The dynamics of postural sway cannot be captured using a one-segment inverted pendulum model: a PCA on segment rotations during unperturbed stance.
Research on unperturbed stance is largely based on a one-segment inverted pendulum model. Recently, an increasing number of studies report a contribution of other major joints to postural control. Therefore this study evaluates whether the conclusions originating from the research based on a one-segment model adequately capture postural sway during unperturbed stance. High-pass filtered kinematic data (cutoff frequency 1/30 Hz) obtained over 3 min of unperturbed stance were analyzed in different ways. Variance of joint angles was analyzed. Principal-component analysis (PCA) was performed on the variance of lower leg, upper leg, and head-arms-trunk (HAT) angles, as well as on lower leg and COM angle (the orientation of the line from ankle joint to center of mass). It was found that the variance in knee and hip joint angles did not differ from the variance found in the ankle angle. The first PCA component indicated that, generally, the upper leg and HAT segments move in the same direction as the lower leg with a somewhat larger amplitude. The first PCA component relating ankle angle variance and COM angle variance indicated that the ankle joint angle displacement gives a good estimate of the COM angle displacement. The second PCA component on the segment angles partly explains the apparent discrepancy between these findings because this component points to a countermovement of the HAT relative to the ankle joint angle. It is concluded that postural control during unperturbed stance should be analyzed in terms of a multiple inverted pendulum model.


Asymmetric Synthesis of Axially Chiral Molecules via Organocatalytic Cycloaddition and Cyclization Reactions.
Atropisomeric molecules are present in many natural products, biologically active compounds, chiral ligands and catalysts. Many elegant methodologies have been developed to access axially chiral molecules. Among them, organocatalytic cycloaddition and cyclization have attracted much attention because they have been widely used in the asymmetric synthesis of biaryl/heterobiaryls atropisomers via construction of carbo- and hetero-cycles. This strategy has undoubtedly become and will continue to be a hot topic in the field of asymmetric synthesis and catalysis. This review aims to highlight the recent advancements in this field of atropisomer synthesis by using different organocatalysts in cycloaddition and cyclization strategies. The construction of each atropisomer, its possible mechanism, the role of catalysts, and its potential applications are illustrated.


Astragalus Polysaccharide Promotes Adriamycin-Induced Apoptosis in Gastric Cancer Cells.
Astragalus polysaccharide (APS), a common Chinese herbal compound extracted from Astragalus membranaceus, has been proposed to increase the tumour response of and stabilize chemotherapy drugs while reducing their toxicity. Here, we examined the effects of APS on apoptosis in gastric cancer (GC) cells in the presence or absence of adriamycin (0.1 µg/mL). GC cells cultured in the presence or absence of adriamycin (0.1 µg/mL) were administered APS (50-200 µg/mL) for 24-72 h and subjected to an MTT assay to examine cell viability. Active caspase-3 expression and DNA fragmentation were assessed to evaluate apoptosis, and real-time PCR was used to analyse the expression levels of multidrug resistance (MDR1) genes and tumour suppressor genes. Western blot analysis was applied to detect cleaved caspase-3 and phosphorylated AMPK (p-AMPK). Cellular viability was profoundly reduced by APS, and GC cell apoptosis was strongly increased by APS in a time- and dose-dependent manner; these changes may be linked to an increase in p-AMPK levels because the AMPK inhibitor compound C blocked the effects of APS. Similarly, adriamycin-induced decreases in cellular viability and apoptosis of GC cells were enhanced by APS administration. The expression of tumour suppressor genes (SEMA3F, P21WAF1/CIP1, FBXW7), but not of MDR1, was increased by APS compared to the control, and p-AMPK levels were lower in adriamycin-resistant GC cells than in either adriamycin-sensitive GC cells or an immortalized human gastric epithelial cell line. APS induces apoptosis independently and strengthens the proapoptotic effect of adriamycin on GC cells, suggesting that APS may act as a chemotherapeutic sensitizer.


Adjuvant immunotherapy for cancer: both dendritic cell-priming and check-point inhibitor blockade are required for immunotherapy.
The immune system eliminates advanced cancer when treated with programmed cell death protein-1 (PD-1) or its ligand (PD-L1) blockade, but PD-1 therapy is effective in only ∼20% of patients with solid cancer. The PD-1 antibody mainly acts on the effector phase of cytotoxic T lymphocytes (CTLs) in tumors but induces no activation of the priming phase of antigen-presenting dendritic cells (DCs). It is reasonable that both DC-priming and PD-1/L1 blocking are mandatory for efficient CTL-mediated tumor cytolysis. For DC-priming, a therapeutic vaccine containing Toll-like receptor (TLR) agonists, namely a priming adjuvant, is a good candidate; however, a means for DC-targeting by TLR adjuvant therapy remains to be developed. TLR adjuvants usually harbor cytokine toxicity, which is a substantial barrier against drug approval. Here, we discuss the functional properties of current TLR adjuvants for cancer immunotherapy and introduce a TLR3-specific adjuvant (ARNAX) that barely induces cytokinemia in mouse models.


Congenital nephrotic syndrome of Finnish type. Study of 75 patients.
Seventy-five patients with congenital nephrotic syndrome of Finnish type were identified in Finland in the period 1965-1973, giving an incidence of 12-2/10(5). A large placenta and proteinuria from birth are the hallmarks of the disease. About one-quarter of the patients had oedema and/or abdominal distension at birth and in all cases the full nephrotic syndrome was documented before 2 months. More than half of the patients died before 6 months and none lived longer than 2 years 3 months. A slight rise in blood urea nitrogen or serum creatinine levels occurred in 14 cases, but in none of these did a frank uraemia develop before death. Infection appeared to be the immediate cause of death in 31% of the cases; in 43% no cause of death other than congenital nephrotic syndrome could be shown. Thrombi in large vessels were found in 11 out of 58 necropsies.


Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells.
Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca2+ concentration [(Ca2+) cyt ] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling. Here, we report that the calcium homeostasis modulator (CALHM), a Ca2+ (and ATP) channel that is allosterically regulated by voltage and extracellular Ca2+, is upregulated during the PASMC contractile-to-proliferative phenotypical transition. Protein expression of CALHM1/2 in primary cultured PASMCs in media containing serum and growth factors (proliferative PASMC) was significantly greater than in freshly isolated PA (contractile PASMC) from the same rat. Upregulated CALHM1/2 in proliferative PASMCs were associated with an increased ratio of pAKT/AKT and pmTOR/mTOR and an increased expression of the cell proliferation marker PCNA, whereas serum starvation and rapamycin significantly downregulated CALHM1/2. Furthermore, CALHM1/2 were upregulated in freshly isolated PA from rats with monocrotaline (MCT)-induced PH and in primary cultured PASMC from patients with PAH in comparison to normal controls. Intraperitoneal injection of CGP 37157 (0.6 mg/kg, q8H), a non-selective blocker of CALHM channels, partially reversed established experimental PH. These data suggest that CALHM upregulation is involved in PASMC contractile-to-proliferative phenotypical transition. Ca2+ influx through upregulated CALHM1/2 may play an important role in the transition of sustained vasoconstriction to excessive vascular remodeling in PAH or precapillary PH. Calcium homeostasis modulator could potentially be a target to develop novel therapies for PAH.


Predominance of biotic over abiotic formation of halogenated hydrocarbons in hypersaline sediments in Western Australia.
Volatile halogenated organic compounds (VOX) contribute to ozone depletion and global warming. There is evidence of natural VOX formation in many environments ranging from forest soils to salt lakes. Laboratory studies have suggested that VOX formation can be chemically stimulated by reactive Fe species while field studies have provided evidence for direct biological (enzymatic) VOX formation. However, the relative contribution of abiotic and biotic processes to global VOX budgets is still unclear. The goals of this study were to quantify VOX release from sediments from a hypersaline lake in Western Australia (Lake Strawbridge) and to distinguish between the relative contributions of biotic and abiotic VOX formation in microbially active and sterilized microcosms. Our experiments demonstrated that the release of organochlorines from Lake Strawbridge sediments was mainly biotic. Among the organochlorines detected were monochlorinated, e.g., chloromethane (CH3Cl), and higher chlorinated VOX compounds such as trichloromethane (CHCl3). Amendment of sediments with either Fe(III) oxyhydroxide (ferrihydrite) or a mixture of lactate/acetate or both ferrihydrite and lactate/acetate did not stimulate VOX formation. This suggests that although microbial Fe(III) reduction took place, there was no stimulation of VOX formation via Fe redox transformations or the formation of reactive Fe species under our experimental conditions.


Association of the Mental Health Parity and Addiction Equity Act and the Affordable Care Act on severe maternal morbidity.
This study aimed to characterize the association between Mental Health Parity and the Affordable Care Act and rates of severe maternal morbidity among a population of commercially insured individuals, including individuals with and without perinatal mood and anxiety disorders. We conducted a serial, cross-sectional analysis of individuals with an inpatient delivery in Optum's Clinformatics® Data Mart Database from 2008 to 2021. We applied an interrupted time series model with autoregressive integrated moving average to evaluate changes in quarterly severe maternal morbidity rates. Adjusted severe maternal morbidity rates declined from 167.2 (95%CI: [152.6, 181.9]) per 10,000 deliveries in the first quarter of 2008 to 98.2 (95%CI: [83.5, 112.8]) per 10,000 deliveries in the last quarter of 2021. Severe maternal morbidity rates remained higher, but declined to a greater degree, among those with perinatal mood and anxiety disorders (435.6, 95%CI: [379.9, 491.3], to 165.0, 95%CI: [109.3, 220.8] per 10,000 deliveries) compared to those without (153.0, 95%CI: [140.7, 165.3] to 81.8, 95%CI: [69.6, 94.1] per 10,000 deliveries). The observed association suggests implementation of Mental Health Parity and Affordable Care Act may have played a role in lowering rates of severe maternal morbidity, particularly among individuals with perinatal mood and anxiety disorders.


Recent developments in molecular biology of mycobacteria.
Molecular biology is beginning to revolutionise the study of tuberculosis and other mycobacterial diseases. DNA hybridization is used to classify strains at the generic and specific level and, when combined with the polymerase chain reaction, may rapidly detect very small amounts of mycobacterial DNA in clinical material. Restriction endonuclease mapping or the more refined restriction length polymorphism analysis is used to type strains at the sub-specific level for epidemiological purposes. Detection of plasmids is also an epidemiological aid and there is considerable interest in the role of plasmids as determinants of pathogenicity and virulence of some mycobacterial species. Genomic libraries provide a source of DNA probes for use in hybridization and restriction length polymorphism analysis and pure antigens in large quantities for experimental and diagnostic use. Vectors for the insertion of genes into mycobacteria provide a way of analysing genes relevant to virulence and protective immunity and a means of producing new vaccines for use against leprosy as well as tuberculosis. Finally, the ability to clone mammalian genes in bacteria enables immunological mediators to be produced in quantity for the elucidation of immune mechanisms in mycobacterial infections and possibly for therapeutic use.


Prophylaxis in congenital hemophilia with inhibitors: the role of recombinant activated factor VII.
The development of inhibitors against therapeutically administered factors VIII or IX is actually the most challenging complication of hemophilia patients with inhibitors. The introduction of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII [rFVIIa]) has dramatically improved the management of bleeding episodes in such patients. Over the last decade, there have been increasing reports on the ability of bypassing agents to prevent surgical, joint, or other bleeds in inhibitor patients. The published data on the use of rFVIIa as a prophylactic treatment in hemophilia patients with inhibitors are reviewed in this article.


Synthesis and Reactivity of Aluminum Disilacyclopropenes. Cyclic AlSi2 Delocalized 2π Systems.
The synthesis, structures, and reactivity of the first unsaturated AlSi2 three-membered ring systems were described. Reactions of dilithiodisilene [(NHB)LiSi═SiLi(NHB)] (1, NHB = diazaborolyl) with aluminum halides AlCl3, Ar(SiMe3)NAlCl2 (Ar = 2,6-iPr2C6H3), Cp*AlBr2 (Cp* = C5Me5), and TipAlBr2·Et2O (Tip = 2,4,6-iPr3C6H2) led to the formation of AlSi2 three-membered ring species, solvated (NHBSi)2AlCl(OEt2) (2) and solvent-free (NHBSi)2AlN(SiMe3) Ar (3), (NHBSi)2AlCp* (4), and (NHBSi)2AlTip (5), in good yields. X-ray diffraction studies and DFT calculations disclosed delocalized AlSi2 2π electron systems. Methanolysis of 4a resulted in cleavage of the Al-Si σ and Si-Si π bonds, giving trihydrodisilane (NHB)H(MeO)SiSiH2 (NHB) (6). Reaction of 4b with 4 equiv of N2O and H2C═CH2 resulted in the insertion of four oxygen atoms and four H2C═CH2 π bonds into all of the Al-Si and Si-Si bonds, yielding the O- and CH2CH2-bridged polycyclic species 7 and 8, demonstrating the synergistic reactivity of the Al-Si and Si-Si bonds in the AlSi2 ring system.


On ratio-based color indexing.
The color ratio approach to indexing has been found to be robust and effective in indexing image and video databases, in different color spaces, and when using transformed color features, such as those from the Karhunen-Loeve transform (KLT) or the discrete cosine transform (DCT). However, the reason for the superior performance of the color ratio model, especially on different color spaces or with transformed color features has, at best, been speculative. This paper develops a generalized form for the color ratio model, based on which we characterize the general distribution of the color ratios. From the distribution, we present a theory that explains and supports the performance of the color ratio approach in image and video indexing. It is shown that the same theory accounts for its effectiveness in different color spaces and in the transform domain. Some general problems encountered in using the original retinex lightness algorithm, and some other issues specific to ratio-based color indexing are discussed in the light of the theory. Results are presented which show that the proposed theory is supported by empirical evidence.


Learning prediction error neurons in a canonical interneuron circuit.
Sensory systems constantly compare external sensory information with internally generated predictions. While neural hallmarks of prediction errors have been found throughout the brain, the circuit-level mechanisms that underlie their computation are still largely unknown. Here, we show that a well-orchestrated interplay of three interneuron types shapes the development and refinement of negative prediction-error neurons in a computational model of mouse primary visual cortex. By balancing excitation and inhibition in multiple pathways, experience-dependent inhibitory plasticity can generate different variants of prediction-error circuits, which can be distinguished by simulated optogenetic experiments. The experience-dependence of the model circuit is consistent with that of negative prediction-error circuits in layer 2/3 of mouse primary visual cortex. Our model makes a range of testable predictions that may shed light on the circuitry underlying the neural computation of prediction errors.


The treatment of solid tumors by alpha emitters released from (224)Ra-loaded sources-internal dosimetry analysis.
Diffusing alpha-emitters radiation therapy (DART) is a proposed new form of brachytherapy, allowing the treatment of solid tumors by alpha particles. DART utilizes implantable sources carrying small activities of radium-224, which continually release into the tumor radon-220, polonium-216 and lead-212 atoms, while radium-224 itself remains fixed to the source. The released atoms disperse inside the tumor by diffusive and convective processes, creating, through their alpha emissions, a high-dose region measuring several mm in diameter about each source. The efficacy of DART has been demonstrated in preclinical studies on mice-borne squamous cell carcinoma and lung tumors and the method is now being developed toward clinical trials. This work studies DART safety with respect to the dose delivered to distant organs as a result of lead-212 leakage from the tumor through the blood, relying on a biokinetic calculation coupled to internal dose assessments. It is found that the dose-limiting organs are the kidneys and red bone marrow. Assuming a typical source spacing of approximately 5 mm and a typical radium-224 activity density of 0.4-0.8 MBq g(-1) of tumor tissue, it is predicted that tumors weighing up to several hundred grams may be treated without reaching the tolerance dose in any organ.


Bundle sheath proteins are more sensitive to oxidative damage than those of the mesophyll in maize leaves exposed to paraquat or low temperatures.
In maize leaves growth at low temperatures causes decreases in maximum catalytic activities of photosynthetic enzymes and reduced amounts of proteins, rather than effects on regulation or co-ordination of the photosynthetic processes. To test the hypothesis that differential localization of antioxidants between the different types of photosynthetic cell in maize leaves is a major determinant of the extreme sensitivity of maize leaves to chilling damage, oxidative damage to proteins, induced by incubation of maize leaves with paraquat, has been measured and compared with the effects incurred by growth at low temperatures. While the increase in protein carbonyl groups caused by paraquat treatment was much greater than that caused by low temperature growth conditions, most carbonyl groups were detected on bundle sheath proteins in both stress conditions. With one or two exceptions proteins located in the mesophyll tissues were free of protein carbonyl groups in both situations. Paraquat treatment caused a complete loss of the psaA gene products, modified the photosystem II reaction centre polypeptide, D1, and increased the number of peptides arising from breakdown of ribulose 1,5-bisphosphate carboxylase oxygenase (Rubisco). In contrast, growth at 15 degrees C increased the abundance (but not number) of Rubisco breakdown products and decreased that of the psaB gene product while the psaA gene product and PEP carboxylase were largely unaffected. Since bundle sheath proteins are more susceptible to oxidative damage than those located in the mesophyll cells, strategies for achieving a more balanced system of antioxidant defence may be effective in improving chilling tolerance in maize.


Enhance Hydrogen Evolution Reaction Performance via Double-Stacked Edges of Black Phosphorene.
Based on the density functional theory (DFT) calculations, we explored the structures and HER catalytic properties of reconstructed and double-stacked black phosphorene (BP) edges. Ten bilayer BP edges were constructed by the double stacking of three typical monolayer edges, i.e., zigzag (ZZ) edge, armchair (AC) edge, skewed diagonal (SD) edge, and their reconstructed derivatives with their layer's configurations, edge deformations and thermodynamic stabilities were discussed. Based on these edges, five chemical sites on four bilayer BP edges were selected to be promising candidates for a HER catalyst, which present higher HER activities than that of Pt(111). Besides, among these four edges, two edges have even lower energetic barriers for the Tafel reaction. Compared with the monolayer edges, these selected bilayer BP edges confirm the remarkable enhancement of the HER catalytic properties, which can be attributed to their unique edge structures and the enhanced electronic densities after the hydrogen adsorptions. Finally, the thermostability of these edges at room temperature has also been proved by the DFT-MD simulations. This theoretic study deepens our fundamental understanding of the double-stacked edge structures of the BP and provides a new way for the rational design of highly efficient and noble-metal-free HER catalysts.


Hope, Arkansas to Hope, Albania: naivete and idealism to reality and tragedy.
The wars in Croatia, Bosnia and Kosovo were perpretrated by a radical nationalist Serbian cultural political consciousness that the American cultural political consciousness and leadership had difficulty responding to and understanding. There is a great cultural divide between a 'pathology' in Serbian culture, Milosević's radical nationalism, and a humane 'naivete' in American cultural consciousness. I discuss why, finally, American political leadership, Bill Clinton from Hope, Arkansas, responded to the tragedy of these wars. However, we are still left with the question of good vs evil: What is the course of human history; psychotic political leadership causing repetitive human tragedy or can there be a higher humane and moral order to human cultural events?


Male pronuclear formation in denuded porcine oocytes after in vitro maturation in the presence of cysteamine.
The present study was conducted to examine effects of cysteamine in culture medium on progression of meiosis, glutathione (GSH) content, kinase activities (histone H1 kinase and mitogen-activated protein kinase), and male pronuclear formation after in vitro insemination of cumulus-denuded oocytes (DOs) in the pig. DOs, obtained by mechanically removing cells from cumulus-oocyte complexes (COCs) with a small-bore pipette, were cultured for 45 h in TCM199 supplemented with sodium pyruvate, gonadotropins, estradiol, and 10% porcine follicular fluid, with or without cysteamine (150 microM). Maturation rates of DOs cultured with and without cysteamine were not different (60-70%) but were significantly lower than those of COCs (90-100%) (p < 0.05). GSH content of matured DOs cultured with cysteamine was significantly higher than that of DOs cultured without cysteamine (p < 0.05). Values for both types of kinase activity in matured DOs cultured with and without cysteamine were not different (p > 0.05). After in vitro insemination, DOs cultured with cysteamine showed significantly higher rates of male pronuclear formation (80.3 +/- 3.0%) than DOs cultured without cysteamine (16.4 +/- 0.5%) (p < 0.05). These results indicate that the addition of cysteamine to culture medium increased oocyte GSH content and promoted male pronuclear formation after sperm penetration of porcine DOs but had no effects on their maturation rates or kinase activities.


Lymphatic venous anastomosis and complex decongestive therapy for lymphoedema: randomized clinical trial.
Lymphatic venous anastomosis is associated with a low incidence of lower extremity lymphoedema-associated cellulitis; however, the exact relationship is unknown. This multicentre RCT evaluated the effect of lymphatic venous anastomosis on prevention of cellulitis. Patients with secondary lower extremity lymphoedema who underwent at least 3 months of non-operative decongestive therapy were assigned randomly to lymphatic venous anastomosis or conservative therapy. The primary and secondary outcomes were cellulitis frequency, and assessments of circumference, hardness, and pain respectively. Overall, 336 patients were divided into two groups: 225 in the full-analysis set (primary outcome 225; secondary outcomes 170) and 156 in the per-protocol set (primary outcome 156; secondary outcomes 110). In both analyses, lymphatic venous anastomosis with non-operative decongestive therapy was more effective in preventing cellulitis than non-operative decongestive therapy alone; the difference between groups in reducing cellulitis frequency over 6 months was -0.35 (95 per cent c.i. -0.62 to -0.09; P = 0.010) in the full-analysis set (FAS) and -0.60 (-0.94 to -0.27; P = 0.001) in the per-protocol set (PPS) Limb circumference and pain were not significantly different, but lymphatic venous anastomosis reduced thigh area hardness (proximal medial and distal and lateral proximal). Four patients experienced contact dermatitis with non-operative decongestive therapy alone. Lymphatic venous anastomosis in combination with non-operative decongestive therapy prevents cellulitis. UMIN00025137, UMIN00031462.


Blood product wastage reduction by utilising low-cost, low-impact multimodal physician-to-physician communication initiatives.
To assess a multimodal physician-to-physician communication initiative that is low in cost and impact to daily workflow to reduce blood product wastage. Blood product stewardship is an important issue in all hospital systems. Previous studies have proposed low-cost interventions to reduce blood product wastage, but few have evaluated improvements in communication between the blood bank and providers. We undertook a prospective quality improvement project focusing on improving communication to reduce blood product wastage. We conducted a prospective quality improvement project over the first quarter of 2017, identifying patients with issued but unused blood products. Each service overseeing the care of patients identified on the unit status report was contacted through two possible methods: (i) phone or (ii) proprietary Health Insurance Portability and Accountability Act of 1996 compliant digital messaging application. Collected variables included reserved blood product type and participant time spent. Outcomes included the rate of blood product release and changes in wastage compared with historical data tracked by the blood bank. Eight hundred and forty products were reserved during the study period, of which 436 (52%) were released. Average participant times ranged from 2 ± 1 min to 15 ± 4 min with no significant differences in time spent between participants (P = 0·194). Compared with the average product wastage 10 months prior to project initiation, there were significant reductions in the average wastage for platelets (5·3 ± 2·5 units vs 2·5 ± 1·5 units, P = 0·05), RBCs (6·1 ± 3·7 units vs 0 ± 0 units, P = 0·01) and overall wastage (58·3 ± 14·9 units vs 40 ± 15·7 units, P = 0·05). Efforts focusing on improving provider-to-provider communication can reduce blood product wastage.


Effects of long-term treatment with recombinant human erythropoietin on physiologic inhibitors of coagulation.
Recombinant human erythropoietin (rHu-EPO) in the treatment of renal anemia might predispose to an increased risk of thrombotic complications. In an attempt to comprehend the involvement of the physiologic inhibitors of coagulation in this process, we studied 2 groups of hemodialysis patients. Group I included 21 patients receiving a starting dose of 90 IU/kg/week s.c., and group II included 17 patients without rHu-EPO. The following coagulation tests were performed before rHu-EPO treatment, and after 1, 6 and 12 months: prothrombin time; activated partial fistula thromboplastin time; fibrinogen; plasminogen activity; antithrombin III activity; protein C activity; total and free protein S antigens, and C4b binding protein. Only the latter three parameters were changed in group 1, while high baseline levels of protein S antigens were found in both groups. A decrease in total and free protein S was observed within 1 month of treatment. At the 6th month total protein S returned to near pretreatment values, whereas a significant fall in free protein S (p = 0.007) was observed. All three parameters returned to near baseline values by 12 months. These results suggest that protein S activity can be altered at the beginning of EPO therapy, a change that under favoring circumstances might contribute to the thrombotic events reported during the early phase of rHu-EPO treatment.


Delayed paraplegia 10 months after endovascular repair of thoracic aortic aneurysm.
Spinal cord ischemia after treatment of thoracic pathologies remains a devastating problem. A 74-year-old man with a history of infrarenal abdominal aortic aneurysm repair presented with bilateral common iliac and left femoral aneurysms as well as a thoracic aortic aneurysm. He underwent an open repair of the iliac and femoral aneurysms, followed by thoracic endovascular aneurysm repair in a staged manner without complications. Ten months later, he presented with hypotension, and permanent paraplegia developed.


Enobarbus is a synonym of Lepidocephalichthys (Osteichthyes, Cobitidae).
External and internal morphological characters of the holotype of Enobarbus maculatus were examined and compared with those of other cobitid species to verify whether Enobarbus is a distinct genus. Analyses of radiographs demonstrated that the neural spines and the pterygiophores of the dorsal fin are of irregular shape, often doubled, reduced or bent. The holotype of E. maculatus bears an ossified structure on the last pectoral-fin ray, a structure otherwise known only from males of the genus Lepidocephalichthys. In Lepidocephalichthys, the shape of the ossified structure is species-specific, and the structure of Enobarbus is very similar to that of Lepidocephalichthys thermalis, the only other known species of the family Cobitidae occurring at the type locality of Enobarbus. Furthermore, the cranial and the axial skeleton of E. maculatus is similar to that of L. thermalis, except for the pterygiophores and the neural spines, that are strongly malformed in Enobarbus. In general, the results presented here show that the genus Enobarbus shares the most important characters (thickening of last two pectoral-fin rays in males, structure of swimbladder capsule, shape of neurocranium and suborbital spine) with Lepidocephalichthys and that its long dorsal fin is correlated with strong malformations of the vertebral column and the fin ray insertions. Consequently, the only known specimen of Enobarbus is most likely a teratological male of L. thermalis, and Enobarbus is a junior synonym of Lepidocephalichthys.


Rejuveinix Shows a Favorable Clinical Safety Profile in Human Subjects and Exhibits Potent Preclinical Protective Activity in the Lipopolysaccharide-Galactosamine Mouse Model of Acute Respiratory Distress Syndrome and Multi-Organ Failure.
Background: New treatment platforms that can prevent acute respiratory distress syndrome (ARDS) or reduce its mortality rate in high-risk coronavirus disease 2019 (COVID-19) patients, such as those with an underlying cancer, are urgently needed. Rejuveinix (RJX) is an intravenous formulation of anti-oxidants and anti-inflammatory agents. Its active ingredients include ascorbic acid, cyanocobalamin, thiamine hydrochloride, riboflavin 5' phosphate, niacinamide, pyridoxine hydrochloride, and calcium D-pantothenate. RJX is being developed as an anti-inflammatory and anti-oxidant treatment platform for patients with sepsis, including COVID-19 patients with viral sepsis and ARDS. Here, we report its clinical safety profile in a phase 1 clinical study (ClinicalTrials.gov Identifier: NCT03680105) and its potent protective activity in the lipopolysaccharide galactosamine (LPS-GalN) mouse model of ARDS. Methods: A phase 1, double-blind, placebo-controlled, randomized, two-part, ascending dose-escalation study was performed in participating 76 healthy volunteer human subjects in compliance with the ICH (E6) good clinical practice guidelines to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RJX (Protocol No. RPI003; ClinicalTrials.gov Identifier: NCT03680105). The ability of RJX to prevent fatal shock, ARDS, and multi-organ failure was examined in the well-established LPS-GalN mouse model of sepsis and ARDS. Standard methods were employed for the statistical analysis of data in both studies. Findings: In the phase 1 clinical study, no participant developed serious adverse events (SAEs) or Grade 3-Grade 4 adverse events (AEs) or prematurely discontinued participation in the study. In the non-clinical study, RJX exhibited potent and dose-dependent protective activity, decreased the inflammatory cytokine responses (interleukin-6, tumor necrosis factor alpha, transforming growth factor beta), and improved survival in the LPS-GalN mouse model of sepsis and ARDS. Histopathological examinations showed that RJX attenuated the LPS-GalN induced acute lung injury (ALI) and pulmonary edema as well as liver damage. Conclusion: RJX showed a very favorable safety profile and tolerability in human subjects. It shows potential to favorably affect the clinical course of high-risk COVID-19 by preventing ARDS and its complications.


Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results.
Primary generalized dystonia (PGD) is a medically refractory disease of the brain causing twisting or spasmodic movements and abnormal postures. In more than 30% of cases it is associated with the autosomal DYT1 mutation. Continuous electrical stimulation of the globus pallidus internus (GPi) has been used successfully in the treatment of PGD. The aim of this study was to examine the long-term efficacy and safety of deep brain stimulation (DBS) in the treatment of PGD in children and adults with and without the DYT1 mutation. Thirty-one patients with PGD were selected for surgery. Electrodes were bilaterally implanted under stereotactic guidance and connected to neurostimulators that were inserted subcutaneously. Efficacy was evaluated by comparing scores on the clinical and functional Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) before and after implantation. The efficacy of stimulation improved with time. After 2 years, compared with preoperative values, the mean (+/- standard deviation) clinical and functional BFMDRS scores had improved by 79 +/- 19% and 65 +/- 33%, respectively. At the 2-year follow-up examination the improvement was comparable in patients with and without the DYT1 mutation in both the functional (p = 0.12) and clinical (p = 0.33) scores. Children displayed greater improvements in the clinical score than adult patients (p = 0.04) at 2 years of follow up. In contrast, there was no significant difference in functional scores between children and adults (p = 0.95). Electrical stimulation of the GPi is an effective, reversible, and adaptable treatment for PGD and should be considered for conditions refractory to pharmaceutical therapies.


Comparative analysis of steroids in cyclic and pregnant killer whales, beluga whales and bottlenose dolphins by liquid chromatography tandem mass spectrometry.
There exists a surprising diversity in the physiology and endocrinology of pregnancy among mammals in both the source (luteal/placental) and metabolism of progesterone. To evaluate the possible diversity of steroid metabolism within toothed cetaceans, we investigated 5α-reduced progesterone metabolites and androgens in cyclic (luteal phase) and pregnant captive killer whales, belugas and bottlenose dolphins (n = 5/species) bled longitudinally in early, mid- and late pregnancy (0.16, 0.50 and 0.85 fractions of 535, 464 and 380 gestation days, respectively). Mid-luteal samples were also collected. Serum was analyzed by liquid chromatography tandem-mass spectrometry as previously validated for (among others) progesterone, 20αOH-progesterone (20αOHP), 5α-dihydroprogesterone (DHP), several additional 5α-reduced metabolites and androgens (dehydroepiandrosterone, androstenedione and testosterone). The predominant mid-luteal pregnanes were: progesterone, belugas; progesterone and 20αOHP, dolphins; allopregnanolone (3α-DHP) and progesterone, killer whales. Progesterone was 2-4-fold higher in early pregnancy than mid-luteal samples but decreased thereafter. The predominant metabolite, 3β,20α-dihydroprogesterone (3β,20α-DHP; 40-80 ng/ml) was higher in mid- and late-than early gestation in all 3 species. Concentrations of 20αOHP and 3β,20α-DHP were similar at mid-gestation but 20αOHP declined in late-gestation in killer whales, and 20αOHP was lower than 3β,20α-DHP in belugas and dolphins throughout gestation. Other 5α-reduced metabolites, DHP, 3α-DHP and 20α-DHP, were far lower throughout pregnancy (<10 ng/ml). DHP and 3α-DHP decreased from early to mid-gestation in belugas, but changed little in killer whales and dolphins. These data suggest that progesterone metabolism is relatively conserved among these cetacean species. As in equine pregnancies, 3β,20α-DHP is the major metabolite, increasing at the expense of progesterone as pregnancy progresses. Androstenedione and testosterone also increased detectably in mid- to late-gestation in these species. The tissue source remains unknown, but progesterone metabolism during gestation in these cetaceans is similar to horses and, together with androgens, may be reliable biomarkers of pregnancy.


Effects of sodium butyrate on glucose transporter and glucose-phosphorylating enzyme gene expression in RINm5F insulinoma cells.
RINm5F insulinoma cells show a defective physiological insulin secretory response to glucose stimulation. The short chain carbonic acid sodium butyrate induced a growth arrest during a 72-h tissue culture period. In contrast to control RINm5F cells, 2 mM glucose increased insulin secretion by more than 70% in these sodium butyrate-treated cells (1 mM) without any further increase of the secretory rate between 2 and 20 mM glucose. This effect of sodium butyrate on insulin secretion was assessed in comparison with its effect on gene expression of the GLUT1 and GLUT2 glucose transporter, hexokinase type I and type II, glucokinase and insulin. Sodium butyrate at a 1 mM concentration decreased GLUT1 gene expression by nearly 50%, but did not induce gene expression of the low-affinity GLUT2 glucose transporter above the detection limit. Furthermore, sodium butyrate increased glucokinase gene expression by more than 50% and hexokinase type II gene expression by more than 100%, while insulin gene expression was increased only by 24%. Hexokinase type II enzyme activity was increased by more than 100% without a concomitant significant change of the glucokinase enzyme activity. Sodium butyrate (2 mM) caused effects comparable with those of 1 mM sodium butyrate. Thus the improved insulin secretory responsiveness of RINm5F insulinoma cells after sodium butyrate treatment at low non-physiological millimolar glucose concentrations can be interpreted as a result of an increased hexokinase-mediated metabolic flux rate through the glycolytic chain.


Foot surgery in Charcot-Marie-Tooth disease.
The preliminary study dealing with surgical treatment of foot deformity associated with CMT shows that the peroneal muscle may be functional in CMT but not measurable because of the deformity that it may have helped to create. The transfer of peroneus longus is designed to decrease deforming forces in conjunction with the Jones suspension that elevates the first ray. It assists the weak anterior muscle group. This, in addition to other surgical procedures as referenced, may be of help in correcting the foot deformity of CMT. Prognosis can be affected by the progression of the disease.


Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors.
Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2-8 μg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists.


Dissecting subunit interfaces in homodimeric proteins.
The subunit interfaces of 122 homodimers of known three-dimensional structure are analyzed and dissected into sets of surface patches by clustering atoms at the interface; 70 interfaces are single-patch, the others have up to six patches, often contributed by different structural domains. The average interface buries 1,940 A2 of the surface of each monomer, contains one or two patches burying 600-1,600 A2, is 65% nonpolar and includes 18 hydrogen bonds. However, the range of size and of hydrophobicity is wide among the 122 interfaces. Each interface has a core made of residues with atoms buried in the dimer, surrounded by a rim of residues with atoms that remain accessible to solvent. The core, which constitutes 77% of the interface on average, has an amino acid composition that resembles the protein interior except for the presence of arginine residues, whereas the rim is more like the protein surface. These properties of the interfaces in homodimers, which are permanent assemblies, are compared to those of protein-protein complexes where the components associate after they have independently folded. On average, subunit interfaces in homodimers are twice larger than in complexes, and much less polar due to the large fraction belonging to the core, although the amino acid compositions of the cores are similar in the two types of interfaces.


Geographical distribution of the red howler monkey (Alouatta seniculus) and yellow fever in Colombia.
Colombia is a country with an important diversity of non-human primates, of which the red howler monkey (Alouatta seniculus) stands out because of its distribution and the role it plays in the occurrence of yellow fever. To describe the geographic co-occurrence of Alouatta seniculus and the reported presence of yellow fever. We conducted a descriptive study. The reported presence of yellow fever in Colombia was obtained from the reports and bulletins issued by the Instituto Nacional de Salud, and the study by Segura, et al. (2013). The occurrence of A. seniculus was determined based on the data from the Global Biodiversity Information Facility and the Colombian Biodiversity Information System. A map of the occurrence was developed using the DIVA-GIS program, and the ecological niche model under current conditions was created with the Maxent program. The departments with the highest occurrence of A. seniculus were Antioquia, Meta and Casanare; 69.5% of the departments with reported history of yellow fever had co-occurrence with A. seniculus. The ecological niche model showed that Antioquia, Bolívar, La Guajira, Magdalena, Meta, Santander, Norte de Santander and Vichada had geographical portions with a probability rate nearing to 0.9 (90%). In 69.5% of the departments with a history of yellow fever there was co-occurrence with A. seniculus, which is relevant because non-human primates play a well-known role as natural reservoirs of the virus, and they might contribute to the occurrence of the yellow fever, which makes them very useful as sentinels.


Reliability and validity of spinal coordination patterns during treadmill walking in persons with thoracic spine pain--a preliminary study.
Persons with low back pain fail to show the same transition as healthy individuals from in-phase to anti-phase rotation of the thorax and pelvis as walking speed increases. The purpose of this study was to determine if the relative phase of the thorax and pelvis during walking was a reliable (within day test-retest) and valid measure for persons with thoracic pain. The time series motion of the spine over C7, T8 and sacrum were measured at five treadmill walking speeds (0.67, 0.89, 1.12, 1.34, 1.56 m/s) in 19 persons with thoracic spine pain and 19 healthy control subjects. After a 20 minute rest, all tests were repeated. The average relative phases of the transverse plane rotation between C7-T8, C7-sacrum and T8-sacrum during a one-minute walk were calculated. The standard error of measurement (SEM) and the intra-class correlation coefficient (ICC) were used to estimate test-retest reliability. Three-way repeated measures analyses of variance were performed to determine the influence of group, walking speed and session on the relative phases. The minimum transverse plane motion amplitudes, across all participants and speeds, for the C7-T8, C7-sacrum, and T8-sacrum were 2.9, 5.1 and 2.8 degrees, respectively. The C7-T8 relative phase changed little with speed. The C7-sacrum and T8-sacrum relative phases showed increases as subjects walked faster, but both groups had similar patterns of change. Only the C7-T8 relative phase at 0.67 and 0.89 m/s exhibited good reliability (ICC > 0.80, SEM 4.2-5.7, no significant time effects) for both groups. The C7-T8 and T8-sacrum relative phases demonstrated significant group by speed effects. The C7-T8 relative phase showed reasonable reliability and some discrimination between groups, but changes in response to walking speed were small. The T8-sacrum relative phase showed some discriminative ability, but reliability was not adequate.


The current role of video-assisted thoracic surgery (VATS) in the overall practice of thoracic surgery. A review of 207 cases.
From December 1991 to June 1995, video-assisted thoracic surgery (VATS) was performed on 207 patients at the Medical Center of Delaware with minimal complications and no mortality. A definitive diagnosis was made in all patients. Results with VATS procedures appear to be comparable to those with the standard open technique. Operating time was comparable to that with the open technique. Length of stay and pain and suffering were dramatically reduced compared with the open technique. We now consider VATS to be the preferred procedure in the following conditions: 1. Undiagnosed pulmonary infiltrate in the non-ventilator-dependent patient. 2. Indeterminate pulmonary nodule. 3. Undiagnosed disease of the pleural space. 4. Recurrent or persistent pneumothorax. 5. Mediastinal or pericardial cystic tumors. 6. Thoracic sympathectomy. 7. Selected patients requiring esophagocardiomyotomy. The utilization of VATS for resection of a pulmonary mass in patients with compromised pulmonary status (i.e., FEV < 1) is being studied.


A Graph Cut Approach to Artery/Vein Classification in Ultra-Widefield Scanning Laser Ophthalmoscopy.
The classification of blood vessels into arterioles and venules is a fundamental step in the automatic investigation of retinal biomarkers for systemic diseases. In this paper, we present a novel technique for vessel classification on ultra-wide-field-of-view images of the retinal fundus acquired with a scanning laser ophthalmoscope. To the best of our knowledge, this is the first time that a fully automated artery/vein classification technique for this type of retinal imaging with no manual intervention has been presented. The proposed method exploits hand-crafted features based on local vessel intensity and vascular morphology to formulate a graph representation from which a globally optimal separation between the arterial and venular networks is computed by graph cut approach. The technique was tested on three different data sets (one publicly available and two local) and achieved an average classification accuracy of 0.883 in the largest data set.


Oral immunization of rabbits against Pasteurella multocida with an alginate microsphere delivery system.
Oral delivery of microencapsulated antigens is a potential means to vaccinate rabbits against Pasteurella multocida, a common bacterial pathogen. Groups of five rabbits were dosed orally on days 0, 7, and 14 with alginate microspheres prepared to contain no added protein, 5 mg of a potassium thiocyanate extract of P. multocida (PTE), or 5 mg of PTE with 200 micrograms of cholera toxin (CT). In addition, groups were dosed orally with 5 mg of soluble PTE with or without 200 micrograms CT, intranasally (IN) with 1 mg of soluble PTE, or with saline. Serum and nasal lavage samples collected prior to initial immunization and 10, 16, and 21 days later were assayed by ELISA for anti-PTE IgG and IgA. Strong nasal lavage IgA and serum IgG activities were found in samples from rabbits immunized with PTE IN or orally when incorporated into microspheres. Addition of CT did not significantly enhance either response. To examine the development of protective immunity, groups were similarly immunized and challenge-exposed IN on day 16 with 10(6) CFU of P. multocida. One week later, rabbits were euthanized, and specimens from the lungs, nasopharynx, liver, and inner ear were cultured for P. multocida. Less severe infections of the lung and nasopharynx developed in rabbits immunized with PTE IN or orally in microspheres, with or without added CT. In addition, culture of liver and tympanic bullae samples from these rabbits yielded growth of P. multocida less frequently compared to other P. multocida-challenged rabbits. Coadministration of CT and PTE did not significantly improve protective immunity to challenge.


Leveraging Technology and Workflow Optimization for Health-Related Social Needs Screening: An Improvement Project at a Large Health System.
The collection of health-related social needs (HRSN) data at one large health system has historically been inconsistent. This project was aimed to increase annual HRSN screening rates by standardizing data collection in the electronic health record (EHR) through optimized clinical workflows. The authors designed a standard screening questionnaire in alignment with the Accountable Health Communities model, and they conducted interviews with eleven US-based health systems and one medical center on best practices for ambulatory HRSN screening and interventions, which identified five possible methods to administer the questionnaire. After testing, the authors opted to send questionnaires to patients through the patient portal three days prior to an ambulatory visit. For inpatients, in-person interviews were implemented. Staff implementing the updated processes included registered nurses, social workers, preventive health coordinators, and community health workers. The annual screening rate for all active ambulatory patients increased from 0.4% to 15.9% (p < 0.001), and 10.7% of all patients had at least one health-related social need. The annual screening rate for inpatients was estimated to be zero at baseline and increased by 66 percentage points (p < 0.001). The most prevalent health-related social need in both settings was financial resource strain, followed closely by food insecurity. Well-designed interventions and technology support were effective in achieving improved screening and data collection. Leadership support, building interventions within preexisting workflows, and ensuring standard data capture in the EHR were key factors leading to successful process improvement.


A New Methodology of Viewing Extra-Axial Fluid and Cortical Abnormalities in Children with Autism via Transcranial Ultrasonography.
Autism spectrum disorders (ASDs) are developmental conditions of uncertain etiology which have now affected more than 1% of the school-age population of children in many developed nations. Transcranial ultrasonography (TUS) via the temporal bone appeared to be a potential window of investigation to determine the presence of both cortical abnormalities and increased extra-axial fluid (EAF). TUS was accomplished using a linear probe (10-5 MHz). Parents volunteered ASD subjects (N = 23; males 18, females 5) for evaluations (mean = 7.46 years ± 3.97 years), and 15 neurotypical siblings were also examined (mean = 7.15 years ± 4.49 years). Childhood Autism Rating Scale (CARS2(®)) scores were obtained and the ASD score mean was 48.08 + 6.79 (Severe). Comparisons of the extra-axial spaces indicated increases in the ASD subjects. For EAF we scored based on the gyral summit distances between the arachnoid membrane and the cortical pia layer (subarachnoid space): (1) <0.05 cm, (2) 0.05-0.07 cm, (3) 0.08-0.10 cm, (4) >0.10 cm. All of the neurotypical siblings scored 1, whereas the ASD mean score was 3.41 ± 0.67. We also defined cortical dysplasia as the following: hypoechoic lesions within the substance of the cortex, or disturbed layering within the gray matter. For cortical dysplasia we scored: (1) none observed, (2) rare hypoechogenic lesions and/or mildly atypical cortical layering patterns, (3) more common, but separated areas of cortical hypoechogenic lesions, (4) very common or confluent areas of cortical hypoechogenicity. Again all of the neurotypical siblings scored 1, while the ASD subjects' mean score was 2.79 ± 0.93. TUS may be a useful screening technique for children at potential risk of ASDs which, if confirmed with repeated studies and high resolution MRI, provides rapid, non-invasive qualification of EAF, and cortical lesions.


Two drosophila melanogaster tRNAGly genes are contained in a direct duplication at chromosomal locus 56F.
One Drosophila melanogaster tRNAGly gene occurs on each 1.1-2.0 kb unit of a direct duplication at chromosomal region 56F. The nucleotide sequence of the gene and the 5' flanking region has been determined. The non-transcribed strand sequence of the tRNA gene is: 5' GCATCGGTGGTTCAGTGGTAGAATGCTCGCCTGCCACGCGGGCGGCCCGGGTTCGATTCCCGGCCGATGCA 3'. This nucleotide sequence is identical to that of the major glycine tRNA in Bombyx mori posterior silk gland. Within the 22 kb region mapped, additional tRNA genes are found, an observation consistent with reports that genes for other isoacceptors are present at this locus.


[Use of ultrasound for diagnosis of foreign bodies of the brain].
With the aid of modern ultrasonic diagnostic devices experiments were conducted in order to receive signals from foreign bodies of a different composition, non-radiocontrast ones including. Experiments on 10 human brain preparations revealed the typical peculiarities of echo-signal from foreign bodies in the cerebral matter. In 30 adult mongrel dogs it was proved that foreign bodies can be diagnosed in the course of primary and secondary debridement of skull and brain wounds. It was found that the shape and size of the foreign bodies in the human brain can be most explicitly determined with the aid of a specially designed device having a high azimuthal resolution.


[Gout and hyperuricaemia--should both be treated?].
Patients with increased levels of uric acid will usually be treated with drugs if symptoms of acute arthritis or kidney stones occur. Drugs for the treatment of acute arthritis attacks include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids systematically or injected into the joint, and colchicine. As prophylactic long-term treatment of recurring attacks, allopurinol, probenicide and colchicine are therapeutic alternatives. There is still no consensus on the treatment of individuals with asymptomatic hyperuricaemia.


Systematic functional perturbations uncover a prognostic genetic network driving human breast cancer.
Prognostic classifiers conceivably comprise biomarker genes that functionally contribute to the oncogenic and metastatic properties of cancer, but this has not been investigated systematically. The transcription factor Fra-1 not only has an essential role in breast cancer, but also drives the expression of a highly prognostic gene set. Here, we systematically perturbed the function of 31 individual Fra-1-dependent poor-prognosis genes and examined their impact on breast cancer growth in vivo. We find that stable shRNA depletion of each of nine individual signature genes strongly inhibits breast cancer growth and aggressiveness. Several factors within this nine-gene set regulate each other's expression, suggesting that together they form a network. The nine-gene set is regulated by estrogen, ERBB2 and EGF signaling, all established breast cancer factors. We also uncover three transcription factors, MYC, E2F1 and TP53, which act alongside Fra-1 at the core of this network. ChIP-Seq analysis reveals that a substantial number of genes are bound, and regulated, by all four transcription factors. The nine-gene set retains significant prognostic power and includes several potential therapeutic targets, including the bifunctional enzyme PAICS, which catalyzes purine biosynthesis. Depletion of PAICS largely cancelled breast cancer expansion, exemplifying a prognostic gene with breast cancer activity. Our data uncover a core genetic and prognostic network driving human breast cancer. We propose that pharmacological inhibition of components within this network, such as PAICS, may be used in conjunction with the Fra-1 prognostic classifier towards personalized management of poor prognosis breast cancer.


[Multidrug resistance P-glycoprotein inhibits the antiapoptotic action of mitochondria-targeted antioxidant SkQR1].
Mitochondria-targeted antioxidants of the SkQR1 family, being accumulated in energized mitochondria, protect cells from oxidative stress by increasing the level of reduced glutathione and decreasing the cell-damaging effect induced by hydrogen peroxide. Using various human transformed cell lines and SkQR1 (a fluorescent member of the SkQ family), we show that SkQRI is ejected from chemotherapy-resistant cells by P-glycoprotein - one of the main transport proteins determining multidrug resistance typical for many neoplastic cells. It is also shown that SkQR1 ejection is neutralized by P-glycoprotein inhibitors (verapamil and pluronic L61). In experiments on K562 cells, it was found that the subline sensitive to chemotherapy is protected by SkQRI from apoptotic action of hydrogen peroxide. Protection of the resistant subline occurs only after inhibition of P-glycoprotein.


Structure and reducibility of yttrium-doped cerium dioxide nanoparticles and (111) surface.
Using periodic density functional calculations, we studied the local structure and preferred locations of yttrium cations and oxygen vacancies in Y-doped cerium dioxide. We employed three kinds of models - a slab of the CeO2(111) surface and two ceria nanoparticles of different sizes and shapes. In the slab models, which represent the (111) surface of ceria and the corresponding extended terraces on the facets of its nanoparticles, Y3+ cation dopants were calculated to be preferentially located close to each other. They tend to surround a subsurface oxygen vacancy that forms to maintain the charge balance. Such general behavior was not found for the nanoparticle models, in which structural flexibility and the presence of various low-coordinated surface centers seem to be crucial and suppress most of the trends. Configurations with four Y3+ cations were calculated to be particularly stable when they combined two of the most stable configurations with two Y3+ cations. However, no clear trend was found regarding the preferential spatial distribution of the Y3+ pairs - they can be stable both in isolation and close to each other. In general, doping by yttrium does not notably change the reducibility of ceria systems but selectively facilitates the formation of oxygen vacancies at the ceria surface in comparison with pristine ceria. Yttrium cations also slightly increase the basicity of the nearby oxygen centers with respect to a stoichiometric ceria surface.


Orexin and Epilepsy: Potential Role of REM Sleep.
Interest in orexin receptor antagonism as a novel mechanism of action against seizures and epilepsy has increased in recent years. Loss of orexinergic activity is associated with rapid eye movement (REM) sleep onset, and REM sleep is generally protective against seizures. This paper discusses the dynamic modulation of seizure threshold by orexin through a postulated "orexi-cortical" axis in which the specific type of orexinergic activity exquisitely regulates sleep-wake states to modify ascending subcortical influences on cortical synchronization with profound subsequent consequences on seizure threshold. This paper also explores the current state of research into experimental orexinergic modulation of seizure threshold and suggests possible future research directions to fully understand the promise and peril of orexinergic manipulation in seizures and epilepsy.


Fluoride-induced changes in renal papillary cyclic-AMP.
Studies were conducted which examined urinary excretion and papillary production of cyclic-AMP in the rat following vasopressin (ADH) stimulation in the presence or absence of inorganic fluoride ion (F). In one set of experiments, six anesthetized Fischer 344 rats were administered 5 munits arginine vasopressin during iv saline and sodium fluoride (NaF) infusions. Urinary cyclic-AMP concentration was unchanged by ADH but declined during NaF infusion, while urinary cyclic-AMP excretion rate was unchanged by ADH or ADH/NaF. In a second set of experiments, 30 rats were divided into six groups of 5 each, and renal papilla and cortex were analyzed for cyclic-AMP. Group I was decapitated and not otherwise surgically manipulated. A second group had iv saline for 90 min while a third group had iv saline and ADH. A fourth group had isotonic NaF iv for 90 min and a fifth group had NaF and ADH. The results indicate that papillary cyclic-AMP is significantly increased by both ADH and NaF doses which did not cause changes in urinary cyclic-AMP excretion rates. We conclude from these experiments that determination of urinary cyclic-AMP concentration is not the best measure of vasopressin action and that tubular sensitivity to the hormone in the presence of F was better demonstrated by changes in papillary cyclic-AMP concentration. Further, it appears that the site of the biochemical renal lesion caused by F is at a site beyond the generation of cyclic-AMP.


The Health Threat Posed by the Hidden Epidemic of Anabolic Steroid Use and Body Image Disorders Among Young Men.
The prevalence of body image disorders and anabolic-androgenic steroid (AAS) use is increasing, despite the evidence of their serious adverse health effects and despite the passage of laws regulating their sales. Here we review the evolution of the dual emerging epidemics of body image disorders and AAS use, adverse health effects of AASs, and the need for an integrated health policy and regulatory response. We searched for studies published prior to June 2018. Quality of evidence was low to moderate because of its observational nature; heterogeneity of eligibility criteria; variable doses; reliance on retrospective self-reported data in many studies; and variable quality of outcome ascertainment. Most AAS users are nonathlete young men, who use these substances to look lean and more muscular. Some of these men suffer from "muscle dysmorphia," a form of body dysmorphic disorder. AASs has been associated with cardiovascular disorders, psychiatric disorders, AAS-withdrawal hypogonadism, infertility, neurotoxic effects, musculoskeletal injuries, liver toxicity, and needle-borne infections. Potential adverse effects may be compounded by the use of other substances (e.g., opioids) and high-risk behaviors. Unregulated Internet sales of AASs and selective androgen receptor modulators, which are easily purchased without a prescription, are of concern because of their potential to fuel the epidemic among adolescents and the military. Integrated nationwide efforts are necessary to raise public awareness of this epidemic, to study long-term health effects of AASs and treatment strategies, and to reform regulations to stem the epidemics of AAS use and body image disorders.


Profiling and Bioinformatic Analysis of Differentially Expressed Cytokines in Aqueous Humor of High Myopic Eyes - Clues for Anti-VEGF Injections.
Purpose: To investigate the aqueous humor growth factor profile in high myopic eyes and analyze the interaction of differentially expressed cytokines.Methods: A case-control study including aqueous humor samples from 36 high myopic patients and 32 controls was conducted. Quantibody® Human Growth Factor Array was used to screen the presence of 40 growth factors in aqueous humor. Expressions of differential growth factors were validated by Bio-Plex ProTM multiplex bead-based immunoassay. Protein-protein interaction (PPI) and gene ontology (GO) analyses were performed.Results: Growth differentiation factor 15 (GDF-15), hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF)-AA were found to be significantly higher and vascular endothelial growth factor (VEGF) was detected to be lower in high myopic eyes (all P = .03). Multi-plex bead-based assay further validated the differential expressions of four growth factors and all of them were significantly correlated with axial length (P < .001). Twenty-six proteins were mapped into PPI network and positive regulation of cell migration, cellular component movement, and cell motility were the most enriched biological processes based on GO analysis.Conclusions: Differential expressed cytokines that indicates a distinctive intraocular microenvironment in high myopic eyes might provide clues for pathological changes within high myopic eyes after anti-VEGF injections.


Teduglutide, a glucagon-like peptide-2 analog for the treatment of gastrointestinal diseases, including short bowel syndrome.
Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential for the prevention or treatment of an expanding number of gastrointestinal diseases, including short bowel syndrome (SBS). Teduglutide, being developed by NPS Allelix and licensee Nycomed, is a protease-resistant analog of GLP-2 for the potential treatment of gastrointestinal disease. Teduglutide has prolonged biological activity compared with native GLP-2, and preclinical studies demonstrated significant intestinotrophic activity in models of SBS, experimental colitis and chemotherapy-induced intestinal mucositis. Patients with SBS rely on parenteral nutrition (PN) following bowel resection, and in a phase III clinical trial with teduglutide, > 20% reduction in PN was observed in patients with SBS receiving teduglutide. A phase II clinical trial for teduglutide in Crohn's disease observed remission rates of 55.6% in patients. At the time of publication, phase III clinical trials for SBS were ongoing, as were preclinical studies for chemotherapy-induced mucositis and pediatric indications. Teduglutide represents a novel, efficacious drug capable of increasing intestinal growth and improving intestinal function, and may change clinical management of intestinal disease and damage.


Developmental programmes of growth and survival in early sensory neurons.
In the developing vertebrate nervous system the survival of neurons becomes dependent on the supply of a neurotrophic factor from their targets when their axons reach these targets. To determine how the onset of neurotrophic factor dependency is coordinated with the arrival of axons in the target field, we have studied the growth and survival of four populations of cranial sensory neurons whose axons have markedly different distances to grow to reach their targets. Axonal growth rate both in vivo and in vitro is related to target distance; neurons with more distant targets grow faster. The onset trophic factor dependency in culture is also related to target distance; neurons with more distant targets survive longer before becoming trophic factor dependent. These data suggest that programmes of growth and survival in early neurons play an important role in coordinating the timing of trophic interactions in the developing nervous system.


High prevalence of daily and multi-site pain--a cross-sectional population-based study among 3000 Danish adolescents.
Daily pain and multi-site pain are both associated with reduction in work ability and health-related quality of life (HRQoL) among adults. However, no population-based studies have yet investigated the prevalence of daily and multi-site pain among adolescents and how these are associated with respondent characteristics. The purpose of this study was to investigate the prevalence of self-reported daily and multi-site pain among adolescents aged 12-19 years and associations of almost daily pain and multi-site pain with respondent characteristics (sex, age, body mass index, HRQoL and sports participation). A population-based cross-sectional study was conducted among 4,007 adolescents aged 12-19 years in Denmark. Adolescents answered an online questionnaire during physical education lessons. The questionnaire contained a mannequin divided into 12 regions on which the respondents indicated their current pain sites and pain frequency (rarely, monthly, weekly, more than once per week, almost daily pain), characteristics, sports participation and HRQoL measured by the EuroQoL 5D. Multivariate regression was used to calculate the odds ratio for the association between almost daily pain, multi-site pain and respondent characteristics. The response rate was 73.7%. A total of 2,953 adolescents (62% females) answered the questionnaire. 33.3% reported multi-site pain (pain in > 1 region) while 19.8% reported almost daily pain. 61% reported current pain in at least one region with knee and back pain being the most common sites. Female sex (OR: 1.35-1.44) and a high level of sports participation (OR: 1.51-2.09) were associated with increased odds of having almost daily pain and multi-site pain. Better EQ-5D score was associated with decreased odds of having almost daily pain or multi-site pain (OR: 0.92-0.94). In this population-based cohort of school-attending Danish adolescents, nearly two out of three reported current pain and, on average, one out of three reported pain in more than one body region. Female sex, and high level of sports participation were associated with increased odds of having almost daily pain and multi-site pain. The study highlights an important health issue that calls for investigations to improve our understanding of adolescent pain and our capacity to prevent and treat this condition.


"Excessive thinking" as explanatory model for schizophrenia: impacts on stigma and "moral" status in Mainland China.
Although psychiatric stigma in China is particularly pervasive and damaging, rates of high expressed emotion ("EE" or family members' emotional attitudes that predict relapse) are generally lower than rates found in Western countries. In light of this seemingly incongruous juxtaposition and because Chinese comprise approximately one-fifth of the world's mentally ill, we examine how one of the most widely held causal beliefs of schizophrenia--excessive thinking (xiang tai duo)--may powerfully shape how those exhibiting psychotic symptoms pass from "normal" status to stigmatized "other." Using a framework by which stigma threatens an actor's capacity to participate in core everyday engagements, we examine how expressions of excessive thinking intersect with psychotic symptoms and how this idiom reduces stigma by preserving essential moral standing. Four focus groups with family members (n = 34 total) of schizophrenia outpatients, who had participated in psychoeducation, were conducted in Beijing. Open coding was conducted by 2 bilingual coders achieving high interrater agreement. Common expressions of excessive thinking--taking things too hard that is perceived as a causal factor and unwarranted suspicion that is used to benignly interpret paranoid symptoms encapsulated disruptive behaviors that closely overlapped with psychotic symptoms. Because excessive thinking is understood to occur universally, this idiom encourages socially accommodating behavior that signifies acceptance of these individuals as full-status community members. In contrast, due to beliefs implying moral contamination, those labeled mentally ill are threatened with both subtle and outright social exclusion. We discuss implications of this idiom for EE and the detection of schizophrenia "prodrome" in China.


Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study.
Rare mutations of the low-density lipoprotein receptor gene (LDLR) cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD). Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD. Imputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP) within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals. Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI) [0.13-0.24] mmol/L, p = 1.5x10(-10)). This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76-0.89], p = 2.1x10(-7)). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD. A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.


Evaluating the traditional day and night shift in an acute care surgery fellowship: Is the swing shift a better choice?
Fellowship trainees in acute care surgery require experience in the management of complex and operative trauma cases. Trauma center staffing usually follows standard 12-hour or 24-hour shifts, with resident and fellow trainees following a similar schedule. Although trauma admissions can be generally unpredictable, we analyzed temporal trends of trauma patient arrival times to determine the best time frame to maximize trainee experience during each day. We reviewed 10 years (2007-2016) of trauma registry data for blunt and penetrating trauma activations. Hourly volumetric trends were observed, and three specific events were chosen for detailed analysis: (1) trauma activation with Injury Severity Score (ISS) greater than 15, (2) laparotomy for trauma, and (3) thoracotomy for trauma. A retrospective shift log was created, which included day (7:00 AM to 7:00 PM), night (7:00 PM to 7:00 AM), and swing (noon to midnight) shifts. A swing shift was chosen because it captures the peak volume for all three events. Means and 95% confidence intervals were calculated, and comparisons were made between shifts using the Wilcoxon matched-pairs signed rank test with Bonferroni correction, and p less than 0.05 considered significant. During the 10-year study period, 28,287 patients were treated at our trauma center. This included the evaluation and management of 7,874 patients with ISS greater than 15, performance of 1,766 laparotomies, and 392 thoracotomies for trauma. Swing shift was superior to both day and night shifts for ISS greater than 15 (p < 0.001). Both swing and night shifts were superior to day shift for laparotomies (p < 0.001). Swing shift was superior to both day shift (p < 0.001) and night shift (p = 0.031). Shifts with the highest yield of ISS greater than 15, laparotomies, and thoracotomies include night and swing shifts on Fridays and Saturdays. Projected experience of acute care surgery fellows in managing complex trauma patients increases with the integration of swing shifts into the schedule. Daily trauma volume follows a temporal pattern which, when used correctly, can increase trainee exposure to complex and operative trauma cases. We encourage other centers to analyze their volume and adjust trainee schedules accordingly to maximize their educational experience. Therapeutic study, level IV.


Successful generation of primary virus-specific and anti-tumor T-cell responses from the naive donor T-cell repertoire is determined by the balance between antigen-specific precursor T cells and regulatory T cells.
One of the major challenges in allogeneic stem cell transplantation is to find a balance between the harmful induction of graft-versus-host disease and the beneficial graft-versus-leukemia and pathogen-specific immune responses. Adoptive transfer of in-vitro generated donor T cells with specific anti-leukemic or pathogen-specific activity may be effective. However, in many cases this requires the in-vitro priming and expansion of antigen-specific precursor T cells from the naïve donor T-cell repertoire. Antigen-specific CD8 T cells were generated by co-culture of CD45RO-depleted, regulatory T cell-depleted donor peripheral blood mononuclear cells with autologous peptide-loaded dendritic cells, followed by two re-stimulations with peptide-loaded autologous monocytes. Responding T cells were isolated based on CD137 expression and further purified using peptide/major histocompatibility complex tetramers. Using this method we were able to reproducibly generate functionally high avidity T cells directed against multiple viral antigens and minor histocompatibility antigens from the naïve T-cell repertoire of seronegative, minor histocompatibility antigen-negative donors. Furthermore, we demonstrated that reduction of the regulatory T-cell frequency by depletion of CD45RO(+) responder cells resulted in improved priming and expansion of antigen-specific precursor T cells. In conclusion, we present a robust method for the in-vitro induction and isolation of antigen-specific T cells from the naïve repertoire. We demonstrate that the likelihood of successful generation of primary immune responses is determined by a delicate balance between the numbers of antigen-specific precursor T cells and the numbers and activation state of regulatory T cells locally at the site of priming of the immune response.


A gene-based analysis of variants in the serum/glucocorticoid regulated kinase (SGK) genes with blood pressure responses to sodium intake: the GenSalt Study.
Serum and glucocorticoid regulated kinase (SGK) plays a critical role in the regulation of renal sodium transport. We examined the association between SGK genes and salt sensitivity of blood pressure (BP) using single-marker and gene-based association analysis. A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) was conducted among 1,906 Chinese participants. BP measurements were obtained at baseline and each intervention using a random-zero sphygmomanometer. Additive associations between each SNP and salt-sensitivity phenotypes were assessed using a mixed linear regression model to account for family dependencies. Gene-based analyses were conducted using the truncated p-value method. The Bonferroni-method was used to adjust for multiple testing in all analyses. In single-marker association analyses, SGK1 marker rs2758151 was significantly associated with diastolic BP (DBP) response to high-sodium intervention (P = 0.0010). DBP responses (95% confidence interval) to high-sodium intervention for genotypes C/C, C/T, and T/T were 2.04 (1.57 to 2.52), 1.79 (1.42 to 2.16), and 0.85 (0.30 to 1.41) mmHg, respectively. Similar trends were observed for SBP and MAP responses although not significant (P = 0.15 and 0.0026, respectively). In addition, gene-based analyses demonstrated significant associations between SGK1 and SBP, DBP and MAP responses to high sodium intervention (P = 0.0002, 0.0076, and 0.00001, respectively). Neither SGK2 nor SGK3 were associated with the salt-sensitivity phenotypes in single-maker or gene-based analyses. The current study identified association of the SGK1 gene and BP salt-sensitivity in the Han Chinese population. Further studies are warranted to identify causal SGK1 gene variants.


[Development of circularity as a manifestation of schizophrenic pathomorphosis].
On the basis of literature data and personal experience the author indicates the pathomorphosis of schizophrenia towards its circularization. It is claimed that this phenomenon cannot be explained entirely by the use of psychotropic drugs. A study of the reasons of such "nontherapeutical" pathomorphosis requires special studies. A necessary condition for such studies is a clear selection of clinical material. In this relation the author proposes to base such studies on the origin of cyclothymic disorders which may stem from typological traits of the circular form, or from a predisposition to vital-affective registers in the premorbid personality or developed in the process of schizophrenia. Some clinical features of the disease connected with affective pathology are discussed.


Iron burns to the hand in the young pediatric patient: a problem in prevention.
Iron burns to the hand may result in both functional and cosmetic deformities in the young pediatric patient. To gain a better understanding of these injuries in terms of demographics, treatment, and outcome, and to address possible measures for prevention, the medical records of 82 pediatric patients suffering iron burns to the hand during the period 1987 to 1993 were reviewed. Iron burns to the hand occurred most commonly in male children less than 2 years of age. Most were minor partial-thickness burns that were treated in the outpatient setting with no adverse sequelae. Fifteen percent of patients, however, sustained full-thickness burns that required grafting. Ten percent of patients developed complications including hypertrophic scarring and scar contractures requiring surgical release. Socioeconomic factors and parental inexperience appeared to play a significant role, as most of these injuries occurred in low-income, single-parent, single-child households. Most injuries were unintentional, however, many were caused by carelessness or neglect. Abuse was suspected or proven in 7% of cases. Parents may be unaware of the consequences of leaving a child unattended in the presence of a hot iron. The incidence of these injuries could be reduced effectively by improved public awareness of the problem and education in prevention.


Silica directly increases permeability of alveolar epithelial cells.
Alveolar epithelial cell injury and increased alveolar-capillary membrane permeability are important features of acute silicosis. To determine whether silica particles contribute directly to this increased permeability, we measured paracellular permeability of rat alveolar epithelium after exposure to silica, in vitro, using markers of the extracellular space. Silica (Minusil) markedly increased permeability in a dose- and time-dependent manner. This was not the result of cytolytic injury, because lactate dehydrogenase release from monolayers exposed to silica was not increased. Pretreatment of the silica with serum, charged dextrans, or aluminum sulfate blocked the increase in permeability. Scanning electron microscopy demonstrated adherence of the silica to the surface of the alveolar epithelial cells. Thus silica can directly increase permeability of alveolar epithelium.


Elastolysis in lichen ruber planus.
The dermal elastic fiber network was studied in specimens from five patients with lichen ruber planus, using a standard elastin staining procedure (orcein), results being compared with those for the elastin-associated microfibrillar network stained using anti-fibrillin antibodies in an immunofluorescence and an avidin-biotin-peroxidase complex technique. Additional specimens of healed apparently normal skin were taken from two of the patients. Orcein-stained fibers were scarce or absent in the inflammatory zone in all the lesions. In contrast, an extensive fibrillin immunoreactive network was present in the papillary zone in all the specimens, in a pattern similar to that of normal skin. In specimens from healed lesions of lichen ruber planus, dermal orcein-stained fibers were present in the papillary dermis. The findings indicate that the amorphous component of elastic fibers is destroyed during the acute phase of lichen ruber planus. Hypothetically, the elastolysis is caused by elastases released from macrophages known to be present in the lichenoid infiltrate. In contrast, the fibrillin fiber network seems to be less or not at all affected by proteolytic events during the inflammatory phase of lichen ruber planus.


What Changes Would Manitoba First Nations Like to See in the Primary Healthcare They Receive? A Qualitative Investigation.
First Nations (FN) have unique perspectives and experiences of health and healthcare services, which are critical to the provision of effective community-based primary healthcare (CBPHC). This paper shares FN perspectives on primary healthcare (PHC), taking geographical, cultural and historical realities into account, to elucidate opportunities to improve current healthcare services. Semi-structured in-depth qualitative interviews were completed with 183 residents of 8 Manitoba FN communities. Grounded theory-guided data analysis was conducted. Improving PHC performance requires delivering timely and holistic healthcare that integrates traditional health knowledge, comprehensive CBPHC increasing services such as healthcare and medical transportation, healthy food as an important preventative measure and a culturally informed workforce backed by local leadership and promoting cultural respect. The relationship between self-determination and health is a critical factor in the implementation of CBPHC. FN must be respected to decide healthcare priorities that reflect the needs and visions of each community.


Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors.
Gastrointestinal stromal tumors (GISTs) have been recognized as the most common mesenchymal tumors of the gastrointestinal tract. The most effective treatment for unresectable tumors is imatinib mesylate, based on two phase II trials. Because no phase III clinical trial has been undertaken, we sought to determine both current population-based incidence and whether improved outcomes noted in both individual centers and clinical trials have also been observed in a large prospective cancer registry earlier and after the introduction of imatinib. The 13-center cumulative tumor registry (April 2005 release) from the Surveillance, Epidemiology, and End Results (SEER) database was queried from 1992 to 2002 to determine incidence and associated outcomes for patients diagnosed with GIST. Confirmations of incidence trends using the incident Florida Cancer Data System (FCDS, 2005 release) were also determined. A 25-fold age-adjusted increase in incidence of GIST, from 0.028 per 100,000 in 1992 to 0.688 per 100,000 in 2002, was observed. This increase is mostly because smooth-muscle tumors have been reclassified as GISTs, but it also represents a 50% increase in population- and age-adjusted gastrointestinal mesenchymal tumor diagnosis since 1992. Despite rising GIST incidence rates, there has been a marked improvement in survival since 2000, coinciding with the introduction of the tyrosine kinase inhibitor imatinib into clinical practice. The diagnosis of GIST has dramatically increased since 1992. Survivals have greatly improved since 2000, when imatinib mesylate was FDA approved.


Enhancement of mammary tumor formation in mice by a cytostatic drug, melphalan.
Melphalan (L-phenylalanine mustard), a cytostatic drug used in treatment of human breast cancer, was injected into mice bearing preneoplastic hyperplastic alveolar nodule mammary outgrowth line D2. Melphalan, doses of either 2.5 or 5.0 mg/kg, markedly enhanced tumor formation in its mammary nodule outgrowth line. Samples of nodule outgrowths in untreated mice produced 13% tumors by 9 months after transplantation, whereas nodule outgrowths in melphalan-treated mice produced 57 and 85% mammary tumors in the lower and higher dose groups, respectively.


Children's capacity to remember a novel problem and to secure its future solution.
Much of humans' success rests on foresight, the ability to predict what will happen or what is needed in the future. Surprisingly little is known about how this faculty develops. In three experiments (N = 170), 3- and 4-year-old children were presented with simple puzzles. Fifteen minutes later in a different room they were given the opportunity to secure a solution to take back to the puzzle. Only the older children performed above chance, whereas both age groups could solve the task in an instant condition. The same pattern of results emerged for another task involving selection of something to 'feed ' a puppet whose favorite food was initially unavailable. Control conditions suggest that temporal rather than spatial displacement influenced performance. Verbal reports substantiated the conclusion that by age 4 some children can remember a novel problem sufficiently enough to recognize a solution and select that solution in anticipation of applying it to the problem in the future.


Prevalence and Characteristics of Antimicrobial-Resistant Staphylococcus aureus and Methicillin-Resistant Staphylococcus aureus from Retail Meat in Korea.
This study was to investigate the prevalence and characteristics of antimicrobial-resistant Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) from 4,264 retail meat samples including beef, pork, and chicken in Korea between 2013 and 2018. A broth microdilution antimicrobial susceptibility testing was performed for S. aureus. Molecular typing by multilocus sequence typing (MLST), spa typing, and pulsed-field gel electrophoresis (PFGE), was performed on mecA-positive S. aureus strain. S. aureus was isolated at a rate of 18.2% (777/4,264), of which MRSA comprised 0.7% (29 strains). MLST analysis showed that 11 out of the 29 MRSA isolates were predominantly sequence type (ST) 398 (37.9%). In addition, ST72, ST692, ST188, ST9, and ST630 were identified in the MRSA isolates. The spa typing results were classified into 11 types and showed a high correlation with MLST. The antimicrobial resistance assays revealed that MRSA showed 100% resistance to cefoxitin and penicillin. In addition, resistance to tetracycline (62.1%), clindamycin (55.2%), and erythromycin (55.2%) was relatively high; 27 of the 29 MRSA isolates exhibited multidrug resistance. PFGE analysis of the 18 strains excluding the 11 ST398 strains exhibited a maximum of 100% homology and a minimum of 64.0% homology. Among these, three pairs of isolates showed 100% homology in PFGE; these results were consistent with the MLST and spa typing results. Identification of MRSA at the final consumption stage has potential risks, suggesting that continuous monitoring of retail meat products is required.


Structure of a paramyxovirus polymerase complex reveals a unique methyltransferase-CTD conformation.
Paramyxoviruses are enveloped, nonsegmented, negative-strand RNA viruses that cause a wide spectrum of human and animal diseases. The viral genome, packaged by the nucleoprotein (N), serves as a template for the polymerase complex, composed of the large protein (L) and the homo-tetrameric phosphoprotein (P). The ∼250-kDa L possesses all enzymatic activities necessary for its function but requires P in vivo. Structural information is available for individual P domains from different paramyxoviruses, but how P interacts with L and how that affects the activity of L is largely unknown due to the lack of high-resolution structures of this complex in this viral family. In this study we determined the structure of the L-P complex from parainfluenza virus 5 (PIV5) at 4.3-Å resolution using cryoelectron microscopy, as well as the oligomerization domain (OD) of P at 1.4-Å resolution using X-ray crystallography. P-OD associates with the RNA-dependent RNA polymerase domain of L and protrudes away from it, while the X domain of one chain of P is bound near the L nucleotide entry site. The methyltransferase (MTase) domain and the C-terminal domain (CTD) of L adopt a unique conformation, positioning the MTase active site immediately above the poly-ribonucleotidyltransferase domain and near the likely exit site for the product RNA 5' end. Our study reveals a potential mechanism that mononegavirus polymerases may employ to switch between transcription and genome replication. This knowledge will assist in the design and development of antivirals against paramyxoviruses.


Measurement of the metabolism of cytochrome P-450 in cultured hepatocytes by a quantitative and specific immunochemical method.
We have defined conditions that permit quantitative and specific measurement of the metabolism of the major phenobarbital-inducible form of cytochrome P-450 protein in primary non-proliferating monolayer cultures of adult rat hepatocytes. Isolated antibodies specifically directed against phenobarbital cytochrome P-450 are used to immunoprecipitate the cytochrome from lysates of cultured hepatocytes pulse-labelled with [(3)H]leucine. Phenobarbital cytochrome P-450 protein is then isolated from the immunoprecipitate by electrophoresis on polyacrylamide gradient slab gels. Specificity of the assay for phenobarbital cytochrome P-450 was established by competition experiments involving other forms of purified cytochrome P-450 as well as by testing antibodies directed against these other forms of the cytochrome. Using purified phenobarbital cytochrome P-450, radiolabelled in both its haem and apoprotein portions, as an internal standard, we demonstrated that, with this immunoassay, recovery of cytochrome P-450 from microsomal samples is nearly complete. Basal rates of synthesis of phenobarbital cytochrome P-450 representing as little as 0.02-0.05% of total cellular protein synthesis were reliably and reproducibly detected in hepatocyte culture maintained in serum-free medium for 72h. Moreover, inclusion of phenobarbital in the culture medium for 96h stimulated not only synthesis de novo of phenobarbital cytochrome P-450 protein, but also accumulation of spectrally and catalytically active cytochrome P-450. Advantages of this immunoassay are that metabolism (synthesis or degradation) of the haem or protein of this important form of the cytochrome can be measured conveniently in the small samples available from cultured cells without the necessity of preparing subcellular fractions.


Missing (in-situ) snow cover data hampers climate change and runoff studies in the Greater Himalayas.
The Himalayas are presently holding the largest ice masses outside the polar regions and thus (temporarily) store important freshwater resources. In contrast to the contemplation of glaciers, the role of runoff from snow cover has received comparably little attention in the past, although (i) its contribution is thought to be at least equally or even more important than that of ice melt in many Himalayan catchments and (ii) climate change is expected to have widespread and significant consequences on snowmelt runoff. Here, we show that change assessment of snowmelt runoff and its timing is not as straightforward as often postulated, mainly as larger partial pressure of H2O, CO2, CH4, and other greenhouse gases might increase net long-wave input for snowmelt quite significantly in a future atmosphere. In addition, changes in the short-wave energy balance - such as the pollution of the snow cover through black carbon - or the sensible or latent heat contribution to snowmelt are likely to alter future snowmelt and runoff characteristics as well. For the assessment of snow cover extent and depletion, but also for its monitoring over the extremely large areas of the Himalayas, remote sensing has been used in the past and is likely to become even more important in the future. However, for the calibration and validation of remotely-sensed data, and even more so in light of possible changes in snow-cover energy balance, we strongly call for more in-situ measurements across the Himalayas, in particular for daily data on new snow and snow cover water equivalent, or the respective energy balance components. Moreover, data should be made accessible to the scientific community, so that the latter can more accurately estimate climate change impacts on Himalayan snow cover and possible consequences thereof on runoff.