Identification of glycogen in electron micrographs of thin tissue sections.
The electron microscopic appearance of glycogen has been studied in the organs of several animal species. Glycogen almost always appears as roughly circular granules from 150 to 400 A in diameter. The intrinsic electron density of glycogen varies from tissue to tissue; however, treatment with lead hydroxide as described by Watson deeply stains the granules. Glycogen pellets were isolated from some of the tissues studied by centrifugation. Such pellets were shown to be glycogen by chemical and histochemical criteria. When thin sections of the pellet are examined under the electron microscope they can be seen to consist of densely packed granules similar to those found in the intact tissues. Such pellets are also stained for electron microscopy by short exposure to lead hydroxide.


Self-etching primer vs phosphoric acid: an alternative concept for composite-to-enamel bonding.
The purpose of this in vitro study was (1) to investigate the composite-to-enamel bond strength and (2) to analyze the marginal adaptation of resin composite restorations in class 2 cavities using three self-etching priming agents in comparison to conventional phosphoric acid etching and bonding application. In the first part of the study 24 extracted bovine incisors were embedded in acrylic resin and ground flat with 800-grit paper. The following three self-etching priming agents/composite resins were applied to the enamel surfaces of six teeth each: Clearfil Liner Bond 2/Clearfil AP-X (Group I), Etch & Prime 3.0/Degufill mineral (Group II), Resulcin AquaPrime + MonoBond/Ecusit (Group III). In Group IV Ecusit-Mono/Ecusit was used after enamel etching with phosphoric acid (37%). Shear bond strength values measured on a T22 K testing machine at a crosshead speed of 1 mm/min were: 24.2 +/- 3.0 MPa (Group I), 21.9 +/- 1.4 MPa (II), 34.0 +/- 3.6 MPa (III), and 26.3 +/- 1.8 MPa (IV). ANOVA revealed significant (P < 0.05) differences in shear bond strength between groups, except comparison of Group I and II, and Group I and IV. In the second part of the study 24 standardized class 2 cavity preparations with the approximal box extending 1 mm above the CEJ were prepared in extracted human molars. Enamel margins were beveled and the teeth were divided into four groups of six teeth each. Cavities were restored using the self-etching priming agents Clearfil Liner Bond 2 (Group I), Etch & Prime 3.0 (Group II), and Resulcin AquaPrime + MonoBond (Group III). In Group IV composite resin restorations were placed after 37% phosphoric acid etching and bonding application (Ecusit-Mono). Quantitative SEM analysis of the marginal adaptation of the restorations after thermocycling (5-55 degrees C, 2500 cycles) and mechanical loading (100 N, 500,000 cycles) revealed excellent, gap-free margins in 91.2% (Group I), 93.0% (Group II), 92.0% (Group III), and 92.5% (Group IV) of the restorations' approximal area. There were no statistically significant differences between the four groups (P < 0.05). In conclusion, results of the present in vitro study indicate that use of self-etching primers may be an alternative to conventional phosphoric acid pre-treatment in composite-to-enamel bonding restorative techniques.


Trophic Specialization Results in Genomic Reduction in Free-Living Marine Idiomarina Bacteria.
The streamlining hypothesis is generally used to explain the genomic reduction events related to the small genome size of free-living bacteria like marine bacteria SAR11. However, our current understanding of the correlation between bacterial genome size and environmental adaptation relies on too few species. It is still unclear whether there are other paths leading to genomic reduction in free-living bacteria. The genome size of marine free-living bacteria of the genus Idiomarina belonging to the order Alteromonadales (Gammaproteobacteria) is much smaller than the size of related genomes from bacteria in the same order. Comparative genomic and physiological analyses showed that the genomic reduction pattern in this genus is different from that of the classical SAR11 lineage. Genomic reduction reconstruction and substrate utilization profile showed that Idiomarina spp. lost a large number of genes related to carbohydrate utilization, and instead they specialized on using proteinaceous resources. Here we propose a new hypothesis to explain genomic reduction in this genus; we propose that trophic specialization increasing the metabolic efficiency for using one kind of substrate but reducing the substrate utilization spectrum could result in bacterial genomic reduction, which would be not uncommon in nature. This hypothesis was further tested in another free-living genus, Kangiella, which also shows dramatic genomic reduction. These findings highlight that trophic specialization is potentially an important path leading to genomic reduction in some marine free-living bacteria, which is distinct from the classical lineages like SAR11.IMPORTANCE The streamlining hypothesis is usually used to explain the genomic reduction events in free-living bacteria like SAR11. However, we find that the genomic reduction phenomenon in the bacterial genus Idiomarina is different from that in SAR11. Therefore, we propose a new hypothesis to explain genomic reduction in this genus based on trophic specialization that could result in genomic reduction, which would be not uncommon in nature. Not only can the trophic specialization hypothesis explain the genomic reduction in the genus Idiomarina, but it also sheds new light on our understanding of the genomic reduction processes in other free-living bacterial lineages.


Assessment of immunotoxicity by multiparameter flow cytometry.
Flow cytometry is a unique technology useful in the examination of effects of immunotoxic agents on target cells of the immune system. The purpose of this workshop was to provide an overview of the use of flow cytometry in new and established models of immunotoxicity, with emphasis on the potential applications, assay validation, and potential pitfalls. This overview begins with a discussion of methods useful in the assessment of Ca2+-dependent mechanisms of lymphoid cell activation in surface marker-defined human B cells, T cells, and monocytes. A discussion of the use of flow cytometry in analysis of apoptosis is also presented in this paper. The second paper presents data on the development and use of flow cytometry as an alternative to a Cr51 release assay for an assessment of cytotoxic T cell activation. The use of surface markers for characterizing and distinguishing the effects of chemical irritants from sensitizers is next presented, followed by an overview of the use of fluorescent probes to assess cell thiol status and overall oxidant-induced injury to lymphoid cells. Finally, an interlaboratory study designed to compare and evaluate the use of flow cytometry procedures in rat splenic cell subtyping is presented. Overall, these studies demonstrate the utility of flow cytometry assays in immunotoxicologic research, but further efforts are needed in the validation of many of these assays for routine use in immunotoxicologic testing.


ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFα inhibitors.
To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315.


Highly sensitive/selective 3D nanostructured immunoparticle-based interface on a multichannel sensor array for detecting amyloid-beta in Alzheimer's disease.
Accumulation of β-amyloid (Aβ) peptides is highly associated with Alzheimer's disease (AD) progression in prevailing studies. The successful development of an ultrasensitive detection assay for Aβ is a challenging task, especially from blood-based samples. Methods: We have developed a one-step electrophoresis/electropolymerization strategy for preparing a CSIP hierarchical immunoelectrochemical interface that is easily integrated into a PoCT device. The interface includes conductive silk fibroin-based immunoparticles (CSIPs) via electropolymerized Poly(3,4-ethylenedioxythiophene) (PEDOT) bridging to enable on-site electrochemical detection of serum amyloid-β42 (Aβ42) and -β40 (Aβ40) peptides from an AD blood test. In addition, micro-positron emission tomography (microPET) neuroimaging and behavioral tests were simultaneously performed. Results: This nanostructured conductive interface favors penetration of water-soluble biomolecules and catalyzes a redox reaction, providing limits of detection (LOD) of 6.63 pg/mL for Aβ40 and 3.74 pg/mL for Aβ42. Our proof-of-concept study confirms that the multi-sensing electrochemical immunosensor array (MEIA) platform enables simultaneous measurement of serum Aβ42 and Aβ40 peptide levels and is more informative in early stage AD animals than amyloid-labeling Aβ plaque PET imaging and behavioral tests. Conclusion: We believe this study greatly expands the applications of silk fibroin-based materials, is an important contribution to the advancement of biomaterials, and would also be valuable in the design of new types of multichannel electrochemical immunosensor arrays for the detection of other diseases.


[Study on screening potential traditional Chinese medicines against 2019-nCoV based on Mpro and PLP].
With the rapid outbreak of COVID-19, traditional Chinese medicine(TCM) has been playing an active role against the epidemic. However, the screening of TCM is limited by the development cycle and laboratory conditions, which greatly limits the screening speed. This study established optimization docking models and virtual screening to discovery potential active herbs for the prevention and treatment of the novel coronavirus based on molecular docking technology. The crystal structures of 3 CL protease(Mpro) and papain-like protease(PLP) were obtained from PDB database and homologous modeling respectively, and were used to conduct virtual screening of TCMD 2009 database by CDOCKER program. The ingredients scored in the top 100 were selected respectively, and the candidate herbs were ranked by the numbers of hit molecules. Based on Mpro inhibitors screening, 12 322 potential active components were obtained, and the representative active components included aster pentapeptide A, ligustrazine, salvianolic acid B, etc., and Zingiberis Rhizoma Recens, Asteris Radix et Rhizoma, Notoginseng Radix et Rhizoma, Chuanxiong Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Zingiberis Rhizoma, Dianthi Herba, Rhei Radix et Rhizoma, Cistanches Herba were obtained. While 11 294 potential active ingredients were obtained by PLP inhibitor screening, representative active ingredients included gingerketophenol, ginkgol alcohol, ferulic acid, etc., and Codonopsis Radix, Notopterygii Rhizoma et Radix, Zingiberis Rhizoma Recens, Ginkgo Semen, Chuanxiong Rhizoma, Trichosanthis Fructus, Paeoniae Radix Alba, Psoraleae Fructus, Sophorae Flavescentis Radix, Notoginseng Radix et Rhizoma, Angelicae Sinensis Radix were chosen. By combining the diagnosis and treatment scheme of Hunan province's and angiotensin converting enzyme 2(ACE2) inhibitors screening from literature, present study also discussed the rational application of candidate herbs to this epidemic situation. Trichosanthis Fructus obtained by PLP inhibitors screening and Fritillaria verticillata obtained by ACE2 inhibitors screening were parts of the Sangbei Zhisou Powder and Xiaoxianxiong Decoction, which might be applicable to the syndromes of cough and dyspnea. Rhei Radix et Rhizoma screened by Mpro and Trichosanthis Fructus screened by PLP were contained in Maxing Shigan Decoction and Xuanbai Chengqi Decoction, and could be applied to the syndromes of epidemic virus blocking lung. Mori Folium, Lonicerae Japonicae Flos and Forsythiae Fructus obtained by ACE2 inhibitors screening were included in the Sangju Decoction and Yinqiaosan, which might be applicable to the syndromes of warm pathogen attacking lung and cough and dyspnea. The results of this study are intended to provide a reference for the further development of traditional Chinese medicine to deal with the new epidemic.


Your Health Is Leaked: PPG Waveform Reconstruction Using Stealthily Recorded Physiological Signals.
In this study, we propose a method to reconstruct photoplethysmogram (PPG) waveforms from other stealthily recorded physiological signals. The proposed method focuses on the frequency characteristics between two physiological signals and reconstructs the target PPG waveform using a regression model. We investigate the feasibility of the proposed method to reconstruct target PPG signals from respiratory (RSP) and PPG signals recorded at non-genuine measurement sites using the two datasets of physiological signals. The results indicate that the proposed method achieves similarities between the target PPG and reconstructed PPG signals with correlation coefficients more than 0.860.


Formation of the embryonic organizer is restricted by the competitive influences of Fgf signaling and the SoxB1 transcription factors.
The organizer is one of the earliest structures to be established during vertebrate development and is crucial to subsequent patterning of the embryo. We have previously shown that the SoxB1 transcription factor, Sox3, plays a central role as a transcriptional repressor of zebrafish organizer gene expression. Recent data suggest that Fgf signaling has a positive influence on organizer formation, but its role remains to be fully elucidated. In order to better understand how Fgf signaling fits into the complex regulatory network that determines when and where the organizer forms, the relationship between the positive effects of Fgf signaling and the repressive effects of the SoxB1 factors must be resolved. This study demonstrates that both fgf3 and fgf8 are required for expression of the organizer genes, gsc and chd, and that SoxB1 factors (Sox3, and the zebrafish specific factors, Sox19a and Sox19b) can repress the expression of both fgf3 and fgf8. However, we also find that these SoxB1 factors inhibit the expression of gsc and chd independently of their repression of fgf expression. We show that ectopic expression of organizer genes induced solely by the inhibition of SoxB1 function is dependent upon the activation of fgf expression. These data allow us to describe a comprehensive signaling network in which the SoxB1 factors restrict organizer formation by inhibiting Fgf, Nodal and Wnt signaling, as well as independently repressing the targets of that signaling. The organizer therefore forms only where Nodal-induced Fgf signaling overlaps with Wnt signaling and the SoxB1 proteins are absent.


Dimensional reduction in networks of non-Markovian spiking neurons: Equivalence of synaptic filtering and heterogeneous propagation delays.
Message passing between components of a distributed physical system is non-instantaneous and contributes to determine the time scales of the emerging collective dynamics. In biological neuron networks this is due in part to local synaptic filtering of exchanged spikes, and in part to the distribution of the axonal transmission delays. How differently these two kinds of communication protocols affect the network dynamics is still an open issue due to the difficulties in dealing with the non-Markovian nature of synaptic transmission. Here, we develop a mean-field dimensional reduction yielding to an effective Markovian dynamics of the population density of the neuronal membrane potential, valid under the hypothesis of small fluctuations of the synaptic current. Within this limit, the resulting theory allows us to prove the formal equivalence between the two transmission mechanisms, holding for any synaptic time scale, integrate-and-fire neuron model, spike emission regimes and for different network states even when the neuron number is finite. The equivalence holds even for larger fluctuations of the synaptic input, if white noise currents are incorporated to model other possible biological features such as ionic channel stochasticity.


Pain Energy Model of Mobility Limitation in the Older Adult.
Chronic pain is prevalent, costly, and disabling among older adults. Although mobility decline is inevitable with aging, it is clear, from current evidence, that older adults with chronic pain experience a greater rate of functional mobility decline than their pain-free peers. Past studies suggest that pain expedites the age-related decline in functional mobility; however, the pathways through which pain affects mobility remain unclear. Gerontological experts hypothesize that the age-related decline in mobility may be driven by alterations in energy expenditure; these concepts are outlined in a model known as the Energetic Pathway of Mobility Loss. Pain may play a critical role in this process through a pathway of energetic inefficiency, physical inactivity, and decreased capacity. The purposes of this article are to 1) summarize the current literature that supports the Energetic Pathway of Mobility Loss model and 2) propose a new framework, known as the Pain Energy Model, to clarify how the disablement process may be amplified among older adults with painful conditions. This new framework is designed to generate new clinical research and to suggest new clinical implications for older adults with painful conditions by identifying key steps and potential treatment targets in the pathway to functional mobility decline.


Genion, an accurate tool to detect gene fusion from long transcriptomics reads.
The advent of next-generation sequencing technologies empowered a wide variety of transcriptomics studies. A widely studied topic is gene fusion which is observed in many cancer types and suspected of having oncogenic properties. Gene fusions are the result of structural genomic events that bring two genes closely located and result in a fused transcript. This is different from fusion transcripts created during or after the transcription process. These chimeric transcripts are also known as read-through and trans-splicing transcripts. Gene fusion discovery with short reads is a well-studied problem, and many methods have been developed. But the sensitivity of these methods is limited by the technology, especially the short read length. Advances in long-read sequencing technologies allow the generation of long transcriptomics reads at a low cost. Transcriptomic long-read sequencing presents unique opportunities to overcome the shortcomings of short-read technologies for gene fusion detection while introducing new challenges. We present Genion, a sensitive and fast gene fusion detection method that can also detect read-through events. We compare Genion against a recently introduced long-read gene fusion discovery method, LongGF, both on simulated and real datasets. On simulated data, Genion accurately identifies the gene fusions and its clustering accuracy for detecting fusion reads is better than LongGF. Furthermore, our results on the breast cancer cell line MCF-7 show that Genion correctly identifies all the experimentally validated gene fusions. Genion is an accurate gene fusion caller. Genion is implemented in C++ and is available at https://github.com/vpc-ccg/genion .


Terrestriality and bacterial transfer: a comparative study of gut microbiomes in sympatric Malagasy mammals.
The gut microbiomes of mammals appear to mirror their hosts' phylogeny, suggesting host-driven microbial community assembly. Yet, much of this evidence stems from comparative studies of distinct wild or captive populations that lack data for disentangling the relative influences of shared phylogeny and environment. Here, we present phylogenetic and multivariate analyses of gut microbiomes from six sympatric (i.e., co-occurring) mammal species inhabiting a 1-km2 area in western Madagascar-three lemur and three non-primate species-that consider genetic, dietary, and ecological predictors of microbiome functionality and composition. Host evolutionary history, indeed, appears to shape gut microbial patterns among both closely and distantly related species. However, we also find that diet-reliance on leaves versus fruit-is the best predictor of microbiome similarity among closely related lemur species, and that host substrate use-ground versus tree-constrains horizontal transmission via incidental contact with feces, with arboreal species harboring far more distinct communities than those of their terrestrial and semi-terrestrial counterparts.


Effects of low-power laser auriculotherapy on chronic spinal pain: Randomized clinical trial.
To evaluate the effect of laser auriculotherapy on chronic spinal pain. It is a randomized controlled clinical trial. Volunteers with chronic spinal pain underwent three evaluations: an initial evaluation, a final evaluation immediately after the last intervention session, and a 15-day follow-up. Pain intensity, nociceptive threshold in relation to mechanical stimulus, and degree of pain (the greatest and least pain) in the last seven days were the assessed variables. The experimental group (EG, n = 24) underwent 10 sessions of laser auriculotherapy twice a week, while the control group (CG, n = 23) did not receive any intervention. The EG showed great clinical improvement in relation to the variable pain intensity between pre- and post-interventions (65.2%) and pre-intervention and follow-up (58.62%) compared to the CG. There was a significant increase in the nociceptive threshold for the EG. In contrast, the CG showed a significant reduction in the nociceptive threshold. The intergroup analysis indicated an improvement in pain intensity for the EG (0.006). This result remained at the follow-up (0.012). The nociceptive threshold increased over time for the EG (0.016). In contrast, the CG showed a reduction in this variable with a significant difference over time (<0.001). The results of this clinical trial suggest that the proposed intervention may be effective in reducing pain intensity and increasing the nociceptive threshold. The effect of the intervention remained 15 days after the end of the treatment, when the volunteers were re-evaluated.


A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies.
The gene encoding nuclear lamins A and C is mutated in at least three inherited disorders. Two of these, Emery-Dreifuss muscular dystrophy (EDMD-AD) and a form of dilated cardiomyopathy (CMD1A), involve muscle defects, and the other, familial partial lipodystrophy (FPLD), involves loss of subcutaneous adipose tissue. Mutations causing FPLD, in contrast to those causing muscle disorders, are tightly clustered within the C-terminal domain of lamin A/C. We investigated the expression and subcellular localization of FPLD lamin A mutants and found no abnormalities. We therefore set out to identify proteins interacting with the C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a yeast two-hybrid interaction screen. Using this approach, the adipocyte differentiation factor, sterol response element binding protein 1 (SREBP1) was identified as a novel lamin A interactor. In vitro glutathione S-transferase pull-down and in vivo co-immunoprecipitation studies confirmed an interaction between lamin A and both SREBP1a and 1c. A binding site for lamin A was identified in the N-terminal transcription factor domain of SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by FPLD mutations. Interestingly, one EDMD-AD mutation also interfered with the interaction between lamin A and SREBP1. Whilst the physiological relevance of this interaction has yet to be elucidated, these data raise the intriguing possibility that fat loss seen in laminopathies may be caused, at least in part, by reduced binding of the adipocyte differentiation factor SREBP1 to lamin A.


Weekly carboplatin in elderly patients with advanced ovarian cancer.
Ovarian cancer is frequently diagnosed in patients over 65 years old, but limited data are available on tolerance and effectiveness of chemotherapy in this subset of patients. A total of 21 patients with epithelial ovarian cancer were treated with weekly carboplatin following failure of first-line chemotherapy. Median age was 73 years (range, 66-85). Patients received carboplatin at the dose 100 mg/m(2)/week with discontinuation for severe toxicity or documented progression. A total of 228 cycles were administered (median per patients, 10 cycles). Six partial remissions (29%; 95% confidence interval, 11-52%), 6 stabilizations of disease, and 9 disease progressions were observed. Median time to progression was 6 months. No toxic deaths were observed. Side effects consisted mainly of anemia (grade 3 in 3 cases) and neutropenia. Non-hematologic toxicity was minimal. In conclusion, the schedule has moderate activity with good tolerability in elderly patients with advanced epithelial ovarian cancer.


ICAM-3 enhances the migratory and invasive potential of human non-small cell lung cancer cells by inducing MMP-2 and MMP-9 via Akt and CREB.
We have previously reported that intercellular adhesion molecule-3 (ICAM-3) is associated with an increase of cellular radio-resistance and cancer cell proliferation. In this study, we hypothesized that ICAM-3 has an additional effect on cancer cell migration and invasion because molecules induced by ICAM-3 are known as regulators of cell migration and invasion. To examine this hypothesis, we used NCI-H1299 non-small cell lung cancer (NSCLC) cell line (p53 and PTEN null cell) and constructed an ICAM-3-over-expressing stable transfectant, which exhibited increased cell migration and invasion. The increased migration and invasion resulted from up-regulation of expression and activities of MMP-2 and MMP-9. ICAM-3 also increased Akt phosphorylation, which caused an increase in cellular migration/invasion and MMP activities. Activity of several transcriptional factors located downstream in the Akt pathway was also tested, and constitutive activation of adenosine 3', 5'-monophosphate response element-binding protein (CREB) by ICAM-3 was detected. Blockage of the Akt pathway attenuated CREB activation, and a decrease in CREB expression reduced cellular migration/invasion and activity of MMPs. This result indicates that CREB functions in the signaling pathway between Akt and MMP. We also showed ICAM-3-induced cell migration and invasion in NCI-H460 NSCLC cells (wild-type p53 and PTEN cell) through the same signaling pathway. Taken together, our findings suggest that ICAM-3 stimulates cancer cell migration/invasion via ICAM-3/Akt/CREB/MMP pathway regardless of p53 and PTEN status, and this reflects the possibility that ICAM-3 could be considered as a candidate for anti-cancer drug development and as a cancer diagnostic marker.


Evolutionary Implications of Anoxygenic Phototrophy in the Bacterial Phylum Candidatus Eremiobacterota (WPS-2).
Genome-resolved environmental metagenomic sequencing has uncovered substantial previously unrecognized microbial diversity relevant for understanding the ecology and evolution of the biosphere, providing a more nuanced view of the distribution and ecological significance of traits including phototrophy across diverse niches. Recently, the capacity for bacteriochlorophyll-based anoxygenic photosynthesis has been proposed in the uncultured bacterial WPS-2 phylum (recently proposed as Candidatus Eremiobacterota) that are in close association with boreal moss. Here, we use phylogenomic analysis to investigate the diversity and evolution of phototrophic WPS-2. We demonstrate that phototrophic WPS-2 show significant genetic and metabolic divergence from other phototrophic and non-phototrophic lineages. The genomes of these organisms encode a new family of anoxygenic Type II photochemical reaction centers and other phototrophy-related proteins that are both phylogenetically and structurally distinct from those found in previously described phototrophs. We propose the name Candidatus Baltobacterales for the order-level aerobic WPS-2 clade which contains phototrophic lineages, from the Greek for "bog" or "swamp," in reference to the typical habitat of phototrophic members of this clade.


Prevention of burns in developing countries.
Burns represent an important health and economic problem in Africa and in the developing countries. Prevention programs in the developing countries are still at an infant phase. It is well known that prevention includes surveillance with data analysis and reporting. With information campaigns, an effort can be made to use regulatory action, to educate the population and modify the environment. The aim of this paper is to identify the risk factors in communities in order to implement communitybased burn prevention strategies, not only on the African continent but also in other developing countries. Effective prevention programs are highlighted. Evidence regarding adequate safety legislation with policing seems to show immediate effects with multiparty involvement and statistical decrease of injury and death. Three examples are discussed where political commitment is mobilised to ensure regulatory action. Other programs are cost-effective and have long-lasting effects, but they take time. Cochrane database system reviews highlighted the problems when people were encouraged to change their lifestyle. NGOs play a definite role in developing countries, and in Bangladesh and Pakistan efforts are being made to curb acid-throwing violence. Communities consist of many groups. There must be a societal responsibility to design products a.


CUDA optimization strategies for compute- and memory-bound neuroimaging algorithms.
As neuroimaging algorithms and technology continue to grow faster than CPU performance in complexity and image resolution, data-parallel computing methods will be increasingly important. The high performance, data-parallel architecture of modern graphical processing units (GPUs) can reduce computational times by orders of magnitude. However, its massively threaded architecture introduces challenges when GPU resources are exceeded. This paper presents optimization strategies for compute- and memory-bound algorithms for the CUDA architecture. For compute-bound algorithms, the registers are reduced through variable reuse via shared memory and the data throughput is increased through heavier thread workloads and maximizing the thread configuration for a single thread block per multiprocessor. For memory-bound algorithms, fitting the data into the fast but limited GPU resources is achieved through reorganizing the data into self-contained structures and employing a multi-pass approach. Memory latencies are reduced by selecting memory resources whose cache performance are optimized for the algorithm's access patterns. We demonstrate the strategies on two computationally expensive algorithms and achieve optimized GPU implementations that perform up to 6× faster than unoptimized ones. Compared to CPU implementations, we achieve peak GPU speedups of 129× for the 3D unbiased nonlinear image registration technique and 93× for the non-local means surface denoising algorithm.


Improving diabetic patient transition to home healthcare: leading risk factors for 30-day readmission.
To identify risk factors of 30-day readmissions due to ambulatory care-sensitive conditions (ACSCs) for diabetic Medicare home healthcare beneficiaries in order to improve transition from hospital-based care to home healthcare. We analyzed diabetic Medicare beneficiaries who received home healthcare within 14 days of hospital discharges in 2009. The unit of analysis is the home health episode for post acute care. The conceptual framework was guided by Andersen's Behavioral Model of Health Services. Data sources included: Medicare Beneficiary Summary File, Medicare Provider Analysis Review, Outcome Assessment Information Set, Home Health Agency Research Identifiable File, Hospital Readmissions Reduction Program Supplemental Data File, Provider of Services File, and Area Health Resources File. The dependent variable was time to first 30-day ACSC-related readmission. Proportional hazards regression was used for the statistical analyses. The 30-day ACSC-related readmission rate was approximately 6% in our study sample, costing the Medicare program about $62 million. Predictors of readmissions due to ACSCs within 30 days of hospital discharge were: being aged 75 to 84 years, being an African American, requiring assistance in medication management, and having 1 or more of the following clinical conditions: congestive heart failure, peripheral vascular disease, chronic obstructive pulmonary disease, renal failure, deficiency anemia, fluid and electrolyte diseases, depression and/or anxiety, and pressure or stasis ulcer. Patients with chronic obstructive pulmonary disease or renal failure had a 40% higher risk of 30-day ACSC-related readmissions than their counterparts. Knowing the risk factors identified above, hospital providers can improve care planning and transition of care to the home healthcare providers.


Detecting Drug Non-Compliance in Internet Fora Using Information Retrieval and Machine Learning Approaches.
Non-compliance situations happen when patients do not follow their prescriptions and take actions that lead to potentially harmful situations. Although such situations are dangerous, patients usually do not report them to their physicians. Hence, it is necessary to study other sources of information. We propose to study online health fora. The purpose of our work is to explore online health fora with supervised classification and information retrieval methods in order to identify messages that contain drug non-compliance. The supervised classification method permits detection of non-compliance with up to 0.824 F-measure, while the information retrieval method permits detection non-compliance with up to 0.529 F-measure. For some fine-grained categories and new data, it shows up to 0.65-0.70 Precision.


Identifying the vulnerable patient with rupture-prone plaque.
Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States, and the obesity epidemic combined with aging of the population seems destined to increase the burden of this disease. Traditional cardiovascular risk assessment accounts for <50% of the variability in risk in the United States. Therefore, better and more effective identification of persons at high cardiovascular risk is needed. Our understanding of atherosclerosis has shifted from a focal disease whose hallmark is symptoms caused by a severe stenosis to a systemic disease characterized by endothelial dysfunction (ED) and plaque inflammation, with the potential for rupture and thrombosis mainly in those with subcritical stenosis. Under the new paradigm, clinicians require updated strategies to better assess the quality of arterial plaque. Effective tools for primary and secondary prevention of heart attack and stroke include intensive lifestyle modification, blood pressure reduction, and lipid-modifying therapies. These interventions are now understood to decrease plaque inflammation and thereby promote plaque stability. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be a specific marker of plaque inflammation that may play a direct role in the formation of rupture-prone plaque. In contrast, traditional risk factors, lipid measurement, and most vascular imaging modalities do not directly assess the acute ischemic potential in the arterial wall. Measuring Lp-PLA(2) levels in human serum or plasma is noninvasive and relatively inexpensive. Lp-PLA(2) may provide additional clinically relevant information that shows which patients have a high level of atherosclerotic disease activity as manifested by vascular inflammation, ED, and increased risk for progression toward rupture-prone plaque.


Complaints and Annoyance caused by Aircraft Operations: Temporal Patterns and Individual Bias.
The impact of aircraft movements on annoyance in the local community surrounding a major international airport was assessed for (a) patterns of complaints for the year, month, day-of-the-week and time-of-day and (b) the frequency of complaining by individuals. Complaint data from Manchester Airport since 1991 and detailed analysis for 1998 were compared with associated information on noise monitoring and aircraft movements to investigate underlying biological and sociological patterns. The annual number of complaints peaked in 1996 when the 'Manchester Airport Second Runway Public Inquiry' was a major local issue and had a high profile in the local media. Since 1996 the number of flights has increased while the number of complaints has steadily fallen; from 50 to13 complaints per 1,000 movements from 1996 to 1999. Detailed inspection of the 1998 data revealed a total of 2072 noise complaints from 594 individuals but, while the majority of individuals complained once or twice, three individuals accounted for 41% of complaints. This introduced some bias into the results but there was; (a) a steady increase in complaints (per 1,000 movements) over the week from a low on Monday to a high on Saturday/Sunday; (b) a marked hourly variation over the 24 hours in both flight frequency (movements per hour) and complaints. However, the hourly patterns in flight frequency and complaints were clearly distinct. Calculations of the complaints per aircraft movement (a reflection of sensitivity) for each hour of the day showed a striking 24h pattern with twice as many complaints between 23.00 and 07.00 as the rest of the day (07.00-23.00). Late evening and night-time, particularly during the early hours of sleep, was the time of greatest sensitivity to aircraft, with or without the serial complainers. These results could be used to inform airport operations to minimize community disturbance.


An approach to the management of chronic myeloid leukemia in British Columbia.
Chronic myeloid leukemia (cml) is a myeloproliferative disorder whose therapy has changed dramatically since the late 1990s. With the introduction of the tyrosine kinase inhibitor (tki) imatinib mesylate, the treatment outcomes for patients with cml have improved markedly, and hematopoietic stem-cell transplantation is no longer routinely offered as first-line therapy for most patients in chronic phase.However, resistance to tki therapy is increasingly being recognized, and alternative therapy is needed for this group of patients. In addition, the development of models predicting response to tki therapy is desired, so that appropriate treatment strategies can be used for individual patients. The present report serves to outline the approach to the treatment of cml in British Columbia and to highlight areas of ongoing research.


Synergistic anti-neoplastic effect of AG1478 in combination with cisplatin or paclitaxel on human endometrial and ovarian cancer cells.
AG1478, a potent inhibitor of epidermal growth factor receptor (EGFR), facilitates the induction of cell death in combination with a variety of cytotoxic and chemotherapeutic agents in certain human tumor cell lines. The purpose of this study was to elucidate the effect of AG1478 on three endometrial cancer and two ovarian cancer cell lines as compared to normal human endometrial epithelial cells. Cells were treated with various concentrations of AG1478 alone or in combination with the chemotherapeutic drugs cisplatin or paclitaxel, and the effect of AG1478 on cell growth, the cell cycle and apoptosis was investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that all the cancer cell lines were sensitive to the growth-inhibitory effect of AG1478. Normal endometrial epithelial cells remained viable after treatment with AG1478 at the same doses as those which induced growth inhibition in the endometrial and ovarian cancer cells. Synergistic anti-neoplastic effects were obtained with a combination of AG1478 and cytostatic drugs. Cell-cycle analysis indicated that exposure to these drugs decreased the proportion of cells in the S-phase and increased the proportion in the sub G0/G1 fractions of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and by loss of mitochondrial transmembrane potential. These results suggest that AG1478 alone or in combination with chemotherapeutic drugs may be a novel therapeutic option for the treatment of endometrial and ovarian cancer.


Global governance and the broader determinants of health: A comparative case study of UNDP's and WTO's engagement with global health.
This comparative case study investigated how two intergovernmental organisations without formal health mandates - the United Nations Development Programme (UNDP) and the World Trade Organization (WTO) - have engaged with global health issues. Triangulating insights from key institutional documents, ten semi-structured interviews with senior officials, and scholarly books tracing the history of both organisations, the study identified an evolving and broadened engagement with global health issues in UNDP and WTO. Within WTO, the dominant view was that enhancing international trade is instrumental to improving global health, although the need to resolve tensions between public health objectives and WTO agreements was recognised. For UNDP, interviewees reported that the agency gained prominence in global health for its response to HIV/AIDS in the 1990s and early 2000s. Learning from that experience, the agency has evolved and expanded its role in two respects: it has increasingly facilitated processes to provide global normative direction for global health issues such as HIV/AIDS and access to medicines, and it has expanded its focus beyond HIV/AIDS. Overall, the study findings suggest the need for seeking greater integration among international institutions, closing key global institutional gaps, and establishing a shared global institutional space for promoting action on the broader determinants of health.


Association between Sexual Activity and Human Papillomavirus (HPV) Vaccine Initiation and Completion among College Students.
HPV vaccination is most effective if received before initiation of sexual activity. Previous studies suggested that young adult women who were not sexually active were not interested in receiving the vaccine because they did not think it was necessary. Whether this misperception is still prevalent today-and also shared by men-is unknown. This study examined whether sexual activity was associated with HPV vaccine uptake (initiation and completion) among university students. A cross-sectional study was conducted between February and May 2021 among students (n = 951) at a public Midwestern University. Sexual activity was categorized as "never" or "ever" had oral and/or vaginal sex. Outcome variables were HPV vaccine initiation, defined as receipt of ≥1 dose, and completion, defined as receipt of ≥3 doses. Multivariable logistic regression models estimated the association between sexual activity and HPV vaccine uptake, adjusting for sociodemographic factors. Approximately 18% of students reported never engaging in sexual activity. Overall, 45.5% initiated the HPV vaccine, and 16.5% completed the vaccine series. After adjusting for covariates, compared to students that reported never engaging in sexual activity, those that had ever engaged in sexual activity were more likely to have initiated the vaccine series (aOR = 2.06, 95% CI: 1.34-3.17); however, no difference was observed for completion. HPV vaccination was low; sexually naïve students were less likely to initiate the HPV vaccine. Since sexually naïve students may benefit from receiving the HPV vaccination, targeted interventions should be implemented towards this population to help increase vaccination rates and prevent HPV-associated diseases.


Determination of oxidative and occupational stress in palliative care workers.
In previous work, we demonstrated that some occupational workers in stressful conditions can have increases in several markers of oxidative stress when compared to other workers. We investigated two antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT) activities, and malondialdehyde (MDA) concentrations, according to demographics, lifestyle and occupational parameters in palliative care unit workers, and analyzed the relationship with occupational burnout. Fifty-two palliative care unit workers and 50 gender- and aged matched healthy individuals as controls were surveyed. Spectrophotometric and high-pressure liquid chromatography methods were used for biochemical determinations. No significant variation with respect to gender were detected with respect to SOD and CAT activities, MDA concentrations or occupational burnout. MDA concentrations increased with age in controls and palliative care unit workers, and we observed significant differences in MDA between controls and palliative care unit workers for all age groups. Significant variation in MDA concentrations were detected between unmarried (287.22±8.31 nmol/mg hemoglobin) and married individuals (317.18±6.24 nmol/mg hemoglobin), but not with respect to divorced individuals (288.41±5.64 nmol/mg hemoglobin). Significant differences were detected between smokers and non-smokers for SOD, CAT and MDA, but not for alcohol, coffee, tea or cola consumption. Significant differences were seen in MDA concentrations between those who frequently practice some kind of sport (280.59±7.62 nmol/mg hemoglobin) and those who never practice any kind of sport (299.12±8.09 nmol/mg hemoglobin), and between those who frequently ate fruit and greens (291.05±8.11 nmol/mg hemoglobin) and those who never eat fruit and greens (316.31±7.42 nmol/mg hemoglobin). SOD activity and MDA concentrations are higher in palliative care workers who work the evening and night shifts (p<0.01), and these workers also show significantly higher levels of stress. Our findings suggest that oxidative stress, occupational stress and occupational burnout levels are similar in men and women. Occupational stress increases oxidative stress levels probably as a response to increased generation of reactive oxygen species. Working during the evening and night shifts increases oxidative levels and burnout levels.


Synthesis, characterization, and crystal structures of two new divalent metal complexes of N,N'-bis(phosphonomethyl)-1,10-diaza-18-crown-6: a hydrogen-bonded 1D array and a 3D network with a large channel.
Reaction of N,N'-bis(phosphonomethyl)-1,10-diaza-18-crown-6 (H(4)L) with copper(II) acetate in 1:1 ethanol/water mixed solvents afforded a new crystal-engineered supramolecular metal phosphonate, Cu(H(2)L) (complex 1). By reaction of the same ligand with cadmium(II) nitrate in a 2:1 (M/L) ratio in methanol, a cadmium(II) complex with a 3D network structure was isolated, Cd(2.75)(L)(H(2)O)(7) x 1.5NO(3) x 7H(2)O x MeOH (complex 2). The copper(II) complex crystallized in the monoclinic space group P2(1)/c, with a =10.125(4), b = 14.103(6), and c = 14.537(6) A, beta = 91.049(8) degrees, V = 2075.4(16) A(3), and Z = 2. The Cu(II) ions in complex 1 are 6-coordinated by two phosphonate oxygen atoms, two nitrogen, and two oxygen atoms from the crown ether ring. Their coordination geometry can be described as Jahn-Teller-distorted octahedral, with elongated Cu-O(crown) distances (2.634(4) and 2.671(4) A for Cu(1) and Cu(2), respectively). The other two crown oxygen atoms remain uncoordinated. Neighboring two Cu(H(2)L) units are further interlinked via a pair of strong hydrogen bonds between uncoordinated phosphonate oxygen atoms, resulting in a one-dimensional supramolecular array along the a axis. The cadmium(II) complex is tetragonal, P4(2)/n (No. 86) with a = 20.8150(9) and c = 18.5846(12) A, V = 8052.0(7) A(3), and Z = 8. Among four cadmium(II) atoms in an asymmetric unit, one is 8-coordinated by four chelating phosphonate groups, the second one is 8-coordinated by 6 coordination atoms from a crown ring and two oxygen atoms from two phosphonate groups, the third Cd(II) atom is octahedrally coordinated by three aqua ligands and three phosphonate oxygen atoms from three phosphonate groups, and the fourth one is 6-coordinated by four aqua ligands and two oxygen atoms from two phosphonate groups in a distorted octahedral geometry. These cadmium atoms are interconnected by bridging phosphonate tetrahedra in such a way as to form large channels along the c direction, in which the lattice water molecules, methanol solvent, and nitrate anions reside. The effect of extent of deprotonation of phosphonic acids on the type of complex formed is also discussed.


High-dose vitamin C enhances cancer immunotherapy.
Vitamin C (VitC) is known to directly impair cancer cell growth in preclinical models, but there is little clinical evidence on its antitumoral efficacy. In addition, whether and how VitC modulates anticancer immune responses is mostly unknown. Here, we show that a fully competent immune system is required to maximize the antiproliferative effect of VitC in breast, colorectal, melanoma, and pancreatic murine tumors. High-dose VitC modulates infiltration of the tumor microenvironment by cells of the immune system and delays cancer growth in a T cell-dependent manner. VitC not only enhances the cytotoxic activity of adoptively transferred CD8 T cells but also cooperates with immune checkpoint therapy (ICT) in several cancer types. Combination of VitC and ICT can be curative in models of mismatch repair-deficient tumors with high mutational burden. This work provides a rationale for clinical trials combining ICT with high doses of VitC.


Efficacy of polyethylene glycol-conjugated bovine granulocyte colony-stimulating factor for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cows and heifers.
To evaluate effects of various doses of polyethylene glycol (PEG)-conjugated bovine granulocyte colony-stimulating factor (bG-CSF) on the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. 211 periparturient Holstein cows and heifers. Approximately 7 days before the anticipated date of parturition (day of parturition = day 0), healthy cattle received SC injections of sterile saline (0.9% NaCl) solution (control treatment) or PEG-bG-CSF at 5, 10, or 20 μg/kg. Cattle were commingled and housed in a pen with dirt flooring, which was kept wet to maximize the incidence of naturally occurring clinical mastitis. Within 24 hours after parturition, each animal again received the assigned treatment. Mammary glands and milk were visually scored for abnormalities twice daily for 28 days after parturition. Milk samples were aseptically collected from mammary glands with an abnormal appearance or abnormal milk and submitted for microbial culture. Daily milk production was recorded, and milk composition was assessed on days 3, 5, 7, and 10. Cattle treated with PEG-bG-CSF at 10 and 20 μg/kg had significantly fewer cases of clinical mastitis (9/54 and 5/53, respectively), compared with control cattle (18/53). Administration of PEG -bG-CSF did not significantly affect daily milk production or milk composition. Results suggested that PEG-bG-CSF was effective for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. Further investigations of the use of PEG-bG-CSF as a potential preventative intervention should be conducted.


Incidence of Congenital Spinal Abnormalities Among Pediatric Patients and Their Association With Scoliosis and Systemic Anomalies.
Congenital abnormalities when present, according to VACTERL theory, occur nonrandomly with other congenital anomalies. This study estimates the prevalence of congenital spinal anomalies, and their concurrence with other systemic anomalies. A retrospective cohort analysis on Health care Cost and Utilization Project's Kids Inpatient Database (KID), years 2000, 2003, 2006, 2009 was performed. ICD-9 coding identified congenital anomalies of the spine and other body systems. Overall incidence of congenital spinal abnormalities in pediatric patients, and the concurrence of spinal anomaly diagnoses with other organ system anomalies. Frequencies of congenital spine anomalies were estimated using KID hospital-and-year-adjusted weights. Poisson distribution in contingency tables tabulated concurrence of other congenital anomalies, grouped by body system. Of 12,039,432 patients, rates per 100,000 cases were: 9.1 hemivertebra, 4.3 Klippel-Fiel, 56.3 Chiari malformation, 52.6 tethered cord, 83.4 spina bifida, 1.2 absence of vertebra, and 6.2 diastematomyelia. Diastematomyelia had the highest concurrence of other anomalies: 70.1% of diastematomyelia patients had at least one other congenital anomaly. Next, 63.2% of hemivertebra, and 35.2% of Klippel-Fiel patients had concurrent anomalies. Of the other systems deformities cooccuring, cardiac system had the highest concurrent incidence (6.5% overall). In light of VACTERL's definition of a patient being diagnosed with at least 3 VACTERL anomalies, hemivertebra patients had the highest cooccurrence of ≥3 anomalies (31.3%). With detailed analysis of hemivertebra patients, secundum ASD (14.49%), atresia of large intestine (10.2%), renal agenesis (7.43%) frequently cooccured. Congenital abnormalities of the spine are associated with serious systemic anomalies that may have delayed presentations. These patients continue to be at a very high, and maybe higher than previously thought, risk for comorbidities that can cause devastating perioperative complications if not detected preoperatively, and full MRI workups should be considered in all patients with spinal abnormalities. Level III.


Nanoengineering gold particle composite fibers for cardiac tissue engineering.
Gold nanostructures can be incorporated into macroporous scaffolds to increase the matrix conductivity and enhance the electrical signal transfer between cardiac cells. Here we report a simple approach for fabricating 3-dimensional (3D) gold nanoparticle (NP)-based fibrous scaffolds, for engineering functional cardiac tissues generating a strong contraction force. A polycaprolactone-gelatin mixture was electrospun to obtain fibrous scaffolds with an average fiber diameter of 250 nm. In a facile method, gold NPs were evaporated on the surface of the fibers, creating nanocomposites with a nominal gold thickness of 2, 4, and 14 nm. Compared to pristine scaffolds, cardiac cells seeded on the nano-gold scaffolds assembled into more elongated and aligned tissues. The gold NPs on the fibers were able to maintain the ratio of cardiomyocytes to fibroblasts in the culture, to encourage the growth of cardiomyocytes with significantly higher aspect ratio, and promote massive cardiac sarcomeric actinin expression. Finally, engineering cardiac tissues within gold NP-based scaffolds exhibited significantly higher contraction amplitudes and rates, as compared to scaffolds without gold. We envision that cardiac tissues engineered within these gold NP scaffolds can be used to improve the function of the infarcted heart.


Relationship between lower limb muscle strength, self-reported pain and function, and frontal plane gait kinematics in knee osteoarthritis.
The relationship between muscle strength, gait biomechanics, and self-reported physical function and pain for patients with knee osteoarthritis is not well known. The objective of this study was to investigate these relationships in this population. Twenty-four patients with knee osteoarthritis and 24 healthy controls were recruited. Self-reported pain and function, lower-limb maximum isometric force, and frontal plane gait kinematics during treadmill walking were collected on all patients. Between-group differences were assessed for 1) muscle strength and 2) gait biomechanics. Linear regressions were computed within the knee osteoarthritis group to examine the effect of muscle strength on 1) self-reported pain and function, and 2) gait kinematics. Patients with knee osteoarthritis exhibited reduced hip external rotator, knee extensor, and ankle inversion muscle force output compared with healthy controls, as well as increased peak knee adduction angles (effect size=0.770; p=0.013). Hip abductor strength was a significant predictor of function, but not after controlling for covariates. Ankle inversion, hip abduction, and knee flexion strength were significant predictors of peak pelvic drop angle after controlling for covariates (34.4% unique variance explained). Patients with knee osteoarthritis exhibit deficits in muscle strength and while they play an important role in the self-reported function of patients with knee osteoarthritis, the effect of covariates such as sex, age, mass, and height was more important in this relationship. Similar relationships were observed from gait variables, except for peak pelvic drop, where hip, knee, and ankle strength remained important predictors of this variable after controlling for covariates.


The identity of nematode genera involved in cases of ovine anthelmintic resistance in the southern North Island of New Zealand.
Larval cultures and faecal egg count reductions were used to determine the identities and frequencies of occurrence of nematode genera involved in cases of ovine anthelmintic resistance submitted to the Batchelar Animal Health Laboratory between 1992 and 1994. Based on an examination of 102 cases, it was found that, while there were some differences relating to the method of assessment, the genera most frequently involved were Trichostrongylus, Ostertagia and Nematodirus. Also implicated, although less commonly, were infections of Oesophagostomum/Chabertia, Haemonchus and Cooperia. The majority of cases involved resistance in two or more genera, with resistance in a single nematode genus occurring in 45% of cases. Most such monogeneric resistances comprised infections of Trichostrongylus (52%), Ostertagia (17%) or Nematodirus (11%). Anthelmintic resistance involving Haemonchus alone was found in only three cases. These results suggest that the potential role of narrow-spectrum drenches in the management and control of anthelmintic-resistant worms in New Zealand sheep is likely to be strictly limited.


Irradiation of the posterior ocular segment with the neodymium-YAG laser in its free-running mode.
A neodymium-YAG laser, operating in its free-running mode with pulse durations of 10 to 20 ms, was used to treat 63 cases of choroidal and retinal diseases. These cases included diabetic background retinopathies, thrombosis of the central retinal vein or branch retinal vein, neovascular membranes under the pigment epithelium, and retinal breaks or degenerations of the peripheral retina. Because the number of diabetic retinopathies (24) and their average follow-up time (25.5 months) are insufficient for the evaluation of irradiation effects, no definite statement as to the merits of this energy modality in such cases can be made. The irradiation of infarcted retina was followed by extensive atrophy of the involved area. No secondary glaucoma was observed during a follow-up period of 16.4 months. The irradiation in four cases of neovascular subretinal membranes was followed by disappearance of the membranes. However, relapse later occurred in all four cases. The irradiation of eight retinal breaks resulted in solid scar tissue. Two choroidal melanomas were destroyed and did not recur during a follow-up period of 22 months.


Topographical and cytopathological lesion analysis of the white matter in Binswanger's disease brains.
The purpose of the present study was to document the topographical and cytopathological lesions in the white matter (WM) of Binswanger's disease (BD) brains. Subcortical WM lesions in each lobe and fiber bundle lesions related to the medial thalamic and hippocampal structures in clinicopathologically proven BD brains were evaluated by Klüver-Barrera staining using a grading score. Lesions in the frontal subcortical WM of BD brains, brains from non-neurological patients, and brains with cerebral hemorrhage or large cortical infarcts were also examined immunohistochemically using molecular markers for axonal flow damage: amyloid precursor protein (APP); and for demyelinating axonopathy: encephalitogenic peptide (EP). Our results indicated that the WM lesions in BD were significantly more prominent in the frontal periventricular and subcortical regions as compared with other subcortical WM lesions, in the order of the parietal, occipital and temporal lobes. Fiber bundle lesions in the capsular genu, including the anterior thalamic peduncle, were also significantly more prominent in BD brains as compared with the other bundle lesions. Furthermore, the frequency of damaged nerve fibers labeled by the EP antiserum and APP immunoreactive fibers was significantly higher in BD brains as compared with the control brains. The grading scores for the WM damage correlated significantly with those for the APP and EP immunoreactive fibers in all brains, including the control brains. The axonal damage in the frontal WM lesions of the BD brains was clearly revealed in our study using immunohistochemistry for APP and EP.


Hidden costs associated with the universal application of risk management in maternity care.
This paper presents a critical analysis of risk management in maternity care and the hidden costs associated with the practice in healthy women. Issues of quality and safety are driving an increased emphasis by health services on risk management in maternity care. Medical risk in pregnancy is known to benefit 15% or less of all pregnancies. Risk management applied to the remaining 85% of healthy women results in the management of risk in the absence of risk. The health cost to mothers and babies and the economic burden on the overall health system of serious morbidity has been omitted from calculations comparing costs of uncomplicated caesarean birth and uncomplicated vaginal birth. The understanding that elective caesarean birth is cost-neutral when compared to a normal vaginal birth has misled practitioners and contributed to over use of the practice. For the purpose of informing the direction of maternity service policy it is necessary to expose the effect the overuse of medical intervention has on the overall capacity of the healthcare system to absorb the increasing demand for operating theatre resources in the absence of clinical need.


Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice.
ADAM22 is a member of the ADAM gene family, but the fact that it is expressed only in the nervous systems makes it unique. ADAM22's sequence similarity to other ADAMs suggests it to be an integrin binder and thus to have a role in cell-cell or cell-matrix interactions. To elucidate the physiological functions of ADAM22, we employed gene targeting to generate ADAM22 knockout mice. ADAM22-deficient mice were produced in a good accordance with the Mendelian ratio and appeared normal at birth. After one week, severe ataxia was observed, and all homozygotes died before weaning, probably due to convulsions. No major histological abnormalities were detected in the cerebral cortex or cerebellum of the homozygous mutants; however, marked hypomyelination of the peripheral nerves was observed. The results of our study demonstrate that ADAM22 is closely involved in the correct functioning of the nervous system. Further analysis of ADAM22 will provide clues to understanding the mechanisms of human diseases such as epileptic seizures and peripheral neuropathy.


Role of real-time polymerase chain reaction in diagnosing Hepatitis E, the commonest cause of acute hepatitis in adult patients seeking institutional care.
This cross-sectional study was performed with the aim of determining the prevalence of hepatitis E virus (HEV) infection among acute hepatitis patients attending a tertiary care teaching hospital in a developing country and to determine the relative performance of prevalent diagnostic assays in establishing its diagnosis. A total of 46 adult patients were included in this study, all of whom presented with jaundice of <4 weeks' duration and elevation of AST and ALT above 500 U/L. The prevalence of HEV among patients with acute hepatitis was calculated on the basis of the proportion of recruited patients reacting positively in serum anti-HEV immunoglobulin M (IgM) and real-time polymerase chain reaction (RT-PCR) assays. Among the recruited patients, 11 (23.91%) and 15 (32.6%) patients were positive for anti-HEV IgM and RT-PCR, respectively. The two tests demonstrated poor inter-test agreement, thereby implying the necessity of performing both tests for reliable diagnosis of acute HEV virus infection. We also observed a significant difference in the duration of illness between RT-PCR positive and negative patients (P = 0.008). The mean (±SD) duration of illness in the two groups was 8.6 (±3.50) and 11.66 (± 5.15) days, respectively. Combining the results of IgM ELISA and RT-PCR, we observed that 23 out of 46 patients (50%) had evidence of acute HEV virus infection among our patients. Our study suggests that HEV is the commonest cause of acute hepatitis in adult patients attending a tertiary care teaching hospital and that the diagnostic algorithm for its confirmation should include both IgM ELISA and RT-PCR assays.


Self-Assembled Multilayer Films for Time-Controlled Ocular Drug Delivery.
The patient's compliance on the therapeutics to treat glaucoma is significantly low contributing for a fast evolution of the disease. This article presents an autonomous system with controlled release using an alpha2-adrenergic receptor agonist, brimonidine, usually used to treat glaucoma. More specifically, biocompatible and layer-by-layer drug delivery films containing monolayers with brimonidine encapsulated in polymer-β-cyclodextrin were prepared with the objective to obtain a system able to release precise amounts of drug at specific times. To delay the erosion-controlled drug release, we included nanosheets of graphene oxide and layers of a biodegradable polymer (poly-β-aminoester) between the drug-containing monolayers to obtain a time-controlled drug delivery system. An increase in the number of graphene oxide layers is proportional to the brimonidine release delay and its kinetic release can be tuned as a function of the number of layers. Two types of films with brimonidine encapsulated in β-cyclodextrin were analyzed. One of them composed of barrier layers with PBAE and another with two types of barrier layers, PBAE and graphene oxide. The results indicate that one graphene oxide bilayer can delay the brimonidine release for more than 24 h. In vitro assays confirmed that the films have a cell viability of 100%.


Ontario chiropractors' knowledge, attitudes, and beliefs about intimate partner violence among their patients: a cross-sectional survey.
This study assessed chiropractors' attitudes, beliefs, knowledge, and experience about intimate partner violence (IPV) and identified if any differences exist between age groups, sex, and year of graduation of respondents. Five hundred five Ontario chiropractors were sampled from the Canadian Chiropractic Association membership using a randomization program. This study used a cross-sectional survey. The sample was mailed an introductory postcard and 3 subsequent Provider Surveys, demographic forms, and information letters depending on nonresponse. The data were analyzed using descriptive statistics, Kruskal-Wallis analyses of variance and Mann-Whitney U tests. A response rate of 61% was attained. Of the respondents, 88% reported that IPV was rare or very rare in their practice. Significant sex differences were identified. Female respondents were almost twice as likely to strongly disagree with victim-blaming statements and were almost twice as concerned for their safety as male chiropractors when broaching the topic with batterers. Older practitioners were significantly more likely to inquire about IPV depending on symptoms, blame victims, have less fear of offending victims, and have fewer safety concerns. Earlier graduates were significantly more likely to inquire about IPV depending on clinical presentation but were also more likely to blame victims. Ontario chiropractors have very little experience identifying IPV. Chiropractors would benefit from educational programs that would enable them to better identify and manage patients experiencing IPV. Sex, age, and experience were important modifiers in Ontario chiropractors' perceptions and behaviors regarding IPV among their patients.


Potential prognostic value of leptin receptor in hepatocellular carcinoma.
Obesity is associated with several human malignancies, including hepatocellular carcinoma (HCC). This association may result from the deregulated expression of adipokines. To explore the potential role and the prognostic value of leptin receptor (Ob-R) in HCC. 66 patients with pathologically confirmed HCC were included in this study. Immunohistochemistry was used to evaluate the expression of Ob-R, microvessel density (MVD) and Ki-67 index in these patients. Eventually, the profiles of Ob-R expression, obtained by a semiquantitative scoring system, were further correlated with Ki-67 expression, intratumour MVD, clinicopathological characteristics and overall survival. High Ob-R expression was seen in 53% of patients with HCC and was significantly correlated with intratumour MVD (high v low; 59.4 (3.2) v 44.7 (3.7); p = 0.004), but not with Ki-67 expression. In addition, Ob-R expression was inversely correlated with vascular invasion (p = 0.037), but not with other known clinicopathological characteristics. The Kaplan-Meier survival curve showed that high Ob-R expression was associated with a better overall survival (p = 0.027). Meanwhile, multivariate analysis showed that Ob-R expression was a significant determinant for HCC (odds ratio 0.02, 95% confidence interval 0.01 to 0.85; p = 0.041). Ob-R expression may have a potential role in the carcinogenesis of HCC. The positive association of Ob-R expression in the cancerous lesions of HCC with the survival outcome can be explained by its inverse correlation with vascular invasion, and may have prognostic value in HCC.


Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference.
The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.


Histopathologic correlates of radial stripes on MR images in lysosomal storage disorders.
Radially oriented hypointense stripes in hyperintense cerebral white matter are recognized on T2-weighted images of certain lysosomal storage disorders. We compared in vivo and postmortem MR imaging with histopathologic findings in three patients with metachromatic leukodystrophy (MLD), globoid cell leukodystrophy (GLD), and infantile GM1 gangliosidosis (GM1) to understand this characteristic MR imaging pattern. The in vivo MR imaging protocol comprised T1- and T2-weighted spin-echo and fluid-attenuated inversion recovery imaging. Postmortem MR imaging, including coronal 1-cm-thick brain sections, was performed after at least 5 weeks of formalin fixation and included T2-weighted spin-echo images and 3D fluid-attenuated inversion recovery images with high spatial resolution. Afterward, the sections were embedded in paraffin, whole-mount sections were made, and neuropathologic stains were applied. Similar imaging features were found in the three patients on in vivo and postmortem images, with more prominent stripes in GLD and MLD than in GM1. Neuropathologic examination revealed that the stripes were related to relative sparing of myelin in the perivenular regions in GM1 and MLD, but lipid-containing glial cells were also present in these areas in MLD. Perivenular clusters of globoid cells containing lipid material in absence of any myelin corresponded to the stripes in GLD. Results of our postmortem study showed that radial stripes of white matter on MR images represented relative myelin sparing in some lysosomal storage disorders, but they may also represent lipid storage.


Hydroperoxy-10,12-octadecadienoic acid stimulates cytochrome P450 3A protein aggregation by a mechanism that is inhibited by substrate.
We recently demonstrated that microsomes from nicardipine-treated rats will form cytochrome P450 3A (CYP3A) aggregates when incubated at 37 degrees C. CYP3A substrates inhibited the protein aggregation and subsequent degradation, suggesting that this process is important in substrate-mediated stabilization of CYP3A. In this paper, we demonstrate that oxidative stress is a key factor in the formation of CYP3A aggregates in incubated microsomes and in a reconstituted system with purified enzymes. Our data further suggest that the effects of oxidative stress are mediated by lipid hydroperoxides, which are efficiently metabolized by CYP3A. In the presence of substrate, the CYP3A-mediated lipid hydroperoxide metabolism is inhibited along with the associated protein aggregation. Therefore, these studies provide a mechanistic model of why CYP3A has a relatively short half-life and how substrates stabilize CYP3A.


Solution-Processable Core-Extended Quinacridone Derivatives with Intact Hydrogen Bonds.
A highly efficient and feasible "condensation followed by annulation" synthetic approach was developed to afford a subset of 9-ring-fused quinacridone derivatives on a 10 g scale. Despite the amenable intermolecular hydrogen-bonding ability of these rigid molecules, good solubility in common organic solvents and solution processability into uniformed thin films were achieved. Integrated advantages in the synthesis and properties make these compounds ideal building blocks for high-performance dyes and optoelectronic materials.


Computer-assisted orthognathic treatment planning.
Computers are being integrated into all aspects of the dental office. This article uses a patient study to demonstrate the capabilities of new software systems to aid the orthodontist and surgeon in orthognathic treatment planning.


Meat, Dietary Heme Iron, and Risk of Type 2 Diabetes Mellitus: The Singapore Chinese Health Study.
We evaluated the relationships of red meat, poultry, fish, and shellfish intakes, as well as heme iron intake, with the risk of type 2 diabetes mellitus (T2D).The Singapore Chinese Health Study is a population-based cohort study that recruited 63,257 Chinese adults aged 45-74 years from 1993 to 1998. Usual diet was evaluated using a validated 165-item semiquantitative food frequency questionnaire at recruitment. Physician-diagnosed T2D was self-reported during 2 follow-up interviews in 1999-2004 and 2006-2010. During a mean follow-up of 10.9 years, 5,207 incident cases of T2D were reported. When comparing persons in the highest intake quartiles with those in the lowest, the multivariate-adjusted hazard ratio for T2D was 1.23 (95% confidence interval (CI): 1.14, 1.33) for red meat intake (P for trend < 0.001), 1.15 (95% CI: 1.06, 1.24) for poultry intake (P for trend = 0.004), and 1.07 (95% CI: 0.99, 1.16) for fish/shellfish intake (P for trend = 0.12). After additional adjustment for heme iron, only red meat intake remained significantly associated with T2D risk (multivariate-adjusted hazard ratio = 1.13, 95% CI: 1.01, 1.25; P for trend = 0.02). Heme iron was associated with a higher risk of T2D even after additional adjustment for red meat intake (multivariate-adjusted hazard ratio = 1.14, 95% CI: 1.02, 1.28; P for trend = 0.03). In conclusion, red meat and poultry intakes were associated with a higher risk of T2D. These associations were mediated completely for poultry and partially for red meat by heme iron intake.


Knowledge, attitudes and behaviors on antimicrobial resistance among general public across 14 member states in the WHO European region: results from a cross-sectional survey.
Antimicrobial resistance (AMR) is a major global public health threat requiring urgent action. Pan-European data on knowledge, attitudes and behaviors among the general public regarding antibiotic use and AMR is limited. A multicentric, cross-sectional survey of the general public was conducted in the capital cities of 14 Member States of the WHO European Region. A validated questionnaire from the AMR Eurobarometer survey was used to collect data on antibiotic use and knowledge, access to antibiotics, and understanding of policy responses through face-to-face exit interviews. Out of 8,221 respondents from 14 Member States, 50% took antibiotics in the past 12 months and the majority (53%) obtained their most recent course from a medical practitioner. The most reported reasons for taking antibiotics orally in the past 12 months were cold (24%), sore throat (21%), cough (18%), and flu (16%). Overall, 84% of participants showed a lack of knowledge about appropriate antibiotic use. However, only 37% of respondents reported receiving any information in the past year about the importance of avoiding unnecessary antibiotic use. Doctors were the most cited (50%) and most trusted (80%) source of information. Among respondents who experienced COVID-19, 28% took antibiotics with a prescription, while 8% took antibiotics without a prescription. This study highlights the urgent need for targeted awareness campaigns and educational initiatives to address knowledge gaps and promote responsible antibiotic use. The findings emphasize the role of the general population in combating AMR. The data serve as baseline information for future evaluations and interventions in the Region.


DISCO: distance and spectrum correlation optimization alignment for two-dimensional gas chromatography time-of-flight mass spectrometry-based metabolomics.
A novel peak alignment algorithm using a distance and spectrum correlation optimization (DISCO) method has been developed for two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC/TOF-MS)-based metabolomics. This algorithm uses the output of the instrument control software, ChromaTOF, as its input data. It detects and merges multiple peak entries of the same metabolite into one peak entry in each input peak list. After a z-score transformation of metabolite retention times, DISCO selects landmark peaks from all samples based on both two-dimensional retention times and mass spectrum similarity of fragment ions measured by Pearson's correlation coefficient. A local linear fitting method is employed in the original two-dimensional retention time space to correct retention time shifts. A progressive retention time map searching method is used to align metabolite peaks in all samples together based on optimization of the Euclidean distance and mass spectrum similarity. The effectiveness of the DISCO algorithm is demonstrated using data sets acquired under different experiment conditions and a spiked-in experiment.


Effectiveness of exercise interventions on urinary incontinence and pelvic organ prolapse in pregnant and postpartum women: umbrella review and clinical guideline development.
Dysfunction related to pelvic floor muscles (PFM) is common among pregnant and postpartum women and can cause symptoms such as urinary incontinence or pelvic organ prolapse (POP). As part of developing a nationwide clinical practice guideline for nursing in Finland, the aim of this umbrella review is to summarize the existing evidence about the effectiveness of exercise interventions on urinary incontinence and POP in pregnant and postpartum women. To promote knowledge translation, recommendations for health care professionals are presented. We conducted an umbrella review to summarize the existing evidence. The JBI methodology for umbrella reviews was used to guide the review. The level of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, and recommendations based on the evidence were formulated by a clinical guideline working group. Altogether, 9 systematic reviews, reporting findings from 89 original studies, were included. The methodological quality of the reviews was evaluated using JBI's checklist. The highest level of evidence was found for preventing the symptoms of postpartum urinary incontinence through exercise and pelvic floor muscle training (PFMT) during pregnancy. Moderate-level evidence showed that exercise and PFMT are likely to reduce the symptoms and severity of urinary incontinence, but the level of evidence was low on PFMT reducing the symptoms of POP. We recommend encouraging and guiding pregnant and postpartum women to exercise and train PFM. We also recommend identifying pregnant and postpartum women with symptoms of PFM dysfunction and directing them to a physiotherapist or other health care professional specializing in pelvic floor function.


Rivaroxaban for the prevention and treatment of venous thromboembolism.
Venous thromboembolism (VTE) is a common and often life-threatening cardiovascular disorder. Patients undergoing total hip replacement or total knee replacement surgery are at increased risk of VTE. In this setting, clinical practice guidelines recommend the use of low molecular weight heparins, vitamin K antagonists or fondaparinux for the prevention of VTE. However, the use of these anticoagulants is beset by practical difficulties that reduce compliance to therapy and adherence to recommended guidelines. New oral anticoagulants (OACs) that are administered in fixed doses without the need for monitoring are now being introduced to clinical practice. Rivaroxaban, dabigatran and apixaban are either approved or in advanced stages of clinical development for the prevention and/or treatment of VTE. This article provides an overview of the phase III clinical development programmes for these novel OACs, with special focus on rivaroxaban. With encouraging data already emerging, the promise of a simplified single-drug approach for VTE treatment is on the horizon.


Relative binding affinities of chlorophylls in peridinin-chlorophyll-protein reconstituted with heterochlorophyllous mixtures.
Peridinin-chlorophyll-protein (PCP), containing differently absorbing chlorophyll derivatives, are good models with which to study energy transfer among monomeric chlorophylls (Chls) by both bulk and single-molecule spectroscopy. They can be obtained by reconstituting the N-terminal domain of the protein (N-PCP) with peridinin and chlorophyll mixtures. Upon dimerization of these "half-mers", homo- and heterochlorophyllous complexes are generated, that correspond structurally to monomeric protomers of native PCP from Amphidinium carterae. Heterochlorophyllous complexes contain two different Chls in the two halves of the complete structure. Here, we report reconstitution of N-PCP with binary mixtures of Chl a, Chl b, and [3-acetyl]-Chl a. The ratios of the pigments were varied in the reconstitution mixture, and relative binding constants were determined from quantification of these pigments in the reconstituted PCPs. We find higher affinities for both Chl b and [3-acetyl]-Chl a than for the native pigment, Chl a.


Diffusion MRI: a new strategy for assessment of cancer therapeutic efficacy.
The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator or treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a nonvolumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.


Early and long-term results of the surgical treatment of tetralogy of Fallot with pulmonary atresia, with or without major aortopulmonary collateral arteries.
We sought to determine the results of surgical treatment of patients with tetralogy of Fallot and pulmonary atresia with or without major aortopulmonary collateral arteries, to clarify variables affecting early and late mortality, and to expose late, nonfatal events affecting surgical patients. The records of 495 patients operated on from 1977 to 1999 were reviewed. Patients were separated into those who did not undergo complete repair (group A) and those who did (group B). Group A consisted of 160 patients. Eighty-one (51%) had palliative procedures, 45 (28%) had preliminary surgical stages (unifocalization and right ventricular outflow tract reconstruction) as initial operations, and 34 (21%) had all surgical stages but were rejected for complete repair. Early and late mortality were 16.3% (n = 26) and 23.1% (n = 31), respectively. Mean follow-up was 72.3 months. The presence of major aortopulmonary collateral arteries was a risk factor for late mortality (P =.0182). Group B consisted of 335 patients. Mean age at complete repair was 11.3 years (SD, 9.2). One hundred three (30%) patients had single-stage complete repair, whereas 232 (69%) had staged reconstruction. Twenty-two (6.6%) patients underwent reopening of the ventricular septal defect for high right ventricular pressure. Early and late mortality were 4.5% (n = 15). Risk factors were a peak right ventricular/left ventricular pressure ratio of greater than 0.7 and reopening of the ventricular septal defect (P < or = .05). Late mortality was 16% (n = 51). Mean follow-up was 11.4 years (SD, 7.5). Risk factors included male sex, nonconfluent central pulmonary arteries, reopening of the ventricular septal defect, and postrepair conduit exchange (n = 137). Ten- and 20-year results were an actuarial survival of 86% and 75% and freedom from reoperation of 55% and 29%, respectively. Surgical repair of patients with simple or complex forms of tetralogy of Fallot with pulmonary atresia can be achieved with low early mortality. Late mortality and need for reoperation, especially conduit replacement, continue to affect the long-term well-being of these patients.


[Diagnosis and therapy of extrauterine pregnancy].
The combined use of transvaginal ultrasound and serial quantitative determination of the serum human chorionic gonadotropin (HCG) concentration offers an early and exact diagnosis of an ectopic pregnancy before the onset of clinical symptoms. Therefore, a large variety of invasive and noninvasive treatment options can be chosen. In patients without severe clinical symptoms, the trophoblast activity should be determined via the HCG course before invasive treatment methods are performed, because a considerable proportion part of the patients show spontaneous resolution of the ectopic pregnancy without further measures. Recently systemic treatment with methotrexate alone or local injection of different substances like prostaglandins, glucose, and methotrexate, etc. became an alternative to surgical therapy, i.e., endoscopic salpingotomy or salpingectomy. The success rates are generally lower in comparison to surgical therapy. Therefore, medical treatment is useful only in patients with a low trophoblast activity (e.g., < 2,500 mIU/ml HCG). However, in cases with low HCG values, observation alone frequently leads to a resolution. Corresponding to the data being available up to now, the postoperative pregnancy rate does not depend on this decision.


Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial.
The primary objective of this phase 3 study was to determine whether postconsolidation immunotherapy with interleukin-2 (IL-2) and histamine dihydrochloride (HDC) improved the leukemia-free survival (LFS) of adult patients with acute myeloid leukemia (AML) in complete remission (CR). Three hundred twenty patients with AML (median age, 57 years; range, 18-84 years) were stratified by CR1 or subsequent CR (CR > 1) and randomly assigned to treatment with HDC/IL-2 or no treatment (control). Treatment comprised 10 21-day cycles with IL-2 (16 400 U/kg) plus HDC (0.5 mg); both compounds were administered by subcutaneous injection twice daily. Study arms were balanced for age, sex, previous treatment, leukemic karyotypes, time from CR to inclusion, and frequency of secondary leukemia. Three years after enrollment of the last patient, treatment with HDC/IL-2 was found to improve LFS over control in the study population (CR1 + CR > 1, n = 320; P < .01, log-rank test). For patients in CR1 (n = 261), treatment significantly improved LFS (P = .01) with 3-year LFS estimates of 40% (HDC/IL-2) compared with 26% (control). Side effects were typically mild to moderate. These results indicate that HDC/IL-2 treatment offers an efficacious and tolerable treatment for patients with AML in remission.


Early steps in thermal unfolding of superoxide dismutase 1 are similar to the conformational changes associated with the ALS-associated A4V mutation.
There are over 100 mutations in Cu/Zn superoxide dismutase (SOD1) that result in a subset of familial amyotrophic lateral sclerosis (fALS) cases. The hypothesis that dissociation of the dimer, misfolding of the monomer and subsequent aggregation of mutant SOD1 leads to fALS has been gaining support as an explanation for how these disparate missense mutations cause the same disease. These forms are only responsible for a fraction of the ALS cases; however, the rest are sporadic. Starting with a folded apo monomer, the species considered most likely to be involved in misfolding, we used high-temperature all-atom molecular dynamics simulations to explore the events of the wild-type protein unfolding through the denatured state. All simulations showed early loss of structure along the β5-β6 edge of the β-sandwich, supporting earlier findings of instability in this region. Transition state structures identified from the simulations are in good agreement with experiment, providing detailed, validated molecular models for this elusive state. Furthermore, we compare the process of thermal unfolding investigated here to that of the lethal A4V mutant-induced unfolding at physiological temperature and find that the pathways are very similar.


Chemical constituents of gentianaceae XIV: tetraoxygenated and pentaoxygenated xanthones of Swertia purpurascens Wall.
The whole plant of Swertia purpurascens Wall. (Gentianaceae) has been shown to contain five tetraoxygenated and three pentaoxygenated zanthones. These are identified as 1,5,8-trihydroxy-3-methoxyxanthone, 1,3,8-trihydroxy-5-methoxyzanthone, 1-hydroxy-3,7,8-trimethoxyxanthone, 1,3,7,8-tetrahydroxyxanthone, 1,3,5,8-tetrahydroxyxanthone, and 1-hydroxy-3,4,7,8-tetramethoxyxanthone by chemical and spectral evidence. Additionally, the crude mixture of natural xanthones has been shown to include two partially emthylated pentaoxygenated xanthones as minor entities, which yield 1-hydroxy-3,4,7,8-tetramethoxyxanthone and 1-hydroxy-3,4,5,8-tetramethoxyxanthone on methylation. This is the first time that pentaoxygenated xanthones have been found in a member of the genus Swertia. 1-Hydroxy-3,4,7,8-tetramethoxyxanthone was previously known only as a synthetic compound. The total xanthones of S. purpurascens produce significant CNS stimulant actions, consistent with some therapeutic uses of the plant extract in the Indian system of medicine. The chemotaxonomic significance of the cooccurrence of various biogenetically related chemical characters in a single plant species is appraised.


St Gallen molecular subtypes in primary breast cancer and matched lymph node metastases--aspects on distribution and prognosis for patients with luminal A tumours: results from a prospective randomised trial.
The St Gallen surrogate molecular subtype definitions classify the oestrogen (ER) positive breast cancer into the luminal A and luminal B subtypes according to proliferation rate and/or expression of human epidermal growth factor receptor 2 (HER2) with differences in prognosis and chemo-responsiveness. Primary tumours and lymph node metastases might represent different malignant clones, but in the clinical setting only the biomarker profile of the primary tumour is used for selection of adjuvant systemic treatment. The present study aimed to classify primary breast tumours and matched lymph node metastases into luminal A, luminal B, HER2-positive and triple-negative subtypes and compare the distributions. Eighty-five patients with available tumour tissue from both locations were classified. The distribution of molecular subtypes in primary tumours and corresponding lymph node metastases were compared, and related to 5-year distant disease-free survival (DDFS). The St Gallen molecular subtypes were discordant between primary tumours and matched lymph node metastases in 11% of the patients (p = 0.06). The luminal A subtype in the primary tumour shifted to a subtype with a worse prognostic profile in the lymph node metastases in 7 of 45 cases (16%) whereas no shift in the opposite direction was observed (0/38) (p = 0.02). All subtypes had an increased hazard for developing distant metastasis during the first 5 years after diagnosis in both primary breast tumours and matched lymph node metastases, compared with the luminal A subtype. The classification according to the St Gallen molecular subtypes in primary tumours and matched lymph node metastases, implicates a shift to a more aggressive subtype in synchronous lymph node metastases compared to the primary breast tumour. The selection of systemic adjuvant therapy might benefit from taking the molecular subtypes in the metastatic node into account.