a remarkable ability to bind the iconic (bipyridine)3Ru(II) (with its huge range of applications) while rejecting the nearly equally iconic (phenanthroline)3Ru(II). These receptors not only selectively capture (bipyridine)3Ru(II) but also can be redox-switched to release the guest. 1D- and 2D(ROESY)-NMR spectroscopy, luminescence spectroscopy, and molecular modeling enabled this discovery. This outcome allows the control of these applications, e.g., as a photocatalyst or as a luminescent sensor, by selectively hiding or exposing (bipyridine)3Ru(II). Overall, a 3D nanometric object is selected, picked-up, and dropped-off by a discrete molecular host. The multianionic receptors protect excited states of these metal complexes from phenolate quenchers so that the initial step in photocatalytic phenolate oxidation is retarded by nearly 2 orders of magnitude. This work opens the way for (bipyridine)3Ru(II) to be manipulated in the presence of other functional nano-objects so that many of its applications can be commanded and controlled. We have a cyclophane-based toolkit that can emulate some aspects of proteins that selectively participate in cell signaling and metabolic pathways by changing shape upon environmental commands being received at a location remote from the active site.