Deformation behaviour of aged coronal dentin.
This study aimed to identify the changes in the time-dependent deformation response of coronal dentin with ageing and its relationship with changes in chemical composition. The structural behaviour of dentin with ageing is affected by changes in the density and diameter of its dentinal tubules (ie porosity), as well as changes in chemical composition throughout the tooth. However, little is known about the time-dependent deformation behaviour of aged dentin and the importance of its hierarchical structure and variations in chemical composition. The spherical indentation response of aged coronal dentin was analysed in the outer, middle and inner regions, and its time-dependent deformation response was modelled in terms of its microstructure and chemical composition using a model recently proposed for young dentin. The viscous deformation behaviour of aged dentin followed a power-law response with a decrease in the stress exponent when compared to young dentin. These results can be explained by cross-linking of the collagen present in the tissue. A decrease in the deformation ability of aged dentin was found. This behaviour could be a result of a dissolution process and reprecipitation of the minerals present in intertubular dentin into the dentinal tubules.


Subcutaneous implantable cardioverter defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy: Results from an Italian multicenter registry.
Despite expanding indication of the subcutaneous implantable cardioverter defibrillator (S-ICD) in clinical practice, limited data exists on safety and efficacy of S-ICD in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. The aim of this multicenter study was to evaluate the safety and efficacy of S-ICD in ARVC patients. The study population included 44 consecutive patients with definite ARVC diagnosis according to the 2010 ITF criteria (57% male, mean age 37 ± 17 years [range 10-75 years]) who received an S-ICD. Eighteen (41%) patients were implanted for secondary prevention. At implant, all inducible patients (34/44) had conversion of ventricular fibrillation at 65 J. No early complications occurred. During a median follow-up of 12 months (7-19), 3 (6.8%) patients experienced complications requiring surgical revision. No local or systemic device-related infections were observed. Six patients (14%) received a total of 61 appropriate and successful shocks on ventricular arrhythmias. Six (14%) patients experienced 8 inappropriate shocks for oversensing of cardiac signal (4 cases) and non-cardiac signal (4 cases) with one patient requiring device explantation. No patients had the device explanted due to the need for antitachycardia pacing. The study shows that S-ICD provides safe and effective therapy for termination of both induced and spontaneous malignant ventricular tachyarrhythmias with high energy shocks in ARVC patients, but the risk of inappropriate shocks and complications needing surgical revision should be considered.


Compatibility of cyclopoid copepods with mosquito insecticides.
Larvivorous copepods (Macrocyclops, Mesocyclops and Acanthocyclops) were tested for their sensitivities to commonly used mosquito larvicides and adulticides. The cyclopoids were not harmed by Bacillus thuringiensis (H-14) (B.t.i.) or larviciding oil. Control of mosquito larvae in field trials was accelerated by applying B.t.i. at the same time cyclopoids were introduced to a breeding site. Among adulticides tested, the cyclopoids were least sensitive to permethrin. Field trials demonstrated that permethrin does not harm cyclopoids when applied at label specifications.


Percutaneous balloon valvuloplasty for severe mitral stenosis in pregnancy. Four case reports.
Four pregnant women with mitral stenosis who did not respond to medical therapy underwent successful percutaneous balloon valvuloplasty with complete resolution of their symptoms. Their clinical features and echocardial and hemodynamic data are presented. The procedures and the remainder of their pregnancy were uncomplicated. Percutaneous balloon valvuloplasty of the mitral valve is a safe and effective alternative to surgical therapy if medical management is unsuccessful.


Responses of B cells with or without C3 receptors to polyclonal B cell activators.
Responses of B cells with or without receptors for C3 (CR) to polyclonal B cell activators (PBA) were studied. Mouse spleen cells were incubated with sheep red blood cells (SRBC) coated with antibody and complement to form rosettes, and they were separated by Ficoll-Hypaque density sedimentation into populations depleted of and enriched with lymphocytes bearing CR (CRL). These 2 populations were cultured with lipopolysaccharide (LPS), purified protein derivative of tuberculin (PPD), or dextran sulfate (DxS) and assayed for anti-TNP PFC. The CRL-depleted population responded well to LPS, poorly to PPD, and it showed practically no response to DxS, whereas the CRL-enriched population seemed to respond poorly to LPS but well to both PPD and DxS. The low responsiveness of the cRL-depleted population to PPD and DxS could not be explained by a shift of time-kinetics, by the dose-response profile of the responding cells, or by the depletion of adherent cells. Suppressor T cells did not take part in the reduced responses, since the treatment of the population with anti-Thy 1.2 plus complement could not restore the responses. These results indicate that B cells with CR [CR(+) B cells] respond well both to PPD and DxS, whereas the cells without CR [CR(-) B cells] respond poorly to PPD and DxS. It was difficult to evaluate the low responsiveness of CR(+) B cells to LPS because of the high background PFC of the cRL-enriched population.


Neurologists' detection and recognition of mental disorder in a tertiary in-patient neurological unit.
Aims and method Psychiatric disorders are common in neurological in-patients, but they are under-recognised and undertreated. We investigated the frequency of detection of mental disorder and referral to psychiatric services in a regional neuroscience centre. The results were compared with the expected prevalence. All in-patient referrals received in 2014 from the in-patient wards of the regional neuroscience centre and acute neurological unit were reviewed. A total of 129 ward referrals were identified; of these, 78 were from the regional in-patient neurological unit, which comprised 11.4% of the total of 679 admissions to that unit. Clinical implications A spectrum of neuropsychiatric conditions were recognised by neurologists, but overall rates of recognition were low. To address the problem of under-recognition, routine screening with validated assessment tools can represent a cost-effective and acceptable method to detect psychiatric disorders in an in-patient neurological setting. Declaration of Interest None.


Long-term sterility of fat frozen for up to 24 months.
Fat transfer is most effective when fresh fat is used, with excess fat frozen and saved for touch-ups. The obvious benefit to using frozen fat is that harvesting does not have to be done each time fat is injected. It is important to be able to easily store the fat in a freezer and be confident that it will not harbor bacterial growth. We studied frozen fat from 10 patients after 12 months and 10 patients after 24 months for sterility. Cultures were negative for all specimens, showing that frozen fat is safe to use and should not cause infection.


A H258Y mutation in subunit B of the succinate dehydrogenase complex of the spider mite Tetranychus urticae confers resistance to cyenopyrafen and pyflubumide, but likely reinforces cyflumetofen binding and toxicity.
Succinate dehydrogenase (SDH) inhibitors such as cyflumetofen, cyenopyrafen and pyflubumide, are selective acaricides that control plant-feeding spider mite pests. Resistance development to SDH inhibitors has been investigated in a limited number of populations of the spider mite Tetranychus urticae and is associated with cytochrome P450 based detoxification and target-site mutations such as I260 T/V in subunit B and S56L in subunit C of SDH. Here, we report the discovery of a H258Y substitution in subunit B of SDH in a highly pyflubumide resistant population of T. urticae. As this highly conserved residue corresponds to one of the ubiquinone binding residues in fungi and bacteria, we hypothesized that H258Y could have a strong impact on SDH inhibitors toxicity. Marker assisted introgression and toxicity bioassays revealed that H258Y caused high cross resistance between cyenopyrafen and pyflubumide, but increased cyflumetofen toxicity. Resistance associated with H258Y was determined as dominant for cyenopyrafen, but recessive for pyflubumide. In vitro SDH assays with extracted H258 mitochondria showed that cyenopyrafen and the active metabolites of pyflubumide and cyflumetofen, interacted strongly with complex II. However, a clear shift in IC50s was observed for cyenopyrafen and the metabolite of pyflubumide when Y258 mitochondria were investigated. In contrast, the mutation slightly increased affinity of the cyflumetofen metabolite, likely explaining its increased toxicity for the mite lines carrying the substitution. Homology modeling and ligand docking further revealed that, although the three acaricides share a common binding motif in the Q-site of SDH, H258Y eliminated an important hydrogen bond required for cyenopyrafen and pyflubumide binding. In addition, the hydrogen bond between cyenopyrafen and Y117 in subunit D was also lost upon mutation. In contrast, cyflumetofen affinity was enhanced due to an additional hydrogen bond to W215 and hydrophobic interactions with the introduced Y258 in subunit B. Altogether, our findings not only highlight the importance of the highly conserved histidine residue in the binding of SDH inhibitors, but also reveal that a resistance mutation can provide both positive and negative cross-resistance within the same acaricide mode of action group.


[The use of multilocus sequence typing (MLST) and randomly amplified polymorphic DNA (RAPD) for the differentiation between strains of Burkholderia mallei].
Burkholderia mallei is highly pathogenic microorganism for both humans and animals. In this work, the possibility of the use of the genotyping method for differentiation between strains of B. mallei was studied. A collection of 14 isolates of B. mallei was characterized using randomly amplified polymorphic DNA (RAPD) and multilocus sequence typing (MLST). RAPD was the best method used for detecting strain differences of B. mallei. It was suggested that this method would be an increasingly useful molecular epidemiological tool.


Ultrafast charge transfer in a type-II MoS2-ReSe2 van der Waals heterostructure.
We fabricated a van der Waals heterostructure by stacking together monolayers of MoS2 and ReSe2. Transient absorption measurements were performed to study the dynamics of charge transfer, indirect exciton formation, and indirect exciton recombination. The results show that the heterostructure form a type-II band alignment with the conduction band minimum and valance band maximum located in the MoS2 and ReSe2 layers, respectively. By using different pump-probe configurations, we found that electrons could efficiently transfer from ReSe2 to MoS2 and holes along the opposite direction. Once transferred, the electrons and holes form spatially indirect excitons, which have longer recombination lifetimes than excitons in individual monolayers. These results provide useful information for developing van der Waals heterostructure involving ReSe2 for novel electronic and optoelectronic applications.


A new zygaenid moth species from Kangaroo Island, South Australia (Lepidoptera: Zygaenidae: Procridinae).
A new species of forester moths, Pollanisus hyacinthus sp. nov., is described from Kangaroo Island, South Australia. It is similar to Pollanisus isolatus Tarmann, 2004 and Pollanisus cyanota (Meyrick, 1886) but differs in several external characters and in the genitalia.


Applying FAIRness: Redesigning a Biomedical Informatics Research Data Management Pipeline.
Managing research data in biomedical informatics research requires solid data governance rules to guarantee sustainable operation, as it generally involves several professions and multiple sites. As every discipline involved in biomedical research applies its own set of tools and methods, research data as well as applied methods tend to branch out into numerous intermediate and output data objects, making it very difficult to reproduce research results. This article gives an overview of our implementation status applying the Findability, Accessibility, Interoperability and Reusability (FAIR) Guiding Principles for scientific data management and stewardship onto our research data management pipeline focusing on the software tools that are in use. We analyzed our progress FAIRificating the whole data management pipeline, from processing non-FAIR data up to data usage. We looked at software tools for data integration, data storage, and data usage as well as how the FAIR Guiding Principles helped to choose appropriate tools for each task. We were able to advance the degree of FAIRness of our data integration as well as data storage solutions, but lack enabling more FAIR Guiding Principles regarding Data Usage. Existing evaluation methods regarding the FAIR Guiding Principles (FAIRmetrics) were not applicable to our analysis of software tools. Using the FAIR Guiding Principles, we FAIRificated relevant parts of our research data management pipeline improving findability, accessibility, interoperability and reuse of datasets and research results. We aim to implement the FAIRmetrics to our data management infrastructure and-where required-to contribute to the FAIRmetrics for research data in the biomedical informatics domain as well as for software tools to achieve a higher degree of FAIRness of our research data management pipeline.


Structural competition involving G-quadruplex DNA and its complement.
Structural competition between the G-quadruplex, the I-motif, and the Watson-Crick duplex has been implicated for repetitive DNA sequences, but the competitive mechanism of these multistranded structures still needs to be elucidated. We investigated the effects of sequence context, cation species, and pH on duplex formation by the G-quadruplex of dG(3)(T(2)AG(3))(3) and its complement the I-motif of d(C(3)TA(2))(3)C(3), using ITC, DSC, PAGE, CD, UV, and CD stopped-flow kinetic techniques. ITC and PAGE experiments confirmed Watson-Crick duplex formation by the complementary strands. The binding constant of the two DNA strands in the presence of 10 mM Mg(2+) at pH 7.0 was shown to be 5.28 x 10(7) M(-1) at 20 degrees C, about 400 times larger than that in the presence of 100 mM Na(+) at pH 5.5. The dynamic transition traces of the duplex formation from the equimolar mixture of G-/C-rich complementary sequences were obtained at both pH 7.0 and pH 5.5. Fitting to a single-exponential function gave an observed rate of 8.06 x 10(-3) s(-1) at 20 degrees C in 10 mM Mg(2+) buffer at pH 7.0, which was about 10 times the observed rate at pH 5.5 under the same conditions. Both of the observed rates increased as temperature rose, implying that the dissociation of the single-stranded structured DNAs is the rate-limiting step for the WC duplex formation. The difference between the apparent activation energy at pH 7.0 and that at pH 5.5 reflects the fact that pH significantly influences the structural competition between the G-quadruplex, the I-motif, and the Watson-Crick duplex, which also implies a possible biological role for I-motifs in biological regulation.


Effects of gastrointestinal and related hormones on glycogenolysis and gluconeogenesis in cultured liver cells.
When isolated rat liver cells were incubated for 15 min in the presence of vasoactive intestinal peptide, secretin, gastrin, caerulein or glucagon at concentrations ranging from 0.2 microgram to 2 microgram per ml, glycogenolysis was stimulated. Among the gastrointestinal hormones or peptides tested, vasoactive intestinal peptide had the highest stimulatory activity. However, somatostatin was inhibitory for liver glycogenolysis. Combination experiments showed that somatostatin also inhibited the stimulatory effects of vasoactive intestinal peptide and secretin, but not that of glucagon, while glucagon and vasoactive intestinal peptide, or glucagon and secretin showed additive effects on glycogenolysis, but secretin and vasoactive intestinal peptide did not. The results suffest that the receptor site of glucagon is different from those of secretin and vasoactive intestinal peptide. Slight but significant stimulation of gluconeogenesis was also observed by vasoactive intestinal peptide and secretin. The evidence presented in this paper indicates that the so-called enterohepatic axis, in which a part of serum glucose levels is regulated directly by gastrointestinal hormones, exists and that the axis is inhibited by somatostatin.


Disorders of childhood growth and development: failure to thrive versus short stature.
Failure to thrive (FTT) describes retarded growth in height and weight, whereas short stature (SS) involves comparison of a child or adolescent's height to that of a reference group or to his or her own height across time. To identify either condition in infants, children, and adolescents, the family physician should focus on accurate measurement of length/height and weight as well as careful plotting and assessment of the rate of linear growth and weight gain based on World Health Organization standards (from birth to 2 years) and Centers for Disease Control and Prevention charts (from age 2 years). Identification of the etiologies of FTT and SS is complex, requiring consideration of such factors as birth weight, prematurity, and familial height. FTT can result from inadequate caloric intake (eg, caused by difficulties with nursing, limited food availability, or incorrect formula preparation), inadequate caloric absorption (eg, resulting from metabolic, gastrointestinal, or other medical conditions), or excessive caloric expenditure/ineffective utilization (eg, due to hyperthyroidism, diabetes, pulmonary or cardiac conditions). Short stature can be due to a primary growth disorder, such as bone disease or chromosomal syndrome; a secondary factor, such as a chronic medical or endocrine disorder; or an undetermined etiology. The management of FTT and SS requires attention to a combination of medical and behavioral/social issues (eg, treating underlying conditions, assisting with the feeding process, addressing stress and social functioning), and often requires a multidisciplinary approach.


Convergent Synthesis of Dronedarone, an Antiarrhythmic Agent.
We have developed a convergent synthesis of dronedarone, an antiarrhythmic agent. The key steps of the process are the construction of a benzofuran skeleton by iodocyclization and the carbonylative Suzuki-Miyaura cross-coupling for biaryl ketone formation. This synthetic route required only eight steps from 2-amino-4-nitrophenol in 23% overall yield.


Analysis of CTNS gene transcripts in nephropathic cystinosis.
Nephropathic cystinosis (NC) is an autosomal recessive disorder caused by mutations of the CTNS gene that encodes for a cystine transmembrane transporter. Several mutations have been described in the coding and promoter regions of the CTNS gene in affected individuals. We selected three patients with NC from two unrelated families, in whom sequence analysis of the CTNS gene detected only one or no mutations. Total RNA was isolated from peripheral blood mononuclear cells or fibroblasts and CTNS transcripts were analyzed. We observed a skipping of exon 5 (85 bp) in two siblings and an intron 9 retention of 75 bp associated with partial replication of exon 9 in the third patient. Genomic DNA analysis of intron regions surrounding exon 5 showed a point mutation in the hypothetical lariat branch site of intron 4 at position -24 (c.141-24 T > C) in the first two patients and a duplication of 266 bp including a part of exon and intron 9 in the third patient. Analysis of CTNS gene transcripts allowed identification of mutations in patients in whom CTNS mutations could not be detected by traditional DNA sequencing. These results support the hypothesis that cystinosis is a monogenic disorder.


Autoantigen-independent deletion of diabetogenic CD4+ thymocytes by protective MHC class II molecules.
Some MHC class II genes provide dominant resistance to certain autoimmune diseases via mechanisms that remain unclear. We have shown that thymocytes bearing a highly diabetogenic, I-Ag7-restricted beta-cell-reactive TCR (4.1-TCR) undergo negative selection in diabetes-resistant H-2g7/x mice by engaging several different antidiabetogenic MHC class II molecules on thymic (but not peripheral) hemopoietic cells, independently of endogenous superantigens. Here we have investigated 1) whether this TCR can also engage protective MHC class II molecules (I-Ab) on cortical thymic epithelial cells in the absence of diabetogenic (I-Ag7) molecules, and 2) whether deletion of 4.1-CD4+ thymocytes in I-Ab-expressing mice might result from the ability of I-Ab molecules to present the target beta-cell autoantigen of the 4.1-TCR. We show that, unlike I-Ag7 molecules, I-Ab molecules can restrict neither the positive selection of 4.1-CD4+ thymocytes in the thymic cortex nor the presentation of their target autoantigen in the periphery. Deletion of 4.1-CD4+ thymocytes by I-Ab molecules in the thymic medulla, however, is a peptide-specific process, since it can be triggered by hemopoietic cells expressing heterogeneous peptide/I-Ab complexes, but not by hemopoietic cells expressing single peptide/I-Ab complexes. Thus, unlike MHC-autoreactive or alloreactive TCRs, which can engage deleting MHC molecules in the thymic cortex, thymic medulla, and peripheral APCs, the 4.1-TCR can only engage deleting MHC molecules (I-Ab) in the thymic medulla. We therefore conclude that this form of MHC-induced protection from diabetes is based on the presentation of an anatomically restricted, nonautoantigenic peptide to highly diabetogenic thymocytes.


Inflammatory bowel disease in childhood--treatment and follow up.
This study is based on 150 patients whose first symptoms of inflammatory bowel disease (IBD) appeared before puberty between 1955 and 1979. Recurrence of disease after improvement on medical treatment occurred within a shorter time in Crohn's disease than in ulcerative colitis. In this series it was twice as probable for surgery to be required within the first five years of illness for a child with Crohn's disease than for a child with ulcerative colitis. Median relapse time after medical treatment was 11 months for ulcerative colitis and 15 months for Crohn's disease, and the median relapse time after surgical treatment (including "incomplete" procedures) was over seven years for ulcerative colitis and just under five years for Crohn's disease. In ulcerative colitis it is suggested that earlier surgery might save the patient a period of distressing symptoms and reduce the risk of recurrence.


The Role of Pre-therapeutic 18F-FDG PET/CT in Pediatric Hemophagocytic Lymphohistiocytosis With Epstein-Barr Virus Infection.
To evaluate the role of pre-therapeutic 18F-FDG PET/CT in pediatric hemophagocytic lymphohistiocytosis (HLH) with Epstein-Barr virus (EBV) infection. This retrospective study included 29 HLH children (1-16 years) with EBV infection, who underwent pre-therapeutic 18F-FDG PET/CT from July 2018 to November 2020. Pathology results were considered as the reference standard. These patients were divided into two groups: EBV-induced malignancy-associated HLH (M-HLH, N = 9) and EBV-induced non-malignancy-associated HLH (NM-HLH, N = 20). The regions of interest (ROIs) of the liver, spleen (Sp), bone marrow (BM), lymph nodes (LN), hypermetabolic lesions, liver background (LiBG), and mediastinum (M) were drawn with software 3D-Slicer. The volumetric and metabolic parameters, including maximum standard uptake value (SUVmax), metabolic tumor volume, and total lesion glycolysis of these ROIs, clinical parameters, and laboratory parameters were compared between the two groups. The efficiency of the above parameters in predicting the treatment response and overall survival (OS) was analyzed. Receiver operating characteristic curve analysis indicated that SUVmax-lesions and SUVmax-LN/M (AUC = 0.822, 0.819, cut-off = 6.04, 5.74, respectively) performed better in differentiating M-HLH from NM-HLH. It had the best diagnostic performance when age was added with the SUVmax-LN/M (AUC = 0.933, sensitivity = 100%, specificity = 85.0%). The presence of extranodal hypermetabolic lesions in multiple organs indicated the M-HLH (P = 0.022). Older age, higher SUVmax-LN and SUVmax-lesions, and the presence of serous effusion were associated with poorer treatment response at the 2nd and 4th week (not reaching partial remission). Multivariate analysis showed that SUVmax-lesions > 7.66 and SUVmax-Sp/LiBG > 2.01 were independent prognostic factors for overall survival (P = 0.025, 0.036, respectively). 18F-FDG PET/CT could be a valuable technique for identifying the underlying malignancy and predicting prognosis in pediatric HLH with EBV infection. M-HLH could be considered when SUVmax-lesions > 6.04, SUVmax-LN/M > 5.74, and the presence of extranodal hypermetabolic lesions in multiple organs on 18F-FDG PET/CT. SUVmax-lesions and SUVmax-Sp/LiBG might be independent prognostic factors for OS.


A new triterpenoid from the fruits of Gardenia jasminoides var. radicans Makino.
A novel triterpenoid 3α,16β,23,24-tetrahydroxy-28-nor-ursane-12,17,19,21-tetraen (1) was isolated from the fruits of Gardenia jasminoides var. radicans Makino. The structure of the new compounds was elucidated on the basis of spectroscopic analysis including MS and NMR data. Compound 1 was in vitro tested for cytostatic activity on human throat cancer (Hep-2) cell line by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide method and showed mild anticancer activity with the IC50 of 31.2 μM.


In chicken leukemia cells globin genes are fully transcribed but their rnas are retained in the perinucleolar area.
Using hybridization in situ with a ribo-probe recognizing transcripts of the chicken alpha A globin gene, we show here that in proliferating AEV-transformed erythroblasts this gene is strongly transcribed, but the corresponding transcripts are retained in the nuclei. Most surprisingly, this globin RNA accumulates in the perinucleolar areas in a pattern never observed before. Upon induction of cells to differentiate, leading to productive expression of the hemoglobins, the transcripts of the alpha A globin gene were found for the most part in the cytoplasm. In the nuclei of differentiated cells, the globin RNA is concentrated in one or two specific spots, which are likely to represent the "processing centers" (PCs) of the globin RNA. The results presented indicate that posttranscriptional steps of regulation involving in particular the perinuclear areas are of major importance for erythroid differentiation.


Hybridization, recombination, and the genetic basis of fitness variation across environments in Avena barbata.
We created Recombinant Inbred Lines (RILs) derived from a cross between ecotypes of Avena barbata associated with moist (mesic) and dry (xeric) habitats in California. Traits which were correlated with fitness across RILs mapped to the same Quantitative Trait Loci (QTLs) as fitness. However, different QTL affected fitness in different environments so that fitness was weakly correlated across environments. Recombination released considerable heritable variation both in fitness, and in ecologically relevant traits. Many traits showed transgressive segregation caused by recombination of QTL associated in repulsion phase in the parents. In addition, some traits were uncorrelated, allowing novel combinations of those traits to be created. Recombination also created heritable variation in reaction norms for at least one trait (root allocation). Altogether these results suggest that recombination can combine the most selectively advantageous genes and traits of the parents to produce broadly adapted genotypes that are capable of outperforming the parents. Indeed, two of the RILs showed higher fitness than the parental ecotypes across a range of environmental treatments in the greenhouse, but their superiority was less pronounced in the field. Although late-generation recombinants exhibited hybrid breakdown, being less fit, on average, than the mid-parent, early generation hybrids appear to exhibit hybrid vigour through the expression of dominance effects in the heterozyotes. This vigour may offset the effects of hybrid breakdown in the early generations following a cross, enhancing the opportunity for recombination to create broadly adapted genotypes. We discuss the implications of these findings to the evolution of colonizing species.


Physical Activity Recognition Using Posterior-Adapted Class-Based Fusion of Multiaccelerometer Data.
This paper proposes the use of posterior-adapted class-based weighted decision fusion to effectively combine multiple accelerometer data for improving physical activity recognition. The cutting-edge performance of this method is benchmarked against model-based weighted fusion and class-based weighted fusion without posterior adaptation, based on two publicly available datasets, namely PAMAP2 and MHEALTH. Experimental results show that: 1) posterior-adapted class-based weighted fusion outperformed model-based and class-based weighted fusion; 2) decision fusion with two accelerometers showed statistically significant improvement in average performance compared to the use of a single accelerometer; 3) generally, decision fusion from three accelerometers did not show further improvement from the best combination of two accelerometers; and 4) a combination of ankle and wrist located accelerometers showed the best overall performance compared to any combination of two or three accelerometers.


VDAC1 functions in Ca2+ homeostasis and cell life and death in health and disease.
In the outer mitochondrial membrane (OMM), the voltage-dependent anion channel 1 (VDAC1) serves as a mitochondrial gatekeeper, controlling the metabolic and energy cross-talk between mitochondria and the rest of the cell. VDAC1 also functions in cellular Ca2+ homeostasis by transporting Ca2+ in and out of mitochondria. VDAC1 has also been recognized as a key protein in mitochondria-mediated apoptosis, contributing to the release of apoptotic proteins located in the inter-membranal space (IMS) and regulating apoptosis via association with pro- and anti-apoptotic members of the Bcl-2 family of proteins and hexokinase. VDAC1 is highly Ca2+-permeable, transporting Ca2+ to the IMS and thus modulating Ca2+ access to Ca2+ transporters in the inner mitochondrial membrane. Intra-mitochondrial Ca2+ controls energy metabolism via modulating critical enzymes in the tricarboxylic acid cycle and in fatty acid oxidation. Ca2+ also determines cell sensitivity to apoptotic stimuli and promotes the release of pro-apoptotic proteins. However, the precise mechanism by which intracellular Ca2+ mediates apoptosis is not known. Here, the roles of VDAC1 in mitochondrial Ca2+ homeostasis are presented while emphasizing a new proposed mechanism for the mode of action of pro-apoptotic drugs. This view, proposing that Ca2+-dependent enhancement of VDAC1 expression levels is a major mechanism by which apoptotic stimuli induce apoptosis, position VDAC1 oligomerization at a molecular focal point in apoptosis regulation. The interactions of VDAC1 with many proteins involved in Ca2+ homeostasis or regulated by Ca2+, as well as VDAC-mediated control of cell life and death and the association of VDAC with disease, are also presented.


A study of cardiac effects of thyroid hormones: evidence for amelioration of the effects of thyroxine by sodium ipodate.
We studied the effects of daily ip administration of T4 (200 micrograms/100 g BW) or T3 (50 micrograms/100 g) to the rat (six per group) for 3 days with or without sodium ipodate (6 mg/100 g), propylthiouracil (PTU; 2 mg/100 g), propranolol (0.5 mg/100 g), or amiodarone (2.5 mg/100 g) on cardiac weight, 3',5'-diiodothyronine (3',5'-T2) to 3'-monoiodothyronine monodeiodinating activity (MA), mitochondrial alpha-glycerophosphate dehydrogenase (alpha GPD), and/or cytosolic ornithine decarboxylase (ODC). T4 treatment caused a 28% increase in cardiac weight, about an 11-fold increase in 3',5'-T2 MA, about a 27% increase in alpha GPD activity, and about a 129% increase in ODC activity. Administration of ipodate with T4 abolished all effects of T4 on the heart. PTU abolished the effect of T4 on alpha GPD and markedly reduced its effect on 3',5'-T2 MA and ODC activity; it had little effect on cardiac hypertrophy caused by T4 treatment. Propranolol reduced the increase in cardiac weight following T4 administration from 28% to 11%, but had a modest or no effect on T4-induced changes in other metabolic variables studied. Amiodarone also reduced the effect of T4 on heart weight, but had little or no influence on 3',5'-T2 MA, the only metabolic variable studied. T3 treatment of the rat caused a 35% increase in heart weight, about a 15-fold increase in 3',5'-T2 MA, about a 35% increase in alpha GPD, and about a 100% increase in ODC activity. Ipodate and PTU reduced the increase in 3',5'-T2 MA following T3 administration, but had no appreciable influence on heart weight, alpha GPD, and/or ODC activity. Propranolol and amiodarone had no significant effect on any of the changes studied after T3 administration. It was concluded that: 1) ipodate markedly lessens or abolishes the effects of T4 on the heart; 2) propranolol and amiodarone decrease cardiac hypertrophy in response to T4 administration, but have little or no effect on metabolic changes due to T4; 3) PTU curtails the metabolic effects of T4 on the heart but has little effect on cardiac hypertrophy; 4) none of the drugs studied affects cardiac changes occurring after T3 administration. The changes observed in 3',5'-T2 MA after ipodate and PTU treatment may have been a result of direct interaction of the drugs with the deiodinase.


Seizures Related to Neurocysticercosis and Cocaine Use.
Neurocysticercosis (NCC) is an infection of the central nervous system with Taenia solium cysts that most commonly results in seizures. In stable patients without recent symptoms, these seizures may be provoked by seizure threshold-lowering drugs such as cocaine. This case details a 38-year-old male with a past medical history of epilepsy presenting with seizures due to comorbid NCC and cocaine use. This case was complicated by the lack of available information regarding the patient's past medical history and medication use. We highlight the importance of obtaining a full work-up, including brain imaging, to provide optimal treatment for patients with seizures despite a history of drug use.


Bone morphogenetic proteins in multiple sclerosis: Role in neuroinflammation.
Bone morphogenetic proteins (BMPs) are growth factors that represent the largest subgroup of signalling ligands of the transforming growth factor beta (TGF-β) superfamily. Their participation in the proliferation, survival and cell fate of several cell types and their involvement in many pathological conditions are now well known. BMP expression is altered in multiple sclerosis (MS) patients, suggesting that BMPs have a role in the pathogenesis of this disease. MS is a demyelinating and neurodegenerative autoimmune disorder of the central nervous system (CNS). MS is a complex pathological condition in which genetic, epigenetic and environmental factors converge, although its aetiology remains elusive. Multifunctional molecules, such as BMPs, are extremely interesting in the field of MS because they are involved in the regulation of several adult tissues, including the CNS and the immune system. In this review, we discuss the extensive data available regarding the role of BMP signalling in neuronal progenitor/stem cell fate and focus on the participation and expression of BMPs in CNS demyelination. Additionally, we provide an overview of the involvement of BMPs as modulators of the immune system, as this subject has not been thoroughly explored even though it is of great interest in autoimmune disorders. Moreover, we describe the data on BMP signalling in autoimmunity and inflammatory diseases, including MS and its experimental models. Thus, we aim to provide an integrated view of the putative role of BMPs in MS pathogenesis and to open the field for the further development of alternative therapeutic strategies for MS patients.


Successful medical management of a left ventricular thrombus and aneurysm following failed thrombolysis in myocardial infarction.
We report the case of a patient with an extensive anterior myocardial infarction complicated by left ventricular systolic dysfunction, left ventricular apical thrombus and an apical left ventricular aneurysm following failed thrombolysis. We obtained serial two-dimensional echocardiograms at short intervals in the acute phase and also during the months of recovery and follow up. The patient was successfully and exclusively medically managed.


Rounded atelectasis due to acute exudative effusion. Spontaneous resolution.
Rounded atelectasis is an interesting roentgenographic entity that must be distinguished from intrathoracic neoplasm. Chronic pleural disease, particularly that due to asbestos exposure, is a frequently cited cause, and is considered to be a sine qua non by some. We report a case of rounded atelectasis with an acute parapneumonic exudative effusion that resolved spontaneously with roentgenographically normal pleura.


Not enough can be enough: feasibility of the Idylla EGFR mutation test when reuse of stained tissue slides is the only option available.
The minimally invasive procedures used in the diagnostic workup of patients with advanced non-small cell lung cancer (NSCLC) often provide poor yields of pathological material suitable for molecular analyses. Not infrequently, the DNA yield from small biopsies/cytological samples is insufficient for the assessment of genomic biomarkers that inform personalised therapies. The Idylla EGFR mutation test (IEMT) has been specifically designed to process formalin-fixed paraffin-embedded sections without requiring preliminary DNA extraction.This study aims to evaluate the diagnostic accuracy of IEMT when used to analyse archival histopathology material. More specifically, our objective was to establish whether or not different staining procedures could affect assay performance. Twenty NSCLC samples were selected accordingly to EGFR mutational status. To mimic archived stained material, sections were subjected to H&E staining, fluorescent in situ hybridisation analyses or immunodetection by immunohistochemistry before being processed for IEMT. Parallel assessment of EGFR mutational status by IEMT on stained sections and next-generation sequencing on DNA yielded a concordant result in 50 out of 60 tests (83.3%). The discoloration of H&E of the archived sample was found to be the optimal procedure to highlight all the actionable alterations of EGFR. IEMT can provide remarkable diagnostic accuracy for the assessment of EGFR mutational status also when the only source of pathological material available for molecular analyses is represented by H&E stained sections. Ad hoc supervision by a qualified molecular biologist is in any case recommended.


Autoimmunity, Autoantibodies, and Autism Spectrum Disorder.
Auism spectrum disorder (ASD) now affects one in 68 births in the United States and is the fastest growing neurodevelopmental disability worldwide. Alarmingly, for the majority of cases, the causes of ASD are largely unknown, but it is becoming increasingly accepted that ASD is no longer defined simply as a behavioral disorder, but rather as a highly complex and heterogeneous biological disorder. Although research has focused on the identification of genetic abnormalities, emerging studies increasingly suggest that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in ASD. This review summarizes the investigations implicating autoimmunity and autoantibodies in ASD.


Psychological response to disasters: focus on adolescents.
The effects of disasters may predispose many adolescents to psychological stress, which can interfere with their growth and development and disrupt their intrapsychic homeostasis. This may lead to negative long-term health outcomes and hamper normal development. Many nurses view traumatic events involving children, including adolescents, as the most frequent and stressful critical incidents. There is a need to address psychological emergency preparedness for mass disasters with the development of protocols and practice guidelines. Assessing and managing physical injuries may take priority in emergencies, but incorporating rapid, cost-effective mental health assessments for children and adolescents is essential.


Switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir DF from non-nucleoside reverse transcriptase inhibitor plus coformulated emtricitabine and tenofovir DF regimens: Week 96 results of STRATEGY-NNRTI.
HIV-1-infected, virologically suppressed adults wanting to simplify or change their non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may benefit from switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF). We examined differences in the proportion of participants with HIV-1 RNA < 50 copies/mL (Snapshot analysis), change in CD4 cell count, safety, and patient-reported outcomes in participants switching to E/C/F/TDF from an NNRTI + FTC/TDF (TVD) regimen. STRATEGY-NNRTI was a 96-week, phase 3b, randomized, open-label, study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF in virologically suppressed individuals (HIV-1 RNA < 50 copies/mL) on an NNRTI + TVD regimen. Participants were randomized to switch or remain on their NNRTI-based regimen (no-switch). At Week 96, 87% (251/290) of switch and 80% (115/143) of no-switch participants maintained HIV-1 RNA < 50 copies/mL (difference 6.1%; 95% CI -1.3 to 14.2%; p = 0.12) according to the FDA-defined snapshot algorithm. Both groups had similar proportions of subjects with virologic failure (2.8% switch, 1.4% no-switch). Discontinuations resulting from adverse events were infrequent (3% [9/291] switch, 2% [3/143] no-switch). Three switch participants (1%) discontinued due to renal adverse events (2 of the 3 before Week 48). Switch participants reported significant improvements in neuropsychiatric symptoms by as early as Week 4, and which were maintained through Week 96. E/C/F/TDF is safe and effective and reduces NNRTI-associated neuropsychiatric symptoms for virologically suppressed HIV-positive adults switching from an NNRTI plus FTC/TDF-based regimen.


Functional relationships between the hippocampus and dorsomedial striatum in learning a visual scene-based memory task in rats.
The hippocampus is important for contextual behavior, and the striatum plays key roles in decision making. When studying the functional relationships with the hippocampus, prior studies have focused mostly on the dorsolateral striatum (DLS), emphasizing the antagonistic relationships between the hippocampus and DLS in spatial versus response learning. By contrast, the functional relationships between the dorsomedial striatum (DMS) and hippocampus are relatively unknown. The current study reports that lesions to both the hippocampus and DMS profoundly impaired performance of rats in a visual scene-based memory task in which the animals were required to make a choice response by using visual scenes displayed in the background. Analysis of simultaneous recordings of local field potentials revealed that the gamma oscillatory power was higher in the DMS, but not in CA1, when the rat performed the task using familiar scenes than novel ones. In addition, the CA1-DMS networks increased coherence at γ, but not at θ, rhythm as the rat mastered the task. At the single-unit level, the neuronal populations in CA1 and DMS showed differential firing patterns when responses were made using familiar visual scenes than novel ones. Such learning-dependent firing patterns were observed earlier in the DMS than in CA1 before the rat made choice responses. The present findings suggest that both the hippocampus and DMS process memory representations for visual scenes in parallel with different time courses and that flexible choice action using background visual scenes requires coordinated operations of the hippocampus and DMS at γ frequencies.


Experimental infection of C3H/HeJ mice with the NY18 isolate of Anaplasma phagocytophilum.
Human granulocytic anaplasmosis (HGA), an emerging disease of public health concern in many areas of the world, is caused by Anaplasma phagocytophilum. Small animal models of A phagocytophilum in laboratory mice have been developed and used to study the pathogenesis of HGA. In this study, we characterized the pathologic changes in acute infection of C3H/HeJ mice experimentally infected with the NY18 isolate of A phagocytophilum. Although no clinical signs were noted, acute infection was associated with gross splenomegaly, microscopic inflammatory lesions in the lung and liver, hyperplastic lesions on the spleen, and clinical pathology abnormalities including neutropenia and monocytosis. This study emphasizes the use of well-defined animal models as a valuable tool for the study of A phagocytophilum infections.


Radial artery access for peripheral endovascular procedures.
The radial artery is often used for coronary angiography, with a demonstrated decrease in local complications and an increase in postoperative mobility of the patient. Data on radial artery access for peripheral endovascular procedures, however, are limited. We describe our experience with radial artery access for diagnostic and endovascular interventions. Between February 2012 and March 2015, there were 95 endovascular procedures performed using radial artery access in 80 unique patients. Demographic and clinical data were recorded. Perioperative, postoperative, and 30-day follow-up data were evaluated retrospectively for major and minor complications. Major adverse events included any immediate hospitalization admission, stroke, hand amputation, bleeding requiring transfusion, hematoma requiring surgery, and death. Minor complications included superficial bleeding and hematoma. The patients (52.6% male, 47.4% female) had a mean age of 72.1 ± 9.4 years. Radial artery access was used for diagnostic purposes in 15.8% of all procedures and for therapeutic intervention, including angioplasty and stenting, in 84.2%. The radial artery was the only access point in 80% of patients and was accessed in conjunction with other sites in 20%. Percutaneous access was achieved in 100% of patients with a 100% technical success rate. Hemostasis after catheterization was achieved by manual compression (22.1%) and TR band (Terumo Medical, Tokyo, Japan; 77.9%). Major adverse events occurred in three cases (3.2%) and were unrelated to radial artery access. Radial artery access site-related complications occurred in three cases (3.2%), all of which were minor hematomas that required no treatment. The risk of radial artery complication was not associated with procedure type, vessels treated, or use of heparin. The incidence of stroke, hand ischemia, and upper extremity limb or finger loss was 0%. Radial artery access for peripheral endovascular procedures appears to be safe and effective and should be considered more often. Complication rates are lower than those reported for femoral artery access.


Determination of unacceptable HLA antigen mismatches in kidney transplant recipients: recommendations of the German Society for Immunogenetics.
One of the major tasks of histocompatibility and immunogenetics laboratories is the pretransplant determination of unacceptable antigen mismatches (UAM) in kidney transplant recipients. In this procedure, human leucocyte antigen (HLA) specificities are defined against which the patient has circulating alloantibodies that are expected to harm the transplanted organ. Using the information on UAM and the potential donor's complete HLA typing, prediction of the crossmatch result, the so called 'virtual crossmatch', is possible. Currently, the laboratories are using different algorithms for the determination of UAM, and depending on the algorithm, more or fewer organ offers are excluded for patients with a similar antibody profile. In order to bring homogeneity into the allocation of organs to immunized patients in Germany, the German Society for Immunogenetics established, on the basis of current knowledge, recommendations for the determination of UAM. The UAM recommendations, which are thought to serve as a common tool for responsible physicians at different transplant centers, contain technical issues that need to be considered and are individualized for sensitized patients with a high or intermediate risk of antibody-mediated rejection. The present review contains these recommendations and puts them into perspective to current international practice.


[Surgical humour at Rigshospitalet].
Medical humour is often an important part of the treatment of patients in hospitals and in general practice. Therefore, medical humour should be distinguished from other forms of humour. The author of this article has served over forty years in Rigshospitalet of Copenhagen. He has observed the remarkable difference in the frequency of homour in the two surgical departments of the hospital. Department D had as a chief Wilhelm Schaldemose. He seemed to be completely without any sense of humour, and this spread to the rest of the department. When Schaldemose died Sigurd Kjaergard became head of the department. His sense of humour was limited, and he was not able to induce the humour to the rest of the department. It was first in 1953 when Erik Husfeldt took over as chief that the humour developed in the department, and it took several years before humour became a part of the daily treatment of patients. On the other department C the humour has always had good days starting with Thorkild Rovsing, the first chief, and later when Erling Dahl-Iversen was leader of the department. He had a special way to educate his staff in his sense of humour which became well known all over the hospital. In the beginning of this year a new society: >>Nordic Society of Medical Humour<< has been founded in Norway. This seems to be a remarkable positive development in the field of medical humour.


Relationship of performance on the ERGOS work simulator to illness behavior in a workers' compensation population with low back versus limb injury.
A prospective blinded cohort study was performed to test for a difference in the pattern of physical activity factors measured with the ERGOS work simulator in subjects with low back injuries versus those with limb injuries. Also tested was the relationship between physical activity factors measured with the ERGOS and several psychological tests and measures of nonorganic pain behavior in subjects with low back pain. Subjects were 70 men, 22 to 64 years old, who attended a 2-week physical capacity assessment after undergoing rehabilitation for a work-related injury. In subjects with a complaint of low back pain, nonorganic pain behavior was measured with the Waddell score. In addition, two brief psychological tests, the Coopersmith Self-Esteem Inventory and analog self-rating of wellness, were administered. It was found that subjects with low back complaints underperformed globally in comparison with subjects with limb complaints. This underperformance was statistically significant (P < .05) for 7 of 13 strength variables and 2 of 7 dexterity variables. In the subjects with low back complaints, those who exhibited excessive illness behavior (Waddell score, 3 to 5) performed significantly worse on all 13 strength variables and on 3 of 7 dexterity variables. In the subjects with low back complaints, those with low self-assessment ratings were found to have a high Waddell score (P < .01) and to perform significantly worse (P < .05) on 12 of 13 strength variables and 6 of 7 dexterity variables. There were no significant relationships (P > .05) between Coopersmith Self-Esteem score and Waddell score or performance on ERGOS testing.(ABSTRACT TRUNCATED AT 250 WORDS)


Photodissociation dynamics of 2-nitropropane and 2-methyl-2-nitropropane at 248 and 193 nm.
Dynamics of formation of electronically excited NO2 and formation of OH fragment, during photo dissociation of 2-nitropropane (NP) and 2-methyl-2-nitropropane (MNP), were investigated at 193 and 248 nm. The radiative lifetime of the electronically excited NO2 fragment, observed at 193 nm, was measured to be 1.2 ( 0.1 micros and the rate coefficient of quenching of its emission by MNP was measured as (2.7 ( 0.1) x 10(-10) molecule(-1) cm3 s(-1). Formation of the ground electronic state of OH was confirmed in both molecules. State selective laser induced fluorescence technique was used to detect the nascent OH (X 2Pi, v'', J'') fragments in different ro-vibrational states, and to obtain information on energy partitioning. Though MNP and NP differ in the types of the available H atoms, the dynamics of OH formation is found to be the same in both. The relative population in different rotational states does not follow Boltzmann equilibrium distribution in both the molecules at 193 and 248 nm. The translational energies of the OH fragments, calculated from the Doppler width, are 21.2 ( 7.2 and 25.0 ( 2.5 kcal mol-1 for NP at 248 and 193 nm, respectively. The translational energies of the OH fragments, in the case of MNP, are found to be lower, 17.5 ( 4.1 and 22.0 ( 3.2 kcal mol-1,respectively, at 248 nm 193 nm. These results are compared with the earlier reports on photodissociation of nitromethane (NM), nitroethane (NE), and other nitroalkanes. All possible dissociation pathways of these molecules--NM, NE, NP, and MNPs leading to the formation of the OH fragment were investigated computationally, with geometry optimization at the B3LYP/6-311+G(d,p) level and energy calculation at the MP4(SDQ)/6-311+G (d,p) level. The results suggest that in NM, OH is formed after isomerization to CH2N(OH)O, whereas in all other cases OH is formed from HONO, a primary product of molecular elimination of nitroalkanes, formed with sufficient internal energy.


Prevalence of depression among young people with Type 1 diabetes: a systematic review.
To determine: (1) prevalence of depression among young people with Type 1 diabetes compared with control groups or population norms; (2) implications of depression for HbA(1c) level; and (3) the relationship between history of depressive symptoms and future depressive symptoms. Among adults with Type 1 diabetes depression is higher than the general population, and has been associated with adverse implications for self-care and HbA(1c) level. The last published review of depression among young people with Type 1 diabetes only included studies up to 1999. Systematic searches were conducted for articles published from January 1999 to December 2011 including young people (up to 25 years old) with Type 1 diabetes. Twenty-three articles met the inclusion criteria. Of five studies that reported prevalence of depression compared with control groups, three found no differences. Of the three studies that investigated prevalence of depression making reference to population norms, all three showed higher rates of depressive symptoms. Fourteen of 15 studies found associations between more depressive symptoms and higher HbA(1c) level either cross-sectionally or longitudinally. Past depressive symptoms were associated with later depressive symptoms. Current evidence is inconclusive about whether there is increased prevalence of depression among young adults with Type 1 diabetes, as established among adults, but those who are more depressed have higher HbA(1c) level. This review is limited by methodological problems and no identified work in the UK met the inclusion criteria. Given the adverse clinical outcomes, we conclude there is a case for routine mental health screening for young adults with Type 1 diabetes.


Comparative Morphology of the Eyes of Postlarval Bresiliid Shrimps From the Region of Hydrothermal Vents.
The structure and ultrastructure of the eyes of postlarval vent shrimps provisionally designated `Alvinocaris' and `Chorocaris' are described. The eyes of the postlarval `Alvinocaris' are cylindrical, borne on short stalks, and contain closely packed rhabdoms. The ommatidia lack dioptric apparatus and have rhabdoms extending almost to the cornea. The rhabdoms consist of orthogonal layers of microvilli typical of crustacean rhabdoms. The eyes of the `Chorocaris' are similar, but the rhabdom layer extends back through the reduced eyestalks and covers some of the dorsal surface of the cephalothorax. The rhabdoms from both the anterior and the thoracic regions consist of layered microvilli. The eyes of a slightly smaller postlarval vent shrimp, termed `Type A', differ. Although clearly related to the other vent shrimps, Type A has stalked eyes held at an angle to the head. The eye displays a gradient of ommatidial development, with the older ommatidia closely resembling those seen in the other postlarval types. Between the cornea and the rhabdom layer, the youngest ommatidia possess quadripartite crystalline cones similar to those seen in related families of caridean shrimps; these are absent in the more mature ommatidia. The external structure of the anterior and thoracic eyes of juvenile Rimicaris exoculata (after settlement at the vent site) is also described. Juveniles up to 9 mm in carapace length have anterior corneas similar to those seen in postlarvae, whereas in larger specimens the corneas are progressively replaced by an ocular plate.


[Prenatal diagnosis: the obstetrician facing new technics].
The fetus and his environment which had remained, for so long, inaccessible to our exploratory techniques, is becoming every day, more and more accessible because of the various examinations now available. The biopsy of trophoblast which, after 10 weeks of amenorrhea, enable to obtain embryonic material and the tap of the umbilical chord under sonogram, permitting to obtain pure fetal blood after 18 weeks of amenorrhea, are an example of the new techniques which have completely modified the classical data of prenatal diagnosis. Now, the knowledge of parameters such as fetal haemostasis, immune status, metabolism and fetal karyotype, enabled the rapid development of fetal studies and already leads up to therapeutic procedures in utero.


Abetimus (La Jolla pharmaceuticals).
La Jolla is developing abetimus (LJP-394), a tetrakis-oligonucleotide conjugate, for the treatment of lupus and in particular, lupus kidney disease. In September 2000, phase III trials were initiated [382931]. These trials were ongoing in July 2001 [415284]. In January 1999, analysts had predicted a US filing in mid-2000 [318933]. The drug was granted Orphan Drug status in the US in September 2000 and in the EU in November 2001 [381379], [431129]. Following a meeting with the FDA, La Jolla planned a phase III trial of abetimus and expected this to begin in the second half of 2000 [364916]. In September 2000, the company anticipated its commencement within a few months [381379]; in fact, it began shortly thereafter. The trial was designed to repeat the positive results from the phase II/III study and the company intended to enroll 300 patients [382931], [386254]. By October 2000, more than ten clinical sites had been initiated into the trial and thefirst patient had been dosed. The company planned to have more than 50 sites in North America enrolling patients by the end of the year and expected to add about 15 more sites across Europe early in 2001 [384402]. In September 1996, US-05552391, covering abetimus, was granted. In October 1996, the company announced that it has received a third US composition of matter patent on abetimus [222901]. In November 1997, the company was issued with broad patents covering its core Tolerance Technology in 16 European countries and in Japan. A US patent on the technology was issued in 1993. These patents cover toleragens, as any composition of matter which contain multiple copies of B-cell epitopes, conjugated to a multivalent platform, where the conjugates lack T-cell epitopes. The patents also cover methods of synthesis and use [269583]. In November 2001, Morgan Keegan & Co estimated sales to be US $150 million in 2003, rising to US $600 million in 2005 [439326].


Changes in Primary Care Health Care Utilization after Inclusion of Epidemiologic Data in Lumbar Spine MR Imaging Reports for Uncomplicated Low Back Pain.
Purpose To determine whether inclusion of an epidemiologic statement in radiology reports of lumbar magnetic resonance (MR) imaging influences downstream health care utilization in the primary care population. Materials and Methods Beginning July 1, 2013, a validated epidemiologic statement regarding prevalence of common findings in asymptomatic patients was included in all lumbar MR imaging reports at a tertiary academic medical center. Data were collected from July 1, 2012, through June 30, 2014, and retrospective analysis was completed in September 2016. The electronic medical record was reviewed to capture health care utilization rates in patients for 1 year after index MR imaging. Of 4527 eligible adult patients with low back pain referred for lumbar spine MR imaging during the study period, 375 patients had their studies ordered by in-network primary care providers, did not have findings other than degenerative disease, and had at least one follow-up encounter within the system within 1 year of index MR imaging. In the before-and-after study design, a pre-statement-implementation cohort was compared with a post-statement-implementation cohort by using univariate and multivariate statistical models to evaluate treatment utilization rates in these groups. Results Patients in the statement group were 12% less likely to be referred to a spine specialist (137 of 187 [73%] vs 159 of 188 [85%]; P = .007) and were 7% less likely to undergo repeat imaging (seven of 187 [4%] vs 20 of 188 [11%]; P = .01) compared with patients in the nonstatement group. The intervention was not associated with any change in narcotic prescription (53 of 188 [28%] vs 54 of 187 [29%]; P = .88) or with the rate of low back surgery (24 of 188 [13%] vs 16 of 187 [9%]; P = .19). Conclusion In this study, inclusion of a simple epidemiologic statement in lumbar MR imaging reports was associated with decreased utilization in high-cost domains of low back pain management. © RSNA, 2018.


Avian sarcoma and leukosis virus pol-endonuclease recognition of the tandem long terminal repeat junction: minimum site required for cleavage is also required for viral growth.
Integration of retroviral DNA is a site-specific reaction involving an endonuclease encoded by the viral pol gene (pol-endo). In vitro the pol-endo from avian sarcoma and leukosis viruses (ASLVs) cleaves both DNA strands near the U5-U3 junction of tandem long terminal repeats (LTR-LTR junction) in single-stranded and replicative form (RF)-I substrates. We have reported previously that the sequences that are required for cleavage of single-stranded substrates by the alpha beta form of the pol-endo differ for the plus and minus strands (G. Duyk, M. Longiaru, D. Cobrinik, R. Kowal, P. deHaseth, A. M. Skalka, and J. Leis, J. Virol. 56:589-599, 1985). This is not the case with RF-I substrates, in which a maximum of 22 base pairs of U5 and 8 base pairs of U3 were required for alpha beta pol-endo cleavage in each strand. Insertion of a palindromic octanucleotide (CATCGATG) at the LTR-LTR junction abolished cleavage in RF-I but not in single-stranded DNA substrates. Deletion of the four nucleotides (TTAA) at the junction prevented cleavage in the plus strand of RF-I DNA, but did not affect cleavage of single-stranded DNA. Furthermore, the alpha beta form of ASLV pol-endo did not recognize heterologous LTR-LTR junction sequences from the reticuloendotheliosis virus or Moloney murine leukemia virus in either substrate form, despite their sequence and structural similarities to the ASLV junction. These results support a role for a sequence-specific interaction between the ASLV pol-endo and the LTR-LTR junction domains that are required for cleavage. By using the infectious Rous sarcoma virus clone pATV8-K, we introduced a set of deletions into the U5 region that would be incorporated into the LTR-LTR junction on viral replication. In the unintegrated provirus, the deletions started 43 base pairs from the LTR-LTR junction and extended various lengths toward the junction. Results of transfection studies with these clones indicated that the U5 sequences that are required for virus production in vivo correspond to those that are required for cleavage of RF-I DNA in vitro.


Combined cyclodialysis and cataract extraction.
Combined cyclodialysis and cataract extraction was performed on 78 eyes in a consecutive series of 26 years duration. This operation was performed on eyes with severe glaucoma, inadequately controlled on maximum medical therapy, and with a cataract needing extraction. Glaucoma types included open-angle, angle-closure with peripheral anterior synechias, combined open-angle and angle-closure, and secondary to uveitis. Seventy of the 78 eyes had follow-up of six months or more and the results in these 70 eyes were analyzed. In thirteen percent of the eyes in this study the postoperative intraocular pressure was the same or higher than the preoperative level, or reductions of intraocular pressure were not clinically significant. Eighty-seven percent (61 eyes) had a clinically significant lowering of intraocular pressure following the combined procedure. Thirty-nine percent (27 eyes) of the 70 eyes in this study had a tension of 0-14 mm Hg, and 44% (31 eyes) had a tension of 15-20 mm Hg. Intraocular pressure was improved significantly more often in patients over 60 years of age. Resulting intraocular pressures of 14 mm Hg or less were more likely when the cyclodialysis was performed in the lower quadrant. The results of the combined procedure were not significantly influenced by the type of glaucoma involved or by a history of previous glaucoma surgery. Bleeding was a frequent complication, but was not related to resulting intraocular pressure. Other complications were rare. We conclude that combining cyclodialysis with cataract extraction is safe and effective, and is a suitable procedure when there is need for surgery to relieve severe glaucoma, along with a need for cataract extraction.


Evaluation of Stigma Related to Perceived Risk for Coronavirus-19 Transmission Relative to the Other Stigmatized Conditions Opioid Use and Depression.
The coronavirus-19 (COVID-19) pandemic was initially characterized by misinformation and fear related to transmission that has been previously shown to produce stigma toward persons perceived to be at risk for transmission. This study evaluated perceptions toward scenarios with variable levels of perceived risk for COVID-19 acquisition, and compared stigma to COVID-19 to depression and opioid use disorder. Respondents (N = 280) from the United States completed a web-based survey 6 months after pandemic declaration. Questions included demographics and COVID-19 misconceptions, expected response to hypothetical scenarios with variable risk for COVID-19, and the Attribution Questionnaire-9 for COVID-19, depression, and opioid use disorder. Participants had several COVID-19 misconceptions, including that opioids increased immunity (63.6%), persons were more susceptible based upon racial/ethnic background (63.2%), and underlying health conditions did not influence risk (58.9%). Respondents were highly likely (64/100) to assume someone coughing had COVID-19 and the majority (93.5%) recommended quarantining persons with recent travel. However, the majority of respondents (>70% in all cases) also believed they would not change their COVID-19-related behavior when interacting with persons of different racial, ethnic, and age backgrounds. Finally, persons with COVID-19 engendered greater pity, less fear, less blame, less anger, and more willingness to help from respondents relative to persons with opioid use disorder. Stigma ratings toward persons perceived at risk of transmitting COVID-19, collected soon after the onset of the pandemic, showed less evidence of stigma relative to persons with opioid use disorder despite pronounced misconceptions regarding COVID-19 risk. Data provide a foundation for additional research in this area.


Activation of an intron enhancer within the keratin 18 gene by expression of c-fos and c-jun in undifferentiated F9 embryonal carcinoma cells.
The mouse forms of human keratins 18 and 8 (K18 and K8) are the first members of the large intermediate filament gene family to be expressed during embryogenesis. To identify potential regulatory elements of the human K18 gene, various recombinant constructions were expressed in cultured cells. An enhancer element was found in the first intron that functions on both the K18 and thymidine kinase promoters in differentiated cells. In F9 embryonal carcinoma cells, the level of expression was low in the presence or absence of the first intron. Cotransfection of F9 cells with K18 constructs that include the first intron and increasing amounts of an expression vector of c-jun results in a modest increase in the reporter gene expression. Cotransfection of the same construct with increasing amount of the mouse c-fos gene results in activation of the reporter gene by as much as 15-fold, with a near linear response to the amount of c-fos gene added. Site-specific mutagenesis of a putative AP-1 site within the intron abolishes trans-activation by c-fos in F9 cells. Furthermore, induction of c-fos in a derivative of F9 cells results in increased expression of the endogenous mouse form of K18. Cotransfection with c-jun or c-fos expression vectors had little effect on the expression of the K18 reporter construct in a parietal endodermal cell line already expressing the endogenous mouse gene. These results identify an enhancer within the first intron of K18 that may interact directly with c-jun and c-fos via a conserved AP-1-binding site. K18 expression in undifferentiated F9 cells may be limited by the low levels of c-jun and c-fos.


Metabarcoding analysis of eukaryotic microbiota in the gut of HIV-infected patients.
Research on the relationship between changes in the gut microbiota and human disease, including AIDS, is a growing field. However, studies on the eukaryotic component of the intestinal microbiota have just begun and have not yet been conducted in HIV-infected patients. Moreover, eukaryotic community profiling is influenced by the use of different methodologies at each step of culture-independent techniques. Herein, initially, four DNA extraction protocols were compared to test the efficiency of each method in recovering eukaryotic DNA from fecal samples. Our results revealed that recovering eukaryotic components from fecal samples differs significantly among DNA extraction methods. Subsequently, the composition of the intestinal eukaryotic microbiota was evaluated in HIV-infected patients and healthy volunteers through clone sequencing, high-throughput sequencing of nuclear ribosomal internal transcribed spacers 1 (ITS1) and 2 (ITS2) amplicons and real-time PCRs. Our results revealed that not only richness (Chao-1 index) and alpha diversity (Shannon diversity) differ between HIV-infected patients and healthy volunteers, depending on the molecular strategy used, but also the global eukaryotic community composition, with little overlapping taxa found between techniques. Moreover, our results based on cloning libraries and ITS1/ITS2 metabarcoding sequencing showed significant differences in fungal composition between HIV-infected patients and healthy volunteers, but without distinct clusters separating the two groups. Malassezia restricta was significantly more prevalent in fecal samples of HIV-infected patients, according to cloning libraries, whereas operational taxonomic units (OTUs) belonging to Candida albicans and Candida tropicalis were significantly more abundant in fecal samples of HIV-infected patients compared to healthy subjects in both ITS subregions. Finally, real-time PCR showed the presence of Microsporidia, Giardia lamblia, Blastocystis and Hymenolepis diminuta in different proportions in fecal samples from HIV patients as compared to healthy individuals. Our work revealed that the use of different sequencing approaches can impact the perceived eukaryotic diversity results of the human gut. We also provide a more comprehensive view of the eukaryotic community in the gut of HIV-infected patients through the complementarity of the different molecular techniques used. Combining these various methodologies may provide a gold standard for a more complete characterization of the eukaryotic microbiome in future studies.


Littoral sediment arsenic concentrations predict arsenic trophic transfer and human health risk in contaminated lakes.
Lake sediments store metal contaminants from historic pesticide and herbicide use and mining operations. Historical regional smelter operations in the Puget Sound lowlands have resulted in arsenic concentrations exceeding 200 μg As g-1 in urban lake sediments. Prior research has elucidated how sediment oxygen demand, warmer sediment temperatures, and alternating stratification and convective mixing in shallow lakes results in higher concentrations of arsenic in aquatic organisms when compared to deeper, seasonally stratified lakes with similar levels of arsenic pollution in profundal sediments. In this study we examine the trophic pathways for arsenic transfer through the aquatic food web of urban lakes in the Puget Sound lowlands, measuring C and N isotopes-to determine resource usage and trophic level-and total and inorganic arsenic in primary producers and primary and secondary consumers. Our results show higher levels of arsenic in periphyton than in other primary producers, and higher concentrations in snails than zooplankton or insect macroinvertebrates. In shallow lakes arsenic concentrations in littoral sediment are similar to deep profundal sediments due to arsenic remobilization, mixing, and redeposition, resulting in direct arsenic exposure to littoral benthic organisms such as periphyton and snails. The influence of littoral sediment on determining arsenic trophic transfer is evidenced by our results which show significant correlations between total arsenic in littoral sediment and total arsenic in periphyton, phytoplankton, zooplankton, snails, and fish across multiple lakes. We also found a consistent relationship between percent inorganic arsenic and trophic level (determined by δ15N) in lakes with different depths and mixing regimes. Cumulatively, these results combine to provide a strong empirical relationship between littoral sediment arsenic levels and inorganic arsenic in edible species that can be used to screen lakes for potential human health risk using an easy, inexpensive sampling and analysis method.


Soft-tissue response to silicone and poly-L-lactic acid implants with a periodic or random surface micropattern.
Tissue reaction to biomaterials is dependent on properties such as surface topography. The aim of this study was to evaluate the tissue reaction around implants with different surface topographies. We made coin-shaped silicone and poly-L-lactic acid (PLLA) implants with double-sided parallel microgrooves (depth 1.0 microm; width 10.0 microm) and random roughness on a micrometer scale. The control implants were smooth. These implants were inserted into subcutaneous pockets created on the flanks of goats. After 1, 3, or 12 weeks, the goats were sacrificed and the implants retrieved and histologically processed. Light microscopic evaluation revealed the formation of fibrous tissue capsules around all implant materials. The PLLA did not visibly degrade during the study period. Histomorphometric analyses were performed on capsule thickness, capsule quality, and on the implant-tissue interface quality. Compared with the silicone implants, the capsules around the PLLA implants showed significantly better capsule quality. Compared to the smooth implants, the capsules around the microgrooved implants were thicker, but the capsules around the roughened implants were thinner. However, randomly roughened implant surfaces generally elicited a stronger and more prolonged inflammatory reaction compared to smooth and microgrooved implant surfaces. We conclude that the application of microgrooves or random surface roughness to polymer implants apparently does not have beneficial effects on peri-implant tissue healing.


Polydopamine Coatings with Nanopores for Versatile Molecular Separation.
The demand for highly efficient and multifunctional membranes in various separation processes is increasing. Recently, mussel-inspired polydopamine (PDA) has provided a promising way to meet these requirements because of its surface-adhesive property and film-forming ability. However, traditional PDA coatings usually suffer from the disadvantages of nonuniformity, incompactness, and instability, leading to poor molecular separation and service performance. Herein, uniform, compact, and robust PDA coatings were fabricated on an ultrafiltration substrate via a reasonable screening of oxidants for the oxidized self-polymerization of dopamine. The as-prepared PDA coatings were nanoporous (0.56 ± 0.04 and 0.93 ± 0.04 nm) with a thickness of ∼75 nm, which endows the composite membranes with a high solute rejection and solvent permeability during molecular separation. They are useful in organic solvent nanofiltration because of their superior structural stability. Moreover, the composite membranes can be used for recycling the nanometer catalyst from organic solvents for the first time, which has significantly broadened the potential applications of these mussel-inspired coatings for versatile separation processes.


Thrombospondin-1 in maladaptive aging responses: a concept whose time has come.
Numerous age-dependent alterations at the molecular, cellular, tissue and organ systems levels underlie the pathophysiology of aging. Herein, the focus is upon the secreted protein thrombospondin-1 (TSP1) as a promoter of aging and age-related diseases. TSP1 has several physiological functions in youth, including promoting neural synapse formation, mediating responses to ischemic and genotoxic stress, minimizing hemorrhage, limiting angiogenesis, and supporting wound healing. These acute functions of TSP1 generally require only transient expression of the protein. However, accumulating basic and clinical data reinforce the view that chronic diseases of aging are associated with accumulation of TSP1 in the extracellular matrix, which is a significant maladaptive contributor to the aging process. Identification of the relevant cell types that chronically produce and respond to TSP1 and the molecular mechanisms that mediate the resulting maladaptive responses could direct the development of therapeutic agents to delay or revert age-associated maladies.


Changes in molecular forms of rat hepatic glutathione S-transferase during chemical hepatocarcinogenesis.
Changes in molecular forms of hepatic cytosolic glutathione S-transferases (GST) during rat chemical hepatocarcinogenesis were investigated. GST activities toward 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene increased with the increased area of gamma-glutamyltranspeptidase-positive foci and hyperplastic nodules induced by diethylnitrosamine followed by 2-acetylaminofluorene plus hepatectomy. Among GSTs with high activities toward 1,2-dichloro-4-nitrobenzene, which were separated by carboxymethyl Sephadex column chromatography, the activity of GST-A ( YbYb ) markedly increased with increased activity towards 1,2-dichloro-4-nitrobenzene in livers bearing foci and nodules and in isolated nodules and hepatomas, while activities of GST-C ( YbYb ') and -D (Yb'Yb') changed little. It was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and two-dimensional gel electrophoresis that Yb as well as Ya , a subunit of ligandin ( YaYa ) and GST-B ( YaYc ), increased in livers bearing foci and nodules, while Yc as well as Yb' changed little. A new placental GST form (GST-P), which has a subunit molecular weight of 21,500 or 26,000, according to the marker proteins used, and neutral pls of 6.8 and 6.3, is immunologically different from any form of basic GSTs and is very low in normal liver; also, it was markedly induced in livers bearing foci and nodules and in well-differentiated hepatomas but not by short-term administration of drugs such as 2-acetylaminofluorene, in contrast to GST-A and ligandin. These results indicate that GST-A and more especially GST-P could be new preneoplastic marker enzymes for chemical hepatocarcinogenesis.


Integer programming-based method for observability of singleton attractors in Boolean networks.
Boolean network (BN) is a popular mathematical model for revealing the behaviour of a genetic regulatory network. Furthermore, observability, an important network feature, plays a significant role in understanding the underlying network. Several studies have been done on analysis of observability of BNs and complex networks. However, the observability of attractor cycles, which can serve as biomarker detection, has not yet been addressed in the literature. This is an important, interesting and challenging problem that deserves a detailed study. In this study, a novel problem was first proposed on attractor observability in BNs. Identification of the minimum set of consecutive nodes can be used to discriminate different attractors. Furthermore, it can serve as a biomarker for different disease types (represented as different attractor cycles). Then a novel integer programming method was developed to identify the desired set of nodes. The proposed approach is demonstrated and verified by numerical examples. The computational results further illustrates that the proposed model is effective and efficient.


Comparative Evaluation of the Physical and Antimicrobial Properties of Mineral Trioxide Aggregate, Biodentine, and a Modified Fast-Setting Mineral Trioxide Aggregate Without Tricalcium Aluminate: An In Vitro Study.
Background Tricalcium aluminate, one of the major constituents of mineral trioxide aggregate (MTA), has been shown to have cytotoxic properties. Mineral trioxide aggregate has moderate to low antimicrobial activity against the most common endodontic pathogen, Enterococcus faecalis. Aim To assess the physical and antimicrobial properties of a newly modified formulation of mineral trioxide aggregate. Materials & methods The final setting time, compressive strength, and antimicrobial properties were tested for three groups of materials. The material used for Group 1 was mineral trioxide aggregate (white MTA, Angelus, Londrina, Brazil); the material for Group 2 was Biodentine (Septodont, Saint Maur des Fossés, France); and for Group 3, a modified MTA formulation was used. Results Group 1 had the longest setting time, and Group 2 had the shortest setting time. Group 3's material was set at 83.65 ± 0.28 minutes. This difference among the groups was statistically significant (p < 0.05). The highest mean compressive strength during all the time periods was seen in Group 2, followed by Group 3, and the least in Group 1. This difference in compressive strength was statistically significant (p=0.001). The largest zone of inhibition against Enterococcus faecalis, Candida albicans, and Streptococcus mutans was seen in Group 3, followed by Group 2 and Group 1. Conclusion Under the limitations of the present study, the newly modified MTA could serve as an alternative to the conventional MTA in terms of faster setting, higher strength, and better antimicrobial properties.


A randomised controlled study on the use of finishing and polishing systems on different resin composites using 3D contact optical profilometry and scanning electron microscopy.
The aim of this study was to evaluate theeffects of different finishing and polishing techniques on the surface roughness of microhybrid and nanofilled resin composites. The resin composites included were Filtek Z250 (a universal microhybrid resin composite) and Filtek Supreme XTE (a universal nanofill resin composite). Ninety cylindrical-shaped specimens were prepared for each composite resin material. The polishing methods used included tungsten carbide bur (TC); diamond bur (Db); Sof-Lex discs (S); Enhance PoGo discs (PG); TC + S; Db + S; TC + PG; Db + PG. Polymerisation against a Mylar strip without finishing and polishing acted as the control group. Surface roughness was measured using a 3D contact optical profilometer and surface morphology was examined by scanning electron microscope examination. The results showed that the Mylar-formed surfaces were smoothest for both composites. Finishing with the 20 μm diamond finishing bur caused significantly greater surface irregularity (P < 0.0001) and damage than finishing with the tungsten carbide finishing bur. The Enhance PoGo polishing system produced smoother surfaces than the Sof-Lex disc polishing system; this difference was statistically highly significant (P < 0.0001). For both composites, the Mylar-formed surfaces were smoothest. Where indicated clinically, finishing is better conducted using a tungsten carbide bur- rather than a diamond finishing bur. The Enhance PoGo system was found to produce a smoother surface finish than the Sof-Lex system. If finishing and polishing is required the use a tungsten carbide finishing bur followed by Enhance PoGo polishing may be found to result in the smoothest surface finish.


Multifocal motor neuropathy.
To conduct a critical review of recent studies on the clinical and therapeutic aspects of multifocal motor neuropathy, and to analyse their implications for patient management. Recent studies have contributed to defining the specific position of multifocal motor neuropathy within the spectrum of chronic immune-mediated polyneuropathies. One study compared features of this condition with multifocal acquired demyelinating sensory and motor neuropathy, while others have focused on pathological alterations at the site of conduction blocks. A further study described six new cases of multifocal acquired motor neuropathy, which should be considered as a variant of multifocal motor neuropathy. Several Cochrane reviews and review articles have shown evidence of the efficacy of intravenous immunoglobulins in the treatment of multifocal motor neuropathy. The issue of long-term intravenous immunoglobulins in multifocal motor neuropathy, however, has yielded controversial results. Two studies have shown progressive motor deterioration in most patients, correlated with electrophysiological signs indicative of axonal degeneration, while a third study found signs of sustained clinical and electrophysiological improvement after a mean follow up of 7.25 years. Multifocal motor neuropathy is a distinct clinical entity that differs from chronic inflammatory demyelinating polyradiculoneuropathy and multifocal acquired demyelinating sensory and motor neuropathy, although they share some electrophysiological characteristics. Although the aetiology remains unsolved, frequent association with high-titer antibodies against ganglioside GM1, together with an often positive response to intravenous immunoglobulins further support an autoimmune mechanism. New therapeutic strategies are required, however, that focus on the effects and the costs of treatment over long-term follow up.


Different effects of calcium channel blockers on matrix metalloproteinase-2 expression in cultured rat cardiac fibroblasts.
The cardiac effects of calcium channel blockers (CCBs) related to cardiac remodeling are inconsistent. Matrix metalloproteinases (MMPs) contribute to tissue remodeling. Cardiac fibroblasts play an important role in the regulation of collagen degradation by MMPs. Using gelatin zymography, Western blotting, Griess reagent, and a calcium kit-fluo 3, we investigated the effects of nifedipine, verapamil, diltiazem, and amlodipine on MMP-2 expression and further elucidate the mechanisms in cultured rat cardiac fibroblasts. Nifedipine increased and amlodipine decreased the expression of MMP-2; however, neither verapamil nor diltiazem altered MMP-2 expression. Nifedipine also increased nitrite production, and this increase was blunted by a nitric oxide (NO) synthases inhibitor (L-NAME). Nifedipine-induced MMP-2 expression was also blunted by L-NAME. An NO donor (sodium nitroprusside) induced MMP-2 expression. Data indicated that nifedipine might increase MMP-2 expression through a possible NO-dependent pathway. Amlodipine had no influence on nitrite production. The amlodipine-induced decrease of MMP-2 expression was abolished by two protein tyrosine kinase inhibitors, genistein and herbimycin A, indicating that amlodipine might decrease MMP-2 expression through a possible protein tyrosine kinase pathway. None of the four CCBs could alter the fluoscence intensity of fluo 3, indicating that the effects of CCBs on MMP-2 expression were independent of the variation in intracellular C2+ concentration. Our findings revealed that different CCBs exerted different effects on MMP-2 expression in cardiac fibroblasts.


Core-APOBEC3C chimerical protein inhibits hepatitis B virus replication.
We tested the capsid targeted viral inactivation method as an anti-HBV strategy. HepG2 cells were cotransfected with HBV expression plasmid and the plasmid encoding fusion protein of either Core-A3C or Core-humanized renilla GFP (hrGFP). Core-A3C had substantial effect on HBV DNA levels. In the HepG2 cells expressing Core-A3C, the number of G-to-A mutations increased dramatically, whereas other nucleotide substitutions were rare. In addition, Core-A3C substantially inhibited HBV production intracellularly and in culture supernatant. These results suggest that Core-A3C may be a candidate as a novel antiviral agent against human HBV infection.


Effects of intravenous infusion of hypotonic lactated Ringer's solution on calves with diarrhea.
The effects of intravenous infusion of hypotonic lactated Ringer's (LR: n=14) on plasma volume and venous blood gases were compared to those of hypotonic Ringer's solutions (RS: n=7) in diarrheic Japanese Black breed calves with metabolic acidosis. Venous blood samples were collected immediately before and after, and at 24 hr after the fluid infusion therapy. The LR and RS infusions increased relative plasma volume to 147.1 +/- 25.5% and 134.2 +/- 18.6%, respectively, just after the fluid therapy. The LR infusion induced an increase in the BE value (+5.1 +/- 4.8 mM) at 24 hr compared to that of RS. LR infusion should be explored as a treatment for dehydration and moderate metabolic acidemia caused by naturally occurring diarrhea in calves.


Stroke family caregivers' support needs change across the care continuum: a qualitative study using the timing it right framework.
Family caregivers provide essential support as stroke survivors' return to community living, but it is not standard clinical practice to prepare or provide ongoing support for their care-giving role. In addition, health care professionals (HCPs) experiences with providing support to caregivers have not been explored previously. The objectives of this qualitative study were to: (1) explore the support needs over time from the perspective of caregivers, (2) explore the support needs over time from the perspective of HCPs, and (3) compare and contrast caregivers' and HCPs' perspectives. A qualitative study with stroke family caregivers (n = 24) and HCPs (n = 14). In-depth interviews were audio taped, transcribed, and analyzed using Framework Analysis. Three main themes emerged concerning: (1) types and intensity of support needed; (2) who provides support and the method of providing support; and (3) primary focus of care. These themes are discussed in relation to the TIR framework. Caregivers' needs for support and the individuals most suited to providing support change across the stroke survivor's recovery trajectory. Changes to service delivery to better support caregivers may include: (1) addressing caregivers' changing needs across the care continuum; (2) implementing a family-centered model of care; and (3) providing 7-day per week inpatient rehabilitation.


Clinical characteristics of chylothorax: results from the International Collaborative Effusion database.
Chylothorax is an uncommon medical condition for which limited data are available regarding the contemporary aetiology, management and outcomes. The goal of this study was to better define these poorly characterised features. The medical records of adult patients diagnosed with chylothorax at 12 centres across Europe, America and South Africa from 2009-2021 were retrospectively reviewed. Descriptive and inferential statistics were performed. 77 patients (median age 69 years, male to female ratio 1.5) were included. Subacute dyspnoea was the most typical presenting symptom (66%). The commonest cause of chylothorax was malignancy (68.8%), with lymphoma accounting for 62% of these cases. Other aetiologies were trauma (13%), inflammatory/miscellaneous conditions (11.7%) and idiopathic cases (6.5%). At the initial thoracentesis, the pleural fluid appeared milky in 73%, was exudative in 89% and exhibited triglyceride concentrations >100 mg·dL-1 in 88%. Lymphangiography/lymphoscintigraphy were rarely ordered (3%), and demonstration of chylomicrons in pleural fluid was never ascertained. 67% of patients required interventional pleural procedures. Dietary measures were infrequently followed (36%). No patient underwent thoracic duct ligation or embolisation. Morbidity included infections (18%), and thrombosis in malignant aetiologies (16%). The 1-year mortality was 47%. Pleural fluid protein >3.5 mg·dL-1 (sub-distribution hazard ratio (SHR) 4.346) or lactate dehydrogenase <500 U·L-1 (SHR 10.21) increased the likelihood of effusion resolution. Pleural fluid protein ≤3.5 mg·dL-1 (HR 4.047), bilateral effusions (HR 2.749) and a history of respiratory disease (HR 2.428) negatively influenced survival. Chylothoraces have a poor prognosis and most require pleural interventions. Despite the standard recommendations, lymphatic imaging is seldom used, nor are dietary restrictions followed.


Group intervention for children bereaved by the suicide of a relative.
This study evaluated efficacy of a manual-based bereavement group intervention for children who suffered suicide of a parent or sibling. Seventy-five families (102 children) were screened from medical examiners' lists of suicide victims. Fifty-two families (75 children) were eligible and assigned in alternating order to receive (27 families, 39 children) or not to receive (25 families, 36 children) the intervention. Intervention efficacy was evaluated as change in children's symptoms of anxiety, depression, posttraumatic stress, social adjustment, and parents' depressive symptoms from initial to outcome assessments. Changes in anxiety and depressive symptoms were significantly greater among children who received the intervention than in those who did not. A greater dropout of children assigned not to receive (75%) than to receive (18%) intervention led to an imbalance in retention of intervention and nonintervention participants. A bereavement group intervention focusing on reactions to death and suicide and strengthening coping skills can lessen distress of children bereaved after parental or sibling suicide. Such intervention may prevent future morbidities.


The Life Span Model of Suicide and Its Neurobiological Foundation.
The very incomprehensibility of the suicidal act has been occupying the minds of researchers and health professionals for a long time. Several theories of suicide have been proposed since the beginning of the past century, and a myriad of neurobiological studies have been conducted over the past two decades in order to elucidate its pathophysiology. Both neurobiology and psychological theories tend to work in parallel lines that need behavioral and empirical data respectively, to confirm their hypotheses. In this review, we are proposing a "Life Span Model of Suicide" with an attempt to integrate the "Stress-Diathesis Model" and the "Interpersonal Model of Suicide" into a neurobiological narrative and support it by providing a thorough compilation of related genetic, epigenetic, and gene expression findings. This proposed model comprises three layers, forming the capability of suicide: genetic factors as the predisposing Diathesis on one side and Stress, characterized by epigenetic marks on the other side, and in between gene expression and gene function which are thought to be influenced by Diathesis and Stress components. The empirical evidence of this model is yet to be confirmed and further research, specifically epigenetic studies in particular, are needed to support the presence of a life-long, evolving capability of suicide and identify its neurobiological correlates.