Visual tracking and its relationship to cortical development.
Measurements of visual tracking in infants have been performed from 2 weeks of age. Although directed appropriately, the eye movements are saccadic at this age. Over the first 4 months of life, a rapid transition to successively smoother eye movements takes place. Timing develops first and at 7 weeks of age the smooth pursuit is well timed to a sinusoidal motion of 0.25 Hz. From this age, the gain of the smooth pursuit improves rapidly and from 4 months of age, smooth pursuit dominates visual tracking in combination with head movements. This development reflects massive cortical and cerebellar changes. The coordination between eyes-head-body and the external events to be tracked presumes predictive control. One common type of model for explaining the acquisition of such control focuses on the maturation of the cerebellar circuits. A problem with such models, however, is that although Purkinje cells and climbing fibers are present in the newborn, the parallel and mossy fibers, essential for predictive control, grow and mature at 4-7 months postnatally. Therefore, an alternative model that also includes the prefrontal cerebral cortex might better explain the early development of predictive control. The prefrontal cortex functions by 3-4 months of age and provides a site for prediction of eye movements as a part of cerebro-cerebellar nets.


Seat belt-related injuries: A surgical perspective.
Legislation making seatbelt use mandatory is considered to have reduced fatal and serious injuries by 25%, with UK government estimates predicting more than 50,000 lives saved since its introduction. However, whilst the widespread use of seatbelts has reduced the incidence of major traumatic injury and death from road-traffic collisions (RTCs), their use has also heralded a range of different injuries. The first ever seatbelt related injury was described in 1956, and since then clear patterns of seatbelt-related injuries have been recognised. This review of the published literature demonstrates that the combination of airbags and three-point seatbelts renders no part of the body free from injury. Serious injuries can, and do, occur even when passengers are properly restrained and attending clinicians should have a high index of suspicion for overt or covert intra-abdominal injuries when patients involved in RTCs attend the Emergency Department. Bruising to the trunk and abdomen in a seatbelt distribution is an obvious sign that suggests an increased risk of abdominal and thoracic injury, but bruising may not be apparent and its absence should not be falsely reassuring. A high index of suspicion should be retained for other subtler signs of injury. Children and pregnant women represent high-risk groups who are particularly vulnerable to injuries. In this review we highlight the common patterns of seatbelt-related injuries. A greater awareness of the type of injuries caused by seatbelt use will help clinicians to identify and treat overt and covert injuries earlier, and help reduce the rates of morbidity and mortality following RTCs.


The interactions between TiO2 and graphene with surface inhomogeneity determined using density functional theory.
TiO2/graphene composites have shown promise as photocatalysts, leading to improved electronic properties. We have modeled using density functional theory TiO2/graphene interfaces formed between graphene with various defects/functional groups (C vacancy, epoxide, and hydroxyl) and TiO2 clusters of various sizes. We considered clusters from 3 to 45 atoms, the latter a nanoparticle of ∼1 nm in size. Our results show that binding to pristine graphene is dominated by van der Waals forces, and that C vacancies or epoxide groups lead to much stronger binding between the graphene and TiO2. Such sites may serve to anchor TiO2 to graphene. Graphene surfaces with hydroxyls however lead to OH transfer to TiO2 and weak interactions between the graphene and the hydroxylated TiO2 cluster. Charge transfer may occur between TiO2 and graphene in various directions (graphene to TiO2 or TiO2 to graphene), depending on the state of the graphene surface, based on overlap of the density of states. Our work indicates that graphene surface defects or functional groups may have a significant effect on the stability, structure, and photoactivity of these materials.


Sex difference in driving speed management: The mediation effect of impulse control.
Previous studies have shown that male drivers drive faster than female drivers, but there is no agreement on whether impulsivity could induce this sex difference, nor is there a cross-sectional comparison of the effects of different road environments. The purpose of this study was to verify whether impulsivity and impulse control could explain the sex differences in driving speed. A driving simulator study (study 1, N = 41) was performed to investigate whether there were sex differences in driving speeds in two road sections of different complexity, and a questionnaire survey (study 2, N = 163) was conducted to investigate the relationship between sex, impulsivity, impulse control and driving behavior of the participants. The results showed that male drivers drove faster on simple roads, but this difference did not show on complex roads. There were no sex differences in impulsivity traits, but male participants had significant lower levels of impulse control. The results also reveal a partial mediating role of impulse control in the relationship between sex and driving speed. These results suggest that impulse control can predict dangerous driving behaviors and is an important factor in explaining sex differences in driving speed.


Using service rationalisation to build a research network: lessons from the centralisation of UK services for children with cleft lip and palate.
In the UK around a thousand children are born annually with a cleft lip and/or palate that requires treatment. In the last decade services have been centralised in the UK reducing the 57 centres operating on these children in 1998, down to 11 centres or managed clinical networks in 2011. While the rationale for centralisation was to improve the standard of care (and in so doing the outcome) for children born with cleft lip and/or palate, research was central to this process. We illustrate how research informed and shaped this service rationalisation and how it facilitated the emergence of a research culture within the newly configured teams. We also describe how these changes in service provision were linked to the development of a national research strategy and to the identification of the resources necessary to support this strategy.


Issues in summer safety: a call for sun protection.
Summer is associated with vacation and time spent in the outdoors. It is also a time when parents and children need to be reminded of the dangers and long-term health effects of being exposed to hazards of the sun. It has been estimated that the regular use of sunscreen during childhood would reduce the lifetime incidence of certain types of skin cancer by 78%. Selecting a sunscreen may be a difficult task. Pediatric nurses and other health care professionals are in a pivotal position to educate both parents and children on the benefits of sun protection and offer information about strategies for enjoying a safe summer.


Response of Human Immunodeficiency Virus-Associated Cerebral Angiitis to the Combined Antiretroviral Therapy.
When secondary causes are excluded, mechanisms underlying central nervous system angiitis (ACNS) in human immunodeficiency virus (HIV)-infected patients are still not understood and optimal treatment remains undefined. We report here a patient with an untreated HIV infection who presented multiple ischemic strokes probably due to HIV-ACNS. ACNS signs on vessel-wall imaging magnetic resonance monitoring retracted with combined antiretroviral therapy without adjunct immunosuppressive drugs.


HIV-1 neuropathogenesis: glial mechanisms revealed through substance abuse.
Neuronal dysfunction and degeneration are ultimately responsible for the neurocognitive impairment and dementia manifest in neuroAIDS. Despite overt neuronal pathology, HIV-1 does not directly infect neurons; rather, neuronal dysfunction or death is largely an indirect consequence of disrupted glial function and the cellular and viral toxins released by infected glia. A role for glia in HIV-1 neuropathogenesis is revealed in experimental and clinical studies examining substance abuse-HIV-1 interactions. Current evidence suggests that glia are direct targets of substance abuse and that glia contribute markedly to the accelerated neurodegeneration seen with substance abuse in HIV-1 infected individuals. Moreover, maladaptive neuroplastic responses to chronic drug abuse might create a latent susceptibility to CNS disorders such as HIV-1. In this review, we consider astroglial and microglial interactions and dysfunction in the pathogenesis of HIV-1 infection and examine how drug actions in glia contribute to neuroAIDS.


Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for prevention and treatment of nephropathy associated with type 2 diabetes mellitus.
Renal complications resulting from type 2 diabetes mellitus are costly and common. Finding optimal therapy is important for the prevention and management of diabetic nephropathy. Research has focused on antihypertensive agents that modify the renin-angiotensin-aldosterone system. Because of their effects on the glomerulus, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have been studied as interventions at various stages of diabetic nephropathy. The ACE inhibitors may delay the progression to microalbuminuria and then clinical albuminuria. The ARBs decrease albuminuria in patients with microalbuminuria and decrease adverse renal events, specifically the progression to end-stage renal disease in patients with clinical albuminuria and hypertension. Limited data suggest that combination therapy with ACE inhibitors and ARBs may slow the progression of microalbuminuria to clinical albuminuria. Because of the variability in degree of albuminuria evaluated and in study designs (numbers of patients, study duration, drug dosages, and outcomes measured), a detailed review of the available literature about ACE inhibitors and ARBs in the prevention or treatment of diabetic nephropathy may provide insight to clinicians.


Evaluation of least significant changes of pulse contour analysis-derived parameters.
Many maneuvers assessing fluid responsiveness (minifluid challenge, lung recruitment maneuver, end-expiratory occlusion test, passive leg raising) are considered as positive when small variations in cardiac index, stroke volume index, stroke volume variation or pulse pressure variation occur. Pulse contour analysis allows continuous and real-time cardiac index, stroke volume, stroke volume variation and pulse pressure variation estimations. To use these maneuvers with pulse contour analysis, the knowledge of the minimal change that needs to be measured by a device to recognize a real change (least significant change) has to be studied. The aim of this study was to evaluate the least significant change of cardiac index, stroke volume index, stroke volume variation and pulse pressure variation obtained using pulse contour analysis (ProAQT®, Pulsion Medical System, Germany). In this observational study, we included 50 mechanically ventilated patients undergoing neurosurgery in the operating room. Cardiac index, stroke volume index, pulse pressure variation and stroke volume variation obtained using ProAQT® (Pulsion Medical System, Germany) were recorded every 12 s during 15-min steady-state periods. Least significant changes were calculated every minute. Least significant changes statistically differed over time for cardiac index, stroke volume index, pulse pressure variation and stroke volume variation (p < 0.001). Least significant changes ranged from 1.3 to 0.7% for cardiac index, from 1.3 to 0.8% for stroke volume index, from 10 to 4.9% for pulse pressure variation and from 10.8 to 4.3% for stroke volume variation. To conclude, the present study suggests that pulse contour analysis is able to detect rapid and small changes in cardiac index and stroke volume index, but the interpretation of rapid and small changes of pulse pressure variation and stroke volume variation must be done with caution.


Cytokine-induced killer cells co-cultured with complete tumor antigen-loaded dendritic cells, have enhanced selective cytotoxicity on carboplatin-resistant retinoblastoma cells.
Retinoblastoma (RB) is a challenging disease that affects mostly young children. Chemical therapy has been shown to have limitations during clinical practice, principally because of the ability of RB to become resistant to the treatment. Nevertheless, chemotherapy is still the main treatment for RB, and immunotherapy has become a promising treatment for most solid tumors with fewer side effects than traditional therapies. In this study, we explored the antitumor effects of cytokine-induced killer (CIK) cells co-cultured with dendritic cells (DCs) pulsed with complete tumor antigens (DC-Ag). Cytotoxicity and specificity were evaluated on an RB cell line (RB-Y79), on a human normal retina cell line (hTERT-RPE1) and a carboplatin-resistant RB cell line. Our results showed that CIK differentiation and cytotoxicity were enhanced by co-culturing CIKs with DC-Ag. Moreover, the co-culture improved the CIK proliferation rate by increasing IL-6 and decreasing IL-10 levels in the culture medium. Furthermore, the use of DC-Ag-CIK cells had little effect on normal retinal cells but high cytotoxicity on RB cells even on carboplatin-resistant retinoblastoma cells. This is the first study showing that DC cells pulsed with the complete tumor antigen improve proliferation, differentiation and cytotoxic activity of CIKs specific not only for RB but also for the chemotherapy-resistant form of the malady. Thus highly efficient immunotherapy based on DC-Ag-CIK cells may be a potential effective and safe mean of treating RB especially to patients where traditional chemical therapy has failed.


Evaluation of a static stretching intervention on vascular endothelial function and arterial stiffness.
Maintenance and enhancement of vascular endothelial function contribute to the prevention of cardiovascular disease and prolong a healthy life expectancy. Given the reversible nature of vascular endothelial function, interventions to improve this function might prevent arteriosclerosis. Accordingly, we studied the effects of a 6-month static stretching intervention on vascular endothelial function (reactive hyperaemia peripheral arterial tonometry index: RH-PAT index) and arterial stiffness (brachial-ankle pulse wave velocity: baPWV) and investigated the reversibility of these effects after a 6-month detraining period following intervention completion. The study evaluated 22 healthy, non-smoking, premenopausal women aged ≥40 years. Subjects were randomly assigned to the full-intervention (n = 11; mean age: 48.6 ± 2.8 years) or a half-intervention that included a control period (n = 11; mean age: 46.9 ± 3.6 years). Body flexibility and vascular endothelial function improved significantly after 3 months of static stretching. In addition to these improvements, arterial stiffness improved significantly after a 6-month intervention. However, after a 6-month detraining period, vascular endothelial function, flexibility, and arterial stiffness all returned to preintervention conditions, demonstrating the reversibility of the obtained effects. A 3-month static stretching intervention was found to improve vascular endothelial function, and an additional 3-month intervention also improved arterial stiffness. However, these effects were reversed by detraining.


Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.


The developmental increase in adrenocortical 17,20-lyase activity (biochemical adrenarche) is driven primarily by increasing cytochrome b5 in neonatal rhesus macaques.
Adrenarche is thought to be experienced only by humans and some Old World primates despite observed regression of an adrenal fetal zone and establishment of a functional zona reticularis (ZR) in other species like rhesus macaques. Adrenal differentiation remains poorly defined biochemically in nonhuman primates. The present studies defined ZR development in the neonatal rhesus by examining androgen synthetic capacity and factors affecting it in rhesus and marmoset adrenals. Western immunoblots examined expression of 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17), cytochrome b5 (b5), and 3beta-hydroxysteroid dehydrogenase (3betaHSD), among other key enzymes. 17,20-lyase activity was quantified in adrenal microsomes, as was the contribution of b5 to 17,20-lyase activity in microsomes and cell transfection experiments with rhesus and marmoset P450c17. Expression of b5 increased from birth to 3 months, and was positively correlated with age and 17,20-lyase activity in the rhesus. Recombinant b5 addition stimulated 17,20-lyase activity to an extent inversely proportional to endogenous levels in adrenal microsomes. Although 3betaHSD expression also increased with age, P450c17, 21-hydroxylase cytochrome P450, and the redox partner, reduced nicotinamide adenine dinucleotide phosphate-cytochrome P450 oxidoreductase, did not; nor did recombinant cytochrome P450 oxidoreductase augment 17,20-lyase activity. Cotransfection with b5 induced a dose-dependent increase in dehydroepiandrosterone synthesis by both nonhuman primate P450c17 enzymes. We conclude that the increase in 17,20-lyase activity characteristic of an adrenarche in rhesus macaques is driven primarily by increased b5 expression, without the need for a decrease in 3betaHSD, as suggested from human studies. The rhesus macaque is a relevant and accessible model for human ZR development and adrenal function.


Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma.
MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of basic cellular functions through posttranscriptional regulations on their target genes. Compelling evidence has shown that miRNAs are involved in cancer initiation and progression. We hypothesized that genetic variations of the miRNA machinery genes could be associated with the risk of renal cell carcinoma. We genotyped 40 single nucleotide polymorphisms (SNP) from 11 miRNA processing genes (DROSHA, DGCR8, XPO5, RAN, DICER1, TARBP2, AGO1, AGO2, GEMIN3, GEMIN4, HIWI) and 15 miRNA genes in 279 Caucasian patients with renal cell carcinoma and 278 matched controls. We found that two SNPs in the GEMIN4 gene were significantly associated with altered renal cell carcinoma risks. The variant-containing genotypes of Asn929Asp and Cys1033Arg exhibited significantly reduced risks, with odds ratios (OR) of 0.67 [95% confidence interval (95% CI), 0.47-0.96] and 0.68 (95% CI, 0.47-0.98), respectively. Haplotype analysis showed that a common haplotype of GEMIN4 was associated with a significant reduction in the risk of renal cell carcinoma (OR, 0.66; 95% CI, 0.45-0.97). We also conducted a combined unfavorable genotype analysis including five promising SNPs showing at least a borderline significant risk association. Compared with the low-risk reference group with one unfavorable genotype, the median-risk and high-risk groups exhibited a 1.55-fold (95% CI, 0.96-2.50) and a 2.49-fold (95% CI, 1.58-3.91) increased risk of renal cell carcinoma, respectively (P for trend < 0.001). Our results suggested that genetic polymorphisms of the miRNA-machinery genes may affect renal cell carcinoma susceptibility individually and jointly.


Effect of solvent and subsequent thermal annealing on the performance of phenylenevinylene copolymer: PCBM solar cells.
The morphology of the photoactive layer used in the bulk heterojunction photovoltaic devices is crucial for efficient charge generation and their collection at the electrodes. We investigated the solvent vapor annealing and thermal annealing effect of an alternating phenylenevinylene copolymer P:PCBM blend on its morphology and optical properties. The UV-visible absorption spectroscopy shows that both solvent and thermal annealing can result in self-assembling of copolymer P to form an ordered structure, leading to enhanced absorption in the red region and hole transport enhancement. By combining the solvent and thermal annealing of the devices, the power conversion efficiency is improved. This feature was attributed to the fact that the PCBM molecules begin to diffuse into aggregates and together with the ordered copolymer P phase form bicontinuous pathways in the entire layer for efficient charge separation and transport. Furthermore, the measured photocurrent also suggests that the space charges no longer limit the values of the short circuit current (J(sc)) and fill factor (FF) for solvent-treated and thermally annealed devices. These results indicate that the higher J(sc) and PCE for the solvent-treated and thermally annealed devices can be attributed to the phase separation of active layers, which leads to a balanced carrier mobility. The overall PCE of the device based on the combination of solvent annealing and thermal annealing is about 3.7 %.


Crystal-Storing Histiocytosis in Bone Marrow: A Clinicopathologic Study of Eight Cases and Review of the Literature.
We report the clinicopathologic characteristics of eight cases of crystal-storing histiocytosis (CSH) with bone marrow (BM) involvement (BM-CSH) and review CSH cases published in the English literature. We queried our pathology database for BM cases with CSH mentioned in the final diagnosis/comments from June 2011 to August 2016. Eight cases of BM-CSH were identified. The underlying diagnoses consisted predominantly of plasma cell disorders (88%) associated with monotypic κ light chain. In BM aspirates, crystals within histiocytes exhibited a morphologic spectrum including brightly eosinophilic, needle-like, or globule-like. In BM core biopsies, the histiocytes were often in aggregates with intracellular needle-like and/or globular, refractile inclusions. BM-CSH is a rare phenomenon and exhibits a heterogeneous crystalline and histiocytic appearance warranting accurate recognition to avoid misinterpretation of a granulomatous condition or storage disorder. In addition, prompt assessment for an underlying B-cell lymphoma or clonal plasmacytic neoplasm is indicated.


Tissue-Specific Sample Dilution: An Important Parameter to Optimise Prior to Untargeted LC-MS Metabolomics.
When developing a sample preparation protocol for LC-MS untargeted metabolomics of a new sample matrix unfamiliar to the laboratory, selection of a suitable injection concentration is rarely described. Here we developed a simple workflow to address this issue prior to untargeted LC-MS metabolomics using pig adipose tissue and liver tissue. Bi-phasic extraction was performed to enable simultaneous optimisation of parameters for analysis of both lipids and polar extracts. A series of diluted pooled samples were analysed by LC-MS and used to evaluate signal linearity. Suitable injected concentrations were determined based on both the number of reproducible features and linear features. With our laboratory settings, the optimum concentrations of tissue mass to reconstitution solvent of liver and adipose tissue lipid fractions were found to be 125 mg/mL and 7.81 mg/mL respectively, producing 2811 (ESI+) and 4326 (ESI-) linear features from liver, 698 (ESI+) and 498 (ESI-) linear features from adipose tissue. For analysis of the polar fraction of both tissues, 250 mg/mL was suitable, producing 403 (ESI+) and 235 (ESI-) linear features from liver, 114 (ESI+) and 108 (ESI-) linear features from adipose tissue. Incorrect reconstitution volumes resulted in either severe overloading or poor linearity in our lipid data, while too dilute polar fractions resulted in a low number of reproducible features (<50) compared to hundreds of reproducible features from the optimum concentration used. Our study highlights on multiple matrices and multiple extract and chromatography types, the critical importance of determining a suitable injected concentration prior to untargeted LC-MS metabolomics, with the described workflow applicable to any matrix and LC-MS system.


Triaquabenzoatocalcium(II) monobenzoate: coordination polymer chains linked into a two-dimensional framework by hydrogen bonds.
In the title complex, catena-poly[[[diaquacalcium(I)]-mu2-aqua-mu3-benzoato-kappa4O:O,O':O'] benzoate], {[Ca(C7H5O2)(H2O)3](C7H5O2)}n, obtained by the reaction of CaCl2 and potassium benzoate in water, the Ca atom is eight-coordinated by four carboxylate O atoms and four water molecules. The structure consists of polymeric {[Ca(C6H5COO)(H2O)3]+}infinity chains alternating with layers of uncoordinated C6H5COO- anions. The nearly planar anions are linked to the chain by short hydrogen bonds to form a two-dimensional network.


Persian couples' experiences of depressive symptoms and health-related quality of life in the pre- and perinatal period.
The aim of this study was to estimate the effect of changes in depressive symptoms on health-related quality of life (HRQoL) in couples. This was examined before, during and after the pregnancy. In addition, (HRQoL) was examined in relation to the mode of delivery. A prospective longitudinal study of 416 couples was conducted in two teaching hospitals in Tehran, Iran. The translated Medical Outcomes Study-Short Form 36 (SF-36) and the Edinburgh Postnatal Depression Scale (EPDS) were used to measure health-related quality of life and depressive symptoms respectively, and are reported here. The results showed that women and their spouses experienced a noticeable decline in their physical HRQoL during and after the pregnancy. However, their mental health functioning showed a significant improvement following conception. The prevalence of depressive symptoms was high but decreased over the course of the pregnancy. Finally, HRQoL was affected by mode of delivery. The results show that women and their husbands experienced marked changes in perceived health-related functioning and depressive symptoms during and after pregnancy. In addition, the study found that those women who had undergone Cesarean section had higher mental well-being scores. Future research should determine the benefits of extending pre-conception and pre-natal guidelines on the benefits of regular physical activity throughout and after pregnancy in Persian couples.


Role of Apoptosis in the Pathogenesis of Osteoarthriti1s: An explicative review.
Apoptosis is a complex regulatory, active cell death process that plays a role in cell development, homeostasis, and ageing. Cancer, developmental defects, and degenerative diseases are all pathogenic disorders caused by apoptosis dysregulation. Osteoarthritis (OA) is by far the most frequently diagnosed joint disease in the aged, and it is characterized by the ongoing breakdown of articular cartilage, which causes severe disability. Multiple variables regulate the anabolic and catabolic pathways of the cartilage matrix, which either directly or indirectly contribute to cartilage degeneration in osteoarthritis. Articular cartilage is a highly specialized tissue made up of an extracellular matrix of cells that are tightly packed together. As a result, chondrocyte survival is crucial for the preservation of an optimal cartilage matrix, and chondrocyte characteristics and survival compromise may result in articular cartilage failure. Inflammatory cytokines can either promote or inhibit apoptosis, the process of programmed cell death. Pro-apoptotic cytokines like TNF-α can induce cell death, while anti-apoptotic cytokines like IL-4 and IL-10 protect against apoptosis. The balance between these cytokines plays a critical role in determining cell fate and has implications for tissue damage and disease progression. Similarly, they contribute to the progression of OA by disrupting the metabolic balance in joint tissues by promoting catabolic and anabolic pathways. Their impact on cell joints, as well as the impacts of cell signalling pathways on cytokines and inflammatory substances, determines their function in osteoarthritis development. Apoptosis is evident in osteoarthritic cartilage; however, determining the relative role of chondrocyte apoptosis in the aetiology of OA is difficult, and the rate of apoptotic chondrocytes in osteoarthritic cartilage is inconsistent. The current study summarises the role of apoptosis in the development of osteoarthritis, the mediators, and signalling pathways that trigger the cascade of events, and the other inflammatory features involved.


[Chemical constituents from safflower injection and their bioactivity].
The chemical constituents of Safflower injection were isolated and purified by polyamide, silica gel, Sephadex LH-20, ODS column chromatographies and preparative HPLC. As a result, sixteen compounds have been isolated. Based on the spectral data analysis, their structures were elucidated as scutellarin (1), kaempferol-3-O-β-rutinoside(2), hydroxysafflor yellow A(3), rutin (4), coumalic acid(5), adenosine(6), syringoside(7), (3E)-4-(4'-hydroxyphenyl)-3-buten-2-one(8), (8Z)-decaene-4, 6-diyne-1-Oβ-D-glucopyranoside(9), 4-hydroxybenzaldehyde (10), (2E, 8E) -tetradecadiene-4, 6-diyne-1, 12, 14-triol-1-O-β-D-glucopyranoside (11), kaem-pferol-3-O-β-sophorose (12), uridine (13), roseoside (14), cinnamic acid (15), and kaempferol (16). Compounds 1,2,7,9,11 and 12 were isolated from the Safflower injection for the first time. The anti-platelet aggregation activities of the isolated compounds were assayed. The results indicated all tested compounds exhibited potent activity except for 5, while 2, 3, 9 and 12 showed strong activity against platelet aggregation.


Predator ontogeny affects expression of inducible defense morphology in rotifers.
Many prey organisms show induced morphological responses to predators including changes in protective spine length, such as in rotifers, although previous studies have mainly focused on how prey become larger than the predator gape-size optimum. Here we show that a large-sized predator makes prey rotifers escape below the gape-size optimum of the predator by reducing spine length. In experiments and field studies we show that during part of their ontogeny fish larvae feed intensively on the common rotifer Keratella cochlearis, and that larval fish predation reduces rotifer spine length both through induction of shorter spines and selective predation on long-spined individuals. We also describe a global scale pattern in spine length of K. cochlearis, showing an increasing variance in spine length with latitude. This pattern may be explained by differences in fish reproduction from once per year at high latitudes to several times per year at lower latitudes. That spine length is adaptively adjusted to the ontogeny of a dominant predator taxa provides a novel view on our understanding of factors affecting temporal and spatial variations in prey defense morphology.


Mesoscopic clustering behavior of thermophoretic-type active particle suspension under quasi-one-dimensional microconfinement.
We experimentally investigate the mesoscopic clustering behavior of thermophoretic-type active particle suspension under quasi-one-dimensional spatial confinement (high aspect ratio microchannel). The microchannel enhances the viscous dissipation to operate the system in subpropulsion regime. We find that, in the subpropulsion regime, the steady-state configuration of active particle suspension exhibits a transition from homogeneous state to sausagelike clustering bundle located at the channel center, quasiperiodic isolated clusters at the channel center, aperiodic isolated cluster deviated from channel center, and finally to the typical propulsion-induced accumulation around the channel boundary as increasing the excitation laser intensity. The formation of those patterns is under the interplay of outward-pointing mesoscopic scaled thermophoretic force and the applied spatial confinement. The finding of those special patterns can provide some further possibilities of particle manipulation at mesoscopic scale.


Molecular variation of Taenia solium in the world.
Complete nucleotide sequences of the mitochondrial cytochrome b (Cytb) and cytochrome c oxidase subunit I (CO I) genes from various isolates of Taenia solium were examined. Eleven isolates were analyzed; two isolates from China, two isolates from Indonesia, one isolate each from India, Thailand, Mexico, Ecuador, Peru, Mozambique and Tanzania. In both genes, two isolates from Indonesia shared the same sequences. Similarly, the isolate from Mexico shared same sequences with that from Peru, and the isolate from Mozambique shared same sequences with that from Tanzania. Phylogenetic trees inferred from different mitochondrial genes yielded almost the same topology. Both the UPGMA and NJ-trees were also very similar. These trees indicate that T. solium may be diverged to 2 genetic groups; isolates from Asia form one group and isolates from Africa and Latin America belong to the other. It seems that T. solium prevalent in Africa and in Latin America shares the related origin and has recently been introduced to each area, perhaps with domestic pigs or human.


Fabrication of superhydrophobic copper surface on various substrates for roll-off, self-cleaning, and water/oil separation.
Superhydrophobic surfaces prevent percolation of water droplets and thus render roll-off, self-cleaning, corrosion protection, etc., which find day-to-day and industrial applications. In this work, we developed a facile, cost-effective, and free-standing method for direct fabrication of copper nanoparticles to engender superhydrophobicity for various flat and irregular surfaces such as glass, transparency sheet (plastic), cotton wool, textile, and silicon substrates. The fabrication of as-prepared superhydrophobic surfaces was accomplished using a simple chemical reduction of copper acetate by hydrazine hydrate at room temperature. The surface morphological studies demonstrate that the as-prepared surfaces are rough and display superhydrophobic character on wetting due to generation of air pockets (The Cassie-Baxter state). Because of the low adhesion of water droplets on the as-prepared surfaces, the surfaces exhibited not only high water contact angle (164 ± 2°, 5 μL droplets) but also superb roll-off and self-cleaning properties. Superhydrophobic copper nanoparticle coated glass surface uniquely withstands water (10 min), mild alkali (5 min in saturated aqueous NaHCO3 of pH ≈ 9), acids (10 s in dilute HNO3, H2SO4 of pH ≈ 5) and thiol (10 s in neat 1-octanethiol) at room temperature (25-35 °C). Again as-prepared surface (cotton wool) was also found to be very effective for water-kerosene separation due to its superhydrophobic and oleophilic character. Additionally, the superhydrophobic copper nanoparticle (deposited on glass surface) was found to exhibit antibacterial activity against both Gram-negative and Gram-positive bacteria.


Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis.
Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor β-positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. Here, we show that tumor vascular function, as well as pericyte coverage is significantly impaired in mice with conditional knockout of PDGFB in platelets. A lack of PDGFB in platelets led to enhanced hypoxia and epithelial-to-mesenchymal transition in the primary tumors, elevated levels of circulating tumor cells, and increased spontaneous metastasis to the liver or lungs in two mouse models. These findings establish a previously unknown role for platelet-derived PDGFB, whereby it promotes and maintains vascular integrity in the tumor microenvironment by contributing to the recruitment of pericytes. SIGNIFICANCE: Conditional knockout of PDGFB in platelets demonstrates its previously unknown role in the maintenance of tumor vascular integrity and host protection against metastasis.


Efficacy and Safety of Complementary Therapy With Jing Si Herbal Tea in Patients With Mild-To-Moderate COVID-19: A Prospective Cohort Study.
Since late 2019, there has been a global COVID-19 pandemic. To preserve medical capacity and decrease adverse health effects, preventing the progression of COVID-19 to severe status is essential. Jing-Si Herbal Tea (JSHT), a novel traditional Chinese medicine formula was developed to treat COVID-19. This study examined the clinical efficacy and safety of JSHT in patients with mild-to-moderate COVID-19. In this prospective cohort study, we enrolled 260 patients with mild-to-moderate COVID-19. The enrolled patients were divided into the JSHT (n = 117) and control (n = 143) groups. Both groups received standard management. The JSHT group was treated with JSHT as a complementary therapy. Compared with standard management alone, JSHT combined with standard management more effectively improved the reverse transcription-polymerase chain reaction cycle threshold value, C-reactive protein level, and Brixia score in the adult patients with mild-to-moderate COVID-19, especially in the male and older patients (those aged ≥60 years). The results revealed that the patients treated with JSHT combined with standard management had 51, 70, and 100% lower risks of intubation, Medisave Care Unit admission, and mortality compared with those receiving standard management only. JSHT combined with standard management more effectively reduced the SARS-CoV-2 viral load and systemic inflammation and alleviated lung infiltrates in the patients with mild-to-moderate COVID-19, especially in the male and older patients (those aged ≥60 years). JSHT combined with standard management may prevent critical status and mortality in patients with mild-to-moderate COVID-19. JSHT is a promising complementary therapy for patients with mild-to-moderate COVID-19.


Atomistic insight into the essential binding event of ACE2-derived peptides to the SARS-CoV-2 spike protein.
The pathogenic agent of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters into human cells through the interaction between the receptor binding domain (RBD) of its spike glycoprotein and the angiotensin-converting enzyme 2 (ACE2) receptor. Efforts have been made towards finding antivirals that block this interaction, therefore preventing infection. Here, we determined the binding affinity of ACE2-derived peptides to the RBD of SARS-CoV-2 experimentally and performed MD simulations in order to understand key characteristics of their interaction. One of the peptides, p6, binds to the RBD of SARS-CoV-2 with nM affinity. Although the ACE2-derived peptides retain conformational flexibility when bound to SARS-CoV-2 RBD, we identified residues T27 and K353 as critical anchors mediating the interaction. New ACE2-derived peptides were developed based on the p6-RBD interface analysis and expecting the native conformation of the ACE2 to be maintained. Furthermore, we found a correlation between the helicity in trifluoroethanol and the binding affinity to RBD of the new peptides. Under the hypothesis that the conservation of peptide secondary structure is decisive to the binding affinity, we developed a cyclized version of p6 which had more helicity than p6 and approximately half of its KD value.


Kiwi fruit is a significant allergen and is associated with differing patterns of reactivity in children and adults.
Allergy to kiwi fruit appears increasingly common, but few studies have evaluated its clinical characteristics, or evaluated methods of investigating the allergy. To characterize the clinical characteristics of kiwi fruit allergy and to study the role of double-blind placebo-controlled food challenge (DBPCFC), skin tests and specific IgE in the diagnosis of this food allergy. Two-hundred and seventy-three subjects with a history suggestive of allergy to kiwi completed a questionnaire. Forty-five were investigated by DBPCFC, prick-to-prick skin testing with fresh kiwi pulp, and specific IgE measurement. Nineteen subjects were also skin tested using a commercially available solution. The most frequently reported symptoms were localized to the oral mucosa (65%), but severe symptoms (wheeze, cyanosis or collapse) were reported by 18% of subjects. Young children were significantly more likely than adults to react on their first known exposure (P<0.001), and to report severe symptoms (P=0.008). Twenty-four of 45 subjects (53%) had allergy confirmed by DBPCFC. Prick-to-prick skin test with fresh kiwi was positive in 93% of subjects who had allergy confirmed by DBPCFC, and also in 55% of subjects with a negative food challenge. The commercial extract was significantly less sensitive, but with fewer false-positive reactions. CAP sIgE was only positive in 54% of subjects who had a positive challenge. Kiwi fruit should be considered a significant food allergen, capable of causing severe reactions, particularly in young children. DBPCFC confirmed allergy to kiwi fruit in 53% of the subjects tested, who had a previous history suggestive of kiwi allergy. Skin testing with fresh fruit has good sensitivity (93%), but poor specificity (45%) in this population. CAP sIgE and a commercially available skin test solution were both much less sensitive (54%; 75%) but had better specificity (90%; 67%).


The interaction between selenium status, sex hormones, and thyroid metabolism in adolescent girls in the luteal phase of their menstrual cycle.
The objective of the present work was to study all physiological relationships among selenium status (SeS), sex hormones secretion (SH), and thyroid metabolism (ThM) in healthy adolescent girls, at one time. Forty-four girls aged 13.4-16.6 years (mean age, 14.5 +/- 0.5 years) entered the statistical model. Parameters reflecting SeS: plasma selenium concentration (Se) and plasma glutathione peroxidase activity (GPX3); SH: serum estradiol (E2) and progesterone (P4); age of menarche (AoM); and ThM: thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), antithyroid peroxidase antibodies (anti-TPO) in serum, and thyroid volume (ThV), were determined, and the interactions between them were evaluated by means of the partial least squares method (PLS). PLS method was, for the first time, successfully applied to the problem of selenium and hormone interactions and revealed that selenium status and female reproductive system are interrelated and affect thyroid physiology in adolescent girls in the luteal phase. The strongest associations were revealed for the pairs of parameters, Se and fT4/fT3, Se and P4, the modest ones for the pairs, Se and ThV, P4 and fT4/fT3, Se and AoM, and P4 and AoM. There was no correlation between E2, GPX3, and TSH, and any other considered parameter. Se and P4 had the greatest influence on ThM parameters.


Effect of acclimatization of microorganisms to heavy metals on the performance of activated sludge process.
Although selected heavy metals (HMs) stimulate biological reactions at low concentrations, all HMs are toxic to microorganisms (MOs) at moderate concentrations and can cause inhibitory effects on the biological processes. Therefore, MOs must be acclimated to HMs or other toxic substances present in wastewaters (WWs) before they are used in an activated sludge process (ASP). In this study, combined effect of Cu(2+) and Zn(2+) ions in a synthetic WW on the efficiency of a laboratory-scale ASP without recycle was investigated using acclimated MOs at different extents.A synthetic feed solution of 1222 mg L(-1) proteose-peptone (corresponding to 1300 mg COD L(-1)) served as a source of carbon. Cu(2+) and Zn(2+) ions at different concentrations (1.5, 4.5 and 9, 27 mg L(-1), respectively) were introduced in the feed to a continuously stirred activated sludge reactor at different hydraulic residence times (2-40 h) keeping pH, temperature and stock feed composition constant. The combined effects of copper and zinc ions were determined by mixing these metallic ions at the specified combinations of concentrations such as "1.5 mg L(-1) of Cu(2+)+9 mg L(-1) of Zn(2+)" and "4.5 mg L(-1) of Cu(2+)+27 mg L(-1) of Zn(2+)". It was observed that using seed MOs acclimatized to two times of the combined threshold concentration of these HMs for an unduly long period of time (1-4 months) caused adverse effects on the ASP performance. Besides, it was found that usual inhibition effects of these HMs were enhanced with increasing period of acclimation. Substantially lower substrate removal efficiencies were obtained with acclimatized MOs than those obtained with non-acclimatized MOs. At the higher initial substrate concentration of 2500 mg COD L(-1), substrate-inhibition occurred causing a decrease in the specific growth rate constant (k); however, HM inhibition was suppressed, resulting to about 20% increase in treatment efficiency of the ASP. It can be concluded that the time period necessary for acclimatization of seed MOs must be adjusted carefully with concentrations of HMs lower than their threshold concentrations to achieve an optimal operation of an aerobic biological process.


Prediction of Pleural Adhesions by Lung Ultrasonography: An Observational Study.
Pleural adhesion makes video-assisted thoracoscopic surgery (VATS) an arduous procedure and can increase postoperative pain from accompanying adhesiolysis. For the present study, the feasibility of lung ultrasonography for the prediction of pleural adhesions and postoperative pain in VATS was investigated. Blinded, prospective, observational study. Tertiary teaching hospital, Seoul, South Korea. Sixty patients (American Society of Anesthesiologists physical status I to III) scheduled to undergo VATS were assessed for eligibility. After exclusions, 53 patients were enrolled and followed-up. None. Patients were evaluated with lung ultrasonography during deep spontaneous respiration before induction of anesthesia, and surgeons confirmed the presence of pleural adhesions during the surgery. Pain was evaluated using a numeric rating scale and by the amount of opioid consumption until 24 hours postoperatively. Lung ultrasonography showed acceptable predictability of pleural adhesions, with the area under the receiver operating characteristic curve (0.75, 95% confidence interval [CI] 0.67-0.83) and high specificity (0.97, 95% CI 0.91-0.99) but low sensitivity (0.53, 95% CI 0.38-0.68). The pain score was not different between sonographic adhesion (+) and (-) groups; however, the sonographic adhesion (+) group consumed more opioids until 24 hours postoperatively (fentanyl 675 [558-805] μg v 420 [356-476] μg; p < 0.001). Lung ultrasonography may help with planning postoperative pain management in VATS; however, it was a better tool for ruling out rather than detecting pleural adhesions.


Three-dimensional visualization of the route of protein import: the role of nuclear pore complex substructures.
The three-dimensional localization of nucleoplasmin and wheat germ agglutinin (WGA) at the nuclear envelope of Xenopus oocytes is demonstrated by microinjecting protein coated gold colloids and examining their distribution using both stereo transmission electron microscopy and field emission in-lens scanning electron microscopy. Localization of many WGA gold particles and nucleoplasmin gold particles at the same nuclear pore complex (NPC) following coinjection is demonstrated. Binding of the WGA gold in the central region of the NPCs appears to form a barrier, preventing the import of nucleoplasmin gold, and includes central localization along radial "tracks" which correspond to the internal filaments connecting the cytoplasmic ring and the central region of the NPC. We suggest that these filaments may in some way be involved in opening and closing of the central channel of the NPC for transport. Transport of nucleoplasmin through the central region of the NPCs appears to be in "single file" regardless of the size of the colloidal gold, and distribution into the nucleoplasm appears to be through the basket rings with no association of the nucleoplasmin gold with the basket filaments being observed.


Cerebral, renal, and splanchnic tissue oxygen saturation values in healthy term newborns.
To determine cerebral regional tissue oxygen saturation (CrSO2), renal regional tissue oxygen saturation (RrSO2), and splanchnic regional tissue oxygen saturation (SrSO2) values in healthy term infants. Near-infrared spectroscopy was used to simultaneously measure CrSO2, RrSO2, and SrSO2 continuously for a 1-hour period on the first and second days of life. A total of 41 subjects were monitored out of which complete data were available for 38 subjects. Mean CrSO2 was 78.2 ± 7.9% on first day; 78.3 ± 6.1% on second day (p = 0.95). Mean RrSO2 was 92.1 ± 5.3% on first day; 88.9 ± 5.9% on second day (p < 0.01). Mean SrSO2 was 69.9 ± 12.1% on first day and 75.3 ± 12.4% on second day (p = 0.02). There appears to be consistency in rSO2 values in healthy newborns. CrSO2 was similar on both days. Differences observed in RrSO2 and SrSO2 between days may represent a shift in somatic blood flow distribution taking place during the first day of life.


Physical model approach to taste studies of drugs and pharmaceutical formulations.
This paper explores the physical model approach in studying the taste of drugs and assessing physical formulation factors for improving the undesirable taste of drugs. Various aspects of physiology relevant to the taste phenomenon have been reviewed to provide the biophysical basis for mathematical modeling. The model involves non-steady-state mass transport across the aqueous boundary layer and buildup of solute concentration at the essentially impermeable tongue surface. The theoretical predictions are consistent with experimental studies on the lag time to taste perception by the electrophysiological method and also with "instantaneous" psychophysical taste perception when solute concentrations much greater than the taste threshold are applied on the tongue. Within the framework of the non-steady-state model, novel experimental studies involving the use of a porous half-diffusion cell placed on the surface of an extended human tongue and the recording of the times for psychophysical taste response are proposed to quantify and provide mechanistic understanding of the taste of drugs and also physical formulation factors in overcoming undesirable taste properties.


Progesterone shortens poly(A) tails of the mRNAs for alpha and beta subunits of ovine luteinizing hormone.
Progesterone (P) and 17 beta-estradiol (E) inhibit transcription of alpha mRNA (alpha mRNA) by about 70% in ovine pituitary cultures. In addition, P, but not E, shortens alpha mRNA during the 3-24-h period following treatment. Data presented here focus on this post-transcriptional effect of P, which appears totally independent from transcriptional changes and may alter the translational efficiency of the affected mRNA or its half-life. Results indicate this shortening occurs at the poly(A) tail. The normal length of this tail was estimated to be 70-100 nucleotides in the case of alpha mRNA, and it was shortened by 30-40 nucleotides during P treatment. Shortening was normally observed after 3-10 h of P treatment and was complete by 10-24 h. Significant shortening occurred at 7-10 nM P in ovine pituitary culture; the 10-15-nM concentration of P in the serum of luteal phase ewes also appears sufficient to shorten alpha mRNA in vivo since alpha mRNA from the pituitaries of these ewes was found to be consistently shorter than alpha mRNA from ovariectomized ewes. Finally, P also shortened the poly(A) tail of mRNA for the beta-subunit of LH. This indicates that P-induced poly(A) shortening not only affects alpha mRNA but may affect several or many mRNAs found in ovine gonadotrophs. The significance of poly(A) shortening is not yet understood, but it could involve post-transcriptional inhibition, which, combined with transcriptional effects, may make P a more potent inhibitor of gonadotropin synthesis than E.


Y-chromosomal diversity suggests that Baltic males share common Finno-Ugric-speaking forefathers.
To elucidate the genetic relationships between Estonian, Latvian and Lithuanian men by studying Y-chromosomal variation in these people. The allelic status of five deep-rooted marker loci (YAP, Tat, M9, 92R7 and SRY-1532) was determined for 346 Baltic males. On the basis of single nucleotide polymorphism (SNP) haplotypes, Y chromosomes were divided into six haplogroups, and the Baltic haplogroup distribution compared with that in 7 European reference populations. Haplogroup frequencies, diversities and genetic distances (F(ST) values) were calculated. The relationships between populations were further illustrated using Mantel test, neighbor-joining tree and principal-component map. We found the Indo-European-speaking Latvians and Lithuanians to be genetically very similar to the Finno-Ugric-speaking Estonians. When compared to the reference populations, Baltic males were most closely related to the Finno-Ugric-speaking Mari, followed by their Finnish and Slavonic neighbors. The genetic similarity existing between Estonian, Latvian and Lithuanian men suggests that they originate from the same male founder population. Since the Baltic Y-chromosomal haplogroup distribution more closely resembles that of Finno-Ugric than Indo-European-speaking populations, we propose a hypothesis that Baltic males share a common Finno-Ugric ancestry.


Multicenter study of environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in 66 Canadian hospitals: A 2016 follow-up study.
Oncology workers are occupationally exposed to antineoplastic drugs. This exposure can induce adverse health effects. To reduce their exposure, contamination on surfaces should be kept as low as possible. The main objective of this study was to monitor environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in oncology pharmacy and patient care areas in Canadian centers. The secondary objective was to describe the impact of some factors that may limit contamination. This is a descriptive study. Twelve standardized sites were sampled in each participating center (six in the pharmacy and six in patient care areas). Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography-tandem mass spectrometry technology. Descriptive statistical analyses were done and results were compared with a Kolmogorov-Smirnov test for independent samples. In 2016, 66 centers participated in this study (66/202, 32.7%). Overall, 43.4% (326/752) of the samples were positive for cyclophosphamide, 13.2% (99/752) for ifosfamide and 6.9% (52/752) for methotrexate. The 75th percentile value of cyclophosphamide surface concentration was 6.8 pg/cm2 and lower than the limit of detection for ifosfamide and methotrexate. Centers who prepared more antineoplastic drugs per year (p < 0.0001), who used more cyclophosphamide per year (p < 0.0001) and who primed antineoplastic IV tubing in patient care unit by nurses (p = 0.004) showed significantly higher surface contamination to cyclophosphamide. Environmental surveillance is one part of a comprehensive approach for minimizing hazardous exposures in healthcare. This study highlights a low level of contamination of three hazardous drugs amongst 66 Canadian centers. Regular environmental monitoring is a good practice to maintain contamination as low as reasonably achievable.


Clinical and pathological features of renal amyloidosis: an analysis of 32 patients in a single Chinese centre.
To summarize the clinical and pathological features of renal amyloidosis in order to achieve early diagnosis. The clinical and pathological data of 32 patients with renal amyloidosis, diagnosed by renal biopsy in one renal centre, were retrospectively analyzed. Immunohistochemistry of amyloid A protein and immunoglobulin light chains was further performed on the renal specimens for further classification. Twenty-four out of the 32 patients (75%) were not considered to have renal amyloidosis by local physicians; 91.7% (22/24) of them had at least one of the following signs: bodyweight loss, organ enlargement and decreased blood pressure. Twenty-nine out of the 32 patients (90.6%) were over 40 years, 30 patients (93.8%) had nephrotic syndrome, and 21 patients (65.6%) were found to have monoclonal light chain in serum or urine by immunofixation. Six patients (18.8%) were negative by Congo red stain and were diagnosed as having early renal amyloidosis by electron microscopy. Twenty-eight patients were diagnosed as having AL amyloidosis, two were suspected of having AL amyloidosis, one had AA amyloidosis and the status of the remaining patient was undetermined. Renal amyloidosis is frequently neglected by local physicians in China. Middle-aged nephrotic patients with weight loss, organ enlargement and monoclonal light chains in serum or urine should be highly suspected of the disease. Renal biopsies, especially electron microscopy, play a crucial role in the early diagnosis of renal amyloidosis.


Review on production of 89Zr in a medical cyclotron for PET radiopharmaceuticals.
This article is intended to provide an overview of the production and application of (89)Zr for the professional development of nuclear medicine technologists. It outlines the cyclotron targeting, separation and labeling options, and techniques for the preparation of the radionuclide (89)Zr (half-life, 78.4 h [3.3 d]) used in PET. Unlike the commonly used (18)F-FDG, with a 109.7-min half-life, the longer half-life of (89)Zr makes it possible to use high-resolution PET/CT to localize and image tumors with monoclonal antibody radiopharmaceuticals and thus potentially expand the use of PET. This paper briefly reviews the cyclotron technique of (89)Zr production and outlines the range and preparation techniques available for making (89)Y targets as a starting material. It then discusses how cyclotron-produced (89)Zr can be separated, purified, and labeled to monoclonal antibodies for PET/CT of specific tumors. We argue that knowledge and understanding of this long-lived PET radionuclide should be part of the professional development of nuclear medicine technologists because it will lead to better patient outcomes and potentially increase the pool of collaborators in this field of research.


Razumab -- the role of biosimilars for the treatment of retinal diseases.
Biologics targeting vascular endothelial growth factor (anti-VEGF) are the mainstay treatment of many vascular retinal pathologies. To date, Razumab is the only approved biosimilar for ophthalmic use. Razumab showed no differences compared to the innovator ranibizumab, in terms of VEGF binding activity nor in inhibition of VEGF-induced proliferation. Clinical and preclinical studies have shown a favorable efficacy and safety profile of Razumab. Nonetheless, even if clinical equivalence is expected, randomized controlled clinical trials are needed to directly compare Razumab with the innovator ranibizumab in different retinal diseases.


Cholesterol among children of men with myocardial infarction.
Plasma cholesterol levels were obtained on 90 children of 39 men with premature myocardial infarction and 86 children of 39 healthy men. The mean cholesterol among children of affected men (195.1 mg/100 ml) was higher than among children of healthy men (176.6 mg/100 ml) (P equal to .009). Higher mean levels were demonstrable at each of nine age groups from 1 to 21 years(P equal to .004). Levels greater than 230 mg/100 ml were found in 16.7% of children of affected fathers and 4.7% of children of healthy fathers, a ratio of 3.6 to 1 (P equal to .01). These findings are compatible with the hypothesis that elevated childhood cholesterol level offers a mechanism whereby family history predicts coronary disease. A dip in cholesterol during adolescence, a finding that varies with population studied, was demonstratable among children of both affected healthy men.


Effective Factors in Severity of Traffic Accident-Related Traumas; an Epidemiologic Study Based on the Haddon Matrix.
Traffic accidents are the 8(th) cause of mortality in different countries and are expected to rise to the 3(rd) rank by 2020. Based on the Haddon matrix numerous factors such as environment, host, and agent can affect the severity of traffic-related traumas. Therefore, the present study aimed to evaluate the effective factors in severity of these traumas based on Haddon matrix. In the present 1-month cross-sectional study, all the patients injured in traffic accidents, who were referred to the ED of Imam Khomeini and Golestan Hospitals, Ahvaz, Iran, during March 2013 were evaluated. Based on the Haddon matrix, effective factors in accident occurrence were defined in 3 groups of host, agent, and environment. Demographic data of the patients and data regarding Haddon risk factors were extracted and analyzed using SPSS version 20. 700 injured people with the mean age of 29.66 ± 12.64 years (3-82) were evaluated (92.4% male). Trauma mechanism was car-pedestrian in 308 (44%) of the cases and car-motorcycle in 175 (25%). 610 (87.1%) cases were traffic accidents and 371 (53%) occurred in the time between 2 pm and 8 pm. Violation of speed limit was the most common violation with 570 (81.4%) cases, followed by violation of right-of-way in 57 (8.1%) patients. 59.9% of the severe and critical injuries had occurred on road accidents, while 61.3% of the injuries caused by traffic accidents were mild to moderate (p < 0.001). The most common mechanisms of trauma for critical injuries were rollover (72.5%), motorcycle-pedestrian (23.8%), and car-motorcycle (13.14%) accidents (p < 0.001). Based on the results of the present study, the most important effective factors in severity of traffic accident-related traumas were age over 50, not using safety tools, and undertaking among host-related factors; insufficient environment safety, road accidents and time between 2 pm and 8 pm among environmental factors; and finally, rollover, car-pedestrian, and motorcycle-pedestrian accidents among the agent factors.


Brucella and Osteoarticular Cell Activation: Partners in Crime.
Osteoarticular brucellosis is the most common presentation of human active disease although its prevalence varies widely. The three most common forms of osteoarticular involvement are sacroiliitis, spondylitis, and peripheral arthritis. The molecular mechanisms implicated in bone damage have been recently elucidated. B. abortus induces bone damage through diverse mechanisms in which TNF-α and the receptor activator of nuclear factor kappa-B ligand (RANKL)-the natural modulator of bone homeostasis are involved. These processes are driven by inflammatory cells, like monocytes/macrophages, neutrophils, Th17 CD4+ T, and B cells. In addition, Brucella abortus has a direct effect on osteoarticular cells and tilts homeostatic bone remodeling. These bacteria inhibit bone matrix deposition by osteoblasts (the only bone cells involved in bone deposition), and modify the phenotype of these cells to produce matrix metalloproteinases (MMPs) and cytokine secretion, contributing to bone matrix degradation. B. abortus also affects osteoclasts (cells naturally involved in bone resorption) by inducing an increase in osteoclastogenesis and osteoclast activation; thus, increasing mineral and organic bone matrix resorption, contributing to bone damage. Given that the pathology induced by Brucella species involved joint tissue, experiments conducted on synoviocytes revealed that besides inducing the activation of these cells to secrete chemokines, proinflammatory cytokines and MMPS, the infection also inhibits synoviocyte apoptosis. Brucella is an intracellular bacterium that replicates preferentially in the endoplasmic reticulum of macrophages. The analysis of B. abortus-infected synoviocytes indicated that bacteria also replicate in their reticulum suggesting that they could use this cell type for intracellular replication during the osteoarticular localization of the disease. Finally, the molecular mechanisms of osteoarticular brucellosis discovered recently shed light on how the interaction between B. abortus and immune and osteoarticular cells may play an important role in producing damage in joint and bone.


[Advances in Research on miR-21 and Breast Cancer].
Breast cancer is a malignant tumor from normal breast epithelial. In recent years, many literature reports sought to determine the expression of predicted target genes of microRNA and their potential function, pathways and networks, which are involved in the tumorigenesis, metastasis and prognosis of breast cancer. The miR-21 has recently been found to be highly expressed in solid tumors than normal tissue, and it has exposed some layers of gene expression regulation that becomes a hot topic of breast cancer. This paper briefly reviews advances in research on miR-21 in breast cancer.


Suppression of sweetness: evidence for central mechanism for suppression of sweetness from sucrose by citric acid.
The underlying mechanisms of taste interactions in humans are not well understood, and three mechanisms have been proposed, namely a chemical interaction, a peripheral physiological, and a central mechanism. In the present study, it was investigated which of these mechanisms causes the suppression of sweetness by citric acid. This was investigated using a split-tongue gustometer that can stimulate the two sides of the tongue with different stimuli simultaneously, enabling a comparison of sucrose and citric acid presented either separately on each side of the tongue simultaneously or in a mixture on one side. Two studies were conducted using low (Study 1; n = 50) and high (Study 2: n = 59) concentrations of sucrose (2.5% (w/w) and 10% (w/w), respectively), and citric acid (0.14% (w/w) and 0.18% (w/w), respectively). In neither of the studies was there a significant difference in sweetness intensity ratings between the two conditions where sucrose and citric acid were presented either separately or in a mixture form. However, both showed significantly lower sweetness ratings than without citric acid indicating suppression of the sweetness of sucrose from citric acid. This provides strong evidence for a central mechanism for the suppression of the sweetness of sucrose by citric acid. This mechanism seems to be equal in high and low concentrations of both sucrose and citric acid.


Natural killer cells in dengue hemorrhagic fever/dengue shock syndrome.
Natural killer (NK) cell activity against K-562 target cells and HNK-1+ cell levels were serially determined in peripheral blood of 62 Thai children with dengue hemorrhagic fever/dengue shock syndrome aged 4-12 years and 59 age-matched normal controls. The studies were performed on febrile stage, 1st and 2nd day of subsidence of fever (shock stage), 3rd and 4th day of subsidence of fever (early convalescent stage) and once again on the late convalescent stage (approximately 14-18 days after subsidence of fever). The study revealed that during the course of disease the NK cell activity was not changed significantly from the normal controls. In contrast, the levels of HNK-1+ cells, which exhibited almost all NK and killer cell functional activities, were significantly decreased in the febrile and the shock stages and were normal in the early and late convalescent stages. The NK cell activity, on the per-cell basis, was significantly increased in the early disease stage when compared to that of the later period of the disease and of the normal controls. The study also revealed that patients with grade III of disease severity exhibited significantly more NK cell functional activities per cell than grade II on febrile stage and the first day of shock. These results suggest that natural killer cells were active in defense against dengue viral infection and might play some role in the pathogenesis of dengue hemorrhagic fever/dengue shock syndrome. Their functions might also determine the severity of the disease.


Non-Invasive Brain Stimulation Improves Paretic Limb Force Production: A Systematic Review and Meta-Analysis.
Non-invasive brain stimulation (NIBS) facilitates motor improvements post stroke. Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) are representative NIBS techniques frequently used in stroke motor rehabilitation. Our primary question is: Do these two techniques improve force production capability in paretic limbs? The current systematic review and meta-analysis investigated the effects of tDCS and rTMS on paretic limb force production in stroke survivors. Our comprehensive search identified 23 studies that reported changes in force production following tDCS or rTMS interventions. Each used random assignment and a sham control group. The 23 qualified studies in our meta-analysis generated 29 comparisons: 14 tDCS and 15 rTMS comparisons. Random effects models indicated improvements in paretic limb force after tDCS and rTMS rehabilitation. We found positive effects on force production in the two sets of stimulation protocols: (a) increasing cortical activity in the ipsilesional hemisphere and (b) decreasing cortical activity in the contralesional hemisphere. Moreover, across acute, subacute, and chronic phases, tDCS and rTMS improved force production. Cumulative meta-analytic results revealed that tDCS and rTMS rehabilitation protocols successfully improved paretic limb force production capabilities.


Mesenteric and Mediastinal Lymphadenopathy in Egyptian Children With Gaucher Disease Types 1 and 3 Treated With Enzyme Replacement Therapy.
Gaucher disease (GD) is characterized by 3 clinical subtypes; type 1 GD (non-neuronopathic) and types 2 and 3 GD (acute and chronic neuronopathic forms, respectively). There are few reports of mesenteric and mediastinal lymphadenopathy, and none in type 1 GD or in African people. We report 8 Egyptian GD children (3 type 1 GD and 5 type 3 GD) who developed mesenteric and mediastinal lymphadenopathy despite receiving enzyme replacement therapy. Biopsy showed infiltration with Gaucher cells and no malignant changes. Pediatric physicians should be aware of possible lymphadenopathy associated with both types 1 and 3 GD as it can mimic malignancy.


Biosynthesis of the prenyl side chains of plastoquinone and related compounds in maize and barley shoots.
The incorporation of (14)C by etiolated maize and barley shoots exposed to light of (14)CO(2) and [2-(14)C]mevalonic acid into phylloquinone, plastoquinone, ubiquinone, alpha-tocopherolquinone and alpha-tocopherol was examined. In maize (the principal tissue studied) it was demonstrated that (14)C from [2-(14)C]mevalonic acid is incorporated into phylloquinone, plastoquinone and ubiquinone. alpha-Tocopherol and alpha-tocopherolquinone, although undoubtedly labelled from this substrate, were not purified completely. As expected, (14)C from (14)CO(2) was incorporated into all components examined. Ozonolytic degradation studies showed that (14)C from [2-(14)C]mevalonic acid was incorporated specifically into the prenyl side chains of plastoquinone and ubiquinone, and from this it was inferred that mevalonic acid can be regarded as the specific distal precursor to the prenyl portions of all terpenoid quinones occurring in plant tissues. From a comparison of the relative incorporation of (14)C from (14)CO(2) and [2-(14)C]mevalonic acid into the intra- and extra-chloroplastidic terpenoids evidence was obtained consistent with the tenet that the prenyl portions of the chloroplastidic quinones phylloquinone and plastoquinone, along with beta-carotene, are biosynthesized within the confines of the chloroplast, the side chain of the extraplastidic ubiquinone and phytosterols being synthesized elsewhere within the cell. The results obtained for the incorporation of (14)C from (14)CO(2) and [2-(14)C]mevalonic acid into alpha-tocopherol and alpha-tocopherolquinone were not readily interpretable with regard to the site of synthesis of these compounds.


The effect of autonomic receptor blockers on the ocular response to topical chemical irritation.
Topical chemical irritants induce an acute reaction in the eye, consisting of an increased intraocular pressure (IOP), breakdown of the blood-aqueous barrier, anterior uveal vasodilation and miosis. In the present study these effects were studied in the rabbit eye after topical application of neutral formaldehyde by measuring IOP continuously using electromanometrical equipment. The protein content of the aqueous humour was measured and miosis as well as anterior hyperemia were analyzed. Intravenously injected sodium fluorescein was used to visualize the site of the disruption of the blood-aqueous barrier in freeze-dried specimens. Iridectomies were performed to study the mechanisms of hypertension and disruption of the blood-aqueous barrier. In iridectomized rabbits the acute irritative response was very similar to that of normal eyes. Breakdown of the blood-aqueous barrier, miosis and anterior hyperemia occurred. However, the increase in IOP was only partially reduced. This indicates that a pupillary block due to the intense miosis plays a minor role in the hypertensive reaction or in the breakdown of the barrier. The effect of three autonomic receptor blocking agents: phentolamine (alpha-adrenergic antagonist), timolol (beta-adrenergic antagonist) and biperiden (cholinergic antagonist) on the irritative ocular response caused by formaldehyde was studied. Phentolamine proved to be an efficient inhibitor of the hypertensive reaction. It also effectively prevented the breakdown of the blood-aqueous barrier. Biperiden inhibited only slightly the increase in IOP caused by formaldehyde. Timolol had no significant effect. None of these three antagonists was able to prevent the miosis or hyperemia. The present findings indicate that a part of the irritative response is mediated by a phentolamine-sensitive neuronal pathway.(ABSTRACT TRUNCATED AT 250 WORDS)


Electrosensory Midbrain Neurons Display Feature Invariant Responses to Natural Communication Stimuli.
Neurons that respond selectively but in an invariant manner to a given feature of natural stimuli have been observed across species and systems. Such responses emerge in higher brain areas, thereby suggesting that they occur by integrating afferent input. However, the mechanisms by which such integration occurs are poorly understood. Here we show that midbrain electrosensory neurons can respond selectively and in an invariant manner to heterogeneity in behaviorally relevant stimulus waveforms. Such invariant responses were not seen in hindbrain electrosensory neurons providing afferent input to these midbrain neurons, suggesting that response invariance results from nonlinear integration of such input. To test this hypothesis, we built a model based on the Hodgkin-Huxley formalism that received realistic afferent input. We found that multiple combinations of parameter values could give rise to invariant responses matching those seen experimentally. Our model thus shows that there are multiple solutions towards achieving invariant responses and reveals how subthreshold membrane conductances help promote robust and invariant firing in response to heterogeneous stimulus waveforms associated with behaviorally relevant stimuli. We discuss the implications of our findings for the electrosensory and other systems.


Empagliflozin improves left ventricular diastolic function of db/db mice.
Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy. SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart. We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress. Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected. In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.


[A philosophical outlook on pain in relation to the patient].
Pain is perceived by the patient as a reduction of his speaking and acting capacity. When the pain gets worse, the patient will anticipate the end of his capacity to enjoy life and relate to other people; he will also see the spectre of death. The patient and his family expect a medical answer to the problem. Today's technological mentality takes into consideration only medical treatments. Medical and human aid is irreplaceable and invaluable to patients, and it is their due. However, it is not the only answer; solidarity also has great value, and so do words and looks.


Preparation and characterization of gastrointestinal wafer formulations.
Many active pharmaceutical ingredients (API) have a very poor or highly variable bioavailability after oral administration. One possibility to overcome this problem might be found in the application of mucoadhesive dosage forms like gastrointestinal wafers. However, a currently unsolved challenge is the control of the adhesion of the wafer to the intestinal mucus. One suggested solution might be the combination of gastrointestinal wafers and expanding systems. Such a combination requires thin and elastic wafers which are further characterized by an unidirectional drug release. In this study gastrointestinal, twolayered wafers containing a water-insoluble backing layer and a drug-loaded, mucoadhesive layer were fabricated by casting solvent technique. The backing layer consists of Ethocel™ Standard 10 Premium and the mucoadhesive layer was prepared using a mixture of Methocel™ E15 Premium LV, polyvinyl alcohol and Macrogol 400. The wafers were characterized regarding their appearance, mechanical properties and dissolution profiles as well as the influence of backing layer thickness on drug transfer and their ability of unidirectional drug release. The wafers with backing layer thickness of 500μg Ethocel™/cm2 presented adequate mechanical properties, a drug transfer about 73% and unidirectional drug release.


Implanon NXT: Expert tips for best-practice insertion and removal.
The single rod etonogestrel contraceptive implant is available in Australia as Implanon NXT. It is a highly effective, long-acting reversible contraceptive method, which is suitable for most women across the reproductive lifespan. This article provides practical advice for clinicians who already insert and remove the contraceptive implant, as well as advice for those who have not yet acquired this procedural skill. Contraceptive implant procedures are usually performed in the general practice setting. Clinicians can support women in making an informed choice to have an implant by providing information about their benefits, side effects and risks, and timely access to insertion. Training in the procedures and compliance with procedural instructions are essential to minimise risks, including deep insertion and damage to neurovascular structures.


Honey bee neurogenomic responses to affiliative and agonistic social interactions.
Social interactions can be divided into two categories, affiliative and agonistic. How neurogenomic responses reflect these opposing valences is a central question in the biological embedding of experience. To address this question, we exposed honey bees to a queen larva, which evokes nursing, an affiliative alloparenting interaction, and measured the transcriptomic response of the mushroom body brain region at different times after exposure. Hundreds of genes were differentially expressed at distinct time points, revealing a dynamic temporal patterning of the response. Comparing these results to our previously published research on agonistic aggressive interactions, we found both shared and unique transcriptomic responses to each interaction. The commonly responding gene set was enriched for nuclear receptor signaling, the set specific to nursing was enriched for olfaction and neuron differentiation, and the set enriched for aggression was enriched for cytoskeleton, metabolism, and chromosome organization. Whole brain histone profiling after the affiliative interaction revealed few changes in chromatin accessibility, suggesting that the transcriptomic changes derive from already accessible areas of the genome. Although only one stimulus of each type was studied, we suggest that elements of the observed transcriptomic responses reflect molecular encoding of stimulus valence, thus priming individuals for future encounters. This hypothesis is supported by behavioral analyses showing that bees responding to either the affiliative or agonistic stimulus exhibited a higher probability of repeating the same behavior but a lower probability of performing the opposite behavior. These findings add to our understanding of the biological embedding at the molecular level.


The functional units of a peptostreptococcal protein L.
Protein L is a cell-surface protein from Peptostreptococcus which interacts with immunoglobulin kappa light chains. A gene from Peptostreptococcus strain 3316 coding for protein L and fragments thereof were expressed in Escherichia coli. The peptides were examined for binding to immunoglobulin and serum albumin. The four C units were shown to be responsible for binding to immunoglobulin and the four D units for binding to albumin. This protein L molecule therefore binds to albumin at a site separate from that involved in binding to immunoglobulin. The albumin-binding units have high amino acid sequence identity with the albumin-binding units of streptococcal cell-surface proteins. The gene contains three sites available for internal initiation of translation resulting in three active proteins. The protein L molecule presented in this report was compared with a previously reported protein from Peptostreptococcus strain 312. The two proteins differ in several respects, including size and the number and types of repeat units.


Combined toxicity of mercury, copper and cadmium on embryogenesis and early larval stages of the Mytilus galloprovincialis.
The aim of this study was to investigate the individual and combined toxicity of dissolved copper-cadmium and mercury using the embriotoxicity test with Mytilus galloprovincialis. Adult stocks of Mytilus galloprovincialis were induced to spawn and early larvae were recorded after incubation of fertilized eggs in seawater. The 48h - EC50 for the single metals, ranged from 10 to 590 microg l(-1), with the following toxicity ranking: Hg > Cd > Cu. One-way ANOVA showed that the toxicity of mercury and copper had a significant effect on larval development beginning from the lowest concentration, but there is no significant difference in the mean responses among all concentrations. Cadmium had a significant effect (p < 0.05) already at the lowest concentrations. To identify the kind of interaction in binary mixtures among metals, the additive toxicity index (S) was calculated. All mixtures tested, after 48h, showed an antagonistic response.


Permeability prediction in deep coal seam: a case study on the No. 3 coal seam of the Southern Qinshui Basin in China.
The coal permeability is an important parameter in mine methane control and coal bed methane (CBM) exploitation, which determines the practicability of methane extraction. Permeability prediction in deep coal seam plays a significant role in evaluating the practicability of CBM exploitation. The coal permeability depends on the coal fractures controlled by strata stress, gas pressure, and strata temperature which change with depth. The effect of the strata stress, gas pressure, and strata temperature on the coal (the coal matrix and fracture) under triaxial stress and strain conditions was studied. Then we got the change of coal porosity with strata stress, gas pressure, and strata temperature and established a coal permeability model under tri-axial stress and strain conditions. The permeability of the No. 3 coal seam of the Southern Qinshui Basin in China was predicted, which is consistent with that tested in the field. The effect of the sorption swelling on porosity (permeability) firstly increases rapidly and then slowly with the increase of depth. However, the effect of thermal expansion and effective stress compression on porosity (permeability) increases linearly with the increase of depth. The most effective way to improve the permeability in exploiting CBM or extracting methane is to reduce the effective stress.


Characteristics of Hypovascular versus Hypervascular Well-Differentiated Hepatocellular Carcinoma Smaller Than 2 cm - Focus on Tumor Size, Markers and Imaging Detectability.
The characteristics of hypovascular and hypervascular well-differentiated hepatocellular carcinomas (HCCs) were compared in terms of tumor size, tumor markers and detectability by imaging modalities. Well-differentiated HCC nodules that are smaller than 2 cm (n = 27) were evaluated in 27 patients using histopathology and divided into 2 groups: hypovascular (n = 10) and hypervascular (n = 17). The diagnostic sensitivity of imaging modalities was then evaluated for efficiency in disclosing tumor size and tumor markers in the 2 types. No difference was observed in tumor size and tumor markers between the 2 types; however, the sensitivity of contrast-enhanced CT, contrast-enhanced ultrasonography and arterioportal angiography was significantly different between the 2 types, whereas that by Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging (Gd-EOB-DTPA MRI) demonstrated no difference. Hypovascular HCC could be diagnosed by Gd-EOB-DTPA MRI in the hepatobiliary phase.


Risk factors for substance use in Swedish adolescents: A study across substances and time points.
Aim: The public health model for prevention of disease and disorder has been influential in informing interventions regarding substance use. While a number of risk factors within this model have been found to predict substance use, few studies have explored the associations across substances, at different time points and in the same individuals. The aim of this study was to test this model across legal and illegal substance use among adolescents, and to identify potential changes in associations over time. Methods: Data from two waves of a nationally representative cohort study among Swedish adolescents were used. Baseline data were collected in 2017 (9th grade) with a follow-up in 2019 (11th grade). Using modified Poisson regression analyses, we explored cross-sectional associations between factors from different domains and prevalence of cigarette use, binge-drinking and illegal drug use at both baseline and follow-up. Results: The results in part supported the public health model. Substance use was predicted by factors within the family, school and the individual/peer domain, but several associations were not statistically significant. The only consistent risk factors across substances and time points were lack of parental monitoring, truancy and minor criminal activities. Conclusion: Despite widely different prevalence rates across substances, some risk factors were consistently associated with adolescent substance use. Nonetheless, the findings challenge the assumption that risk factors are stable over adolescence. They suggest a need for flexible prevention interventions spanning across substances and legal boundaries of substances, but also over domains to reflect the heterogenous needs of adolescents.


Sarcocystis in caribou (Rangifer tarandus terraenorae) in Newfoundland.
Prevalence of species of Sarcocystis in muscle of 36 caribou, Rangifer tarandus terraenorae, shot in Newfoundland, Canada, was 53%. A greater percentage of infected animals were obtained from the central part of the island. The highest concentration of microscopic sarcocysts, 1/mm2 of tissue, was observed in a 5-year old animal. Although widely distributed throughout the body, cysts were more prevalent in the tongue and diaphragm. The potential of Sarcocystis in caribou as a food-borne disease organism in man cannot be overlooked in view of its prevalence in meat and its widespread consumption, when lightly cooked, in rural Newfoundland.


Pilot Survey of Breast Cancer Management in Sub-Saharan Africa.
To understand the current state of breast cancer management in sub-Saharan Africa. We conducted an anonymous online survey of breast cancer management among African Organization for Research and Treatment in Cancer (AORTIC) members by using a 42-question structured questionnaire in both English and French in 2013. Twenty members from 19 facilities in 14 countries responded to the survey. Twelve members (60%) belonged to a multidisciplinary breast cancer team. Radiotherapy equipment was available in seven facilities (36%), but equipment had down time at least once a week in four facilities. Available chemotherapy drugs included methotrexate, cyclophosphamide, fluorouracil, anthracyclines, and vincristine, whereas trastuzumab, taxanes, vinorelbine, and gemcitabine were available in few facilities. Core-needle biopsy was available in 16 facilities (84%); mammogram, in 17 facilities (89%); computed tomography scan, in 15 facilities (79%); magnetic resonance imaging, in 11 facilities (58%); and bone scans, in nine facilities (47%). It took an average of 1 to 3 weeks to report histopathology. Immunohistochemistry was available locally in eight facilities (42%), outside hospitals but within the country in seven facilities (37%), and outside the country in four facilities (21%). Thirteen facilities (68%) performed axillary node dissections as part of a breast protocol. Neoadjuvant chemotherapy was the most common therapy for locally advanced breast cancer in 13 facilities (68%). In three facilities (16%), receptor status did not influence the prescription of hormone treatment. This pilot survey suggests that AORTIC members in sub-Saharan Africa continue to make gains in the provision of access to multidisciplinary breast cancer care, but the lack of adequate pathology and radiotherapy services is a barrier. Focused attention on in-country and regional training needs and improvement of health systems deliverables is urgently needed.


An ARC-Regulated IL1β/Cox-2/PGE2/β-Catenin/ARC Circuit Controls Leukemia-Microenvironment Interactions and Confers Drug Resistance in AML.
The apoptosis repressor with caspase recruitment domain (ARC) protein is a strong independent adverse prognostic marker in acute myeloid leukemia (AML). We previously reported that ARC regulates leukemia-microenvironment interactions through the NFκB/IL1β signaling network. Malignant cells have been reported to release IL1β, which induces PGE2 synthesis in mesenchymal stromal cells (MSC), in turn activating β-catenin signaling and inducing the cancer stem cell phenotype. Although Cox-2 and its enzymatic product PGE2 play major roles in inflammation and cancer, the regulation and role of PGE2 in AML are largely unknown. Here, we report that AML-MSC cocultures greatly increase Cox-2 expression in MSC and PGE2 production in an ARC/IL1β-dependent manner. PGE2 induced the expression of β-catenin, which regulated ARC and augmented chemoresistance in AML cells; inhibition of β-catenin decreased ARC and sensitized AML cells to chemotherapy. NOD/SCIDIL2RγNull-3/GM/SF mice transplanted with ARC-knockdown AML cells had significantly lower leukemia burden, lower serum levels of IL1β/PGE2, and lower tissue human ARC and β-catenin levels, prolonged survival, and increased sensitivity to chemotherapy than controls. Collectively, we present a new mechanism of action of antiapoptotic ARC by which ARC regulates PGE2 production in the tumor microenvironment and microenvironment-mediated chemoresistance in AML.Significance: The antiapoptotic protein ARC promotes AML aggressiveness by enabling detrimental cross-talk with bone marrow mesenchymal stromal cells.


Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals.
It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m2) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51-4.25) and 2.56 (95% CI: 1.14-5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61-2.33). Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.


Improved low molecular weight Myc-Max inhibitors.
Compounds that selectively prevent or disrupt the association between the c-Myc oncoprotein and its obligate heterodimeric partner Max (Myc-Max compounds) have been identified previously by high-throughput screening of chemical libraries. Although these agents specifically inhibit the growth of c-Myc-expressing cells, their clinical applicability is limited by their low potency. We describe here several chemical modifications of one of these original compounds, 10058-F4, which result in significant improvements in efficacy. Compared with the parent structure, these analogues show enhanced growth inhibition of c-Myc-expressing cells in a manner that generally correlates with their ability to disrupt c-Myc-Max association and DNA binding. Furthermore, we show by use of a sensitive fluorescence polarization assay that both 10058-F4 and its active analogues bind specifically to monomeric c-Myc. These studies show that improved Myc-Max compounds can be generated by a directed approach involving deliberate modification of an index compound. They further show that the compounds specifically target c-Myc, which exists in a dynamic and relatively unstructured state with only partial and transient alpha-helical content.


Autologous peripheral blood stem cell transplantation in malignancies involving bone marrow.
Six patients suffering from refractory malignancies (3 NHL, 1 MM, 1 AML, 1 neuroblastoma) received high dose of chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT). The recruitment of PBSC was performed using conventional salvatage schedules of therapy. The patients received a median of 8.69 MNC/kg bw and 20.87 CFU-GM x 10(4)/kg bw. Prompt engraftment occurred in all patients and the median number of days to achieve WBC greater than 1 x 10(9)/l was 16.5 (range 7-26), PMN greater than 0.5 x 10(9)/l was 21.5 (range 6-37) and PLTs greater than 50 x 10(9)/l was 17.5 (range 4-31). Four patients achieved a complete remission. One patient (neuroblastoma) died of progressive disease after a partial response. One patient died in relapse because of drug related toxicity.


[Tension-free plasty in the surgery of abdominal wall hernias].
The article presents an experience with application of tension-free plasty of the anterior abdominal wall using reticular endoprostheses. New endoprostheses of Reperen are developed and applied, a method of sutureless fixation of polypropylene net in the abdominal wall tissues is proposed when performing plasty for great ventral hernias. Advantages of new methods are shown compared with analogs both in selective and in emergency surgery, in different age groups of patients. The direct and long-term postoperative results and parameters of quality of life are investigated.