Influence of physical exercise on β-amyloid, α-synuclein and tau accumulation: an in vitro model of oxidative stress in human red blood cells.
A common pathological feature of neurodegenerative disorders (NDs), such as Alzheimer's (AD) and Parkinson's (PD) diseases, is the abnormal accumulation and misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1-42 (Aβ) and tau, in brain and in peripheral tissues too. Oxidative stress has been proved to be involved in NDs at various levels and, in particular, in such protein alterations, on the contrary physical activity is emerging as a counteracting factor in NDs. In the present work, the content of Aβ, α-syn and tau in red blood cells (RBCs) derived from ten endurance athletes (ATHL) and ten sedentary volunteers (SED) were compared before and after in vitrooxidative stress treatment. Total Aβ, α-syn and tau were quantified in RBCs (isolated from the subjects) by immunoenzymatic assays. Oxidative stress was induced by in vitro H₂O₂ administration to RBCs. H₂O₂ treatment was confirmed to significantly enhance ROS accumulation in RBCs. Total Aβ content in RBCs was lower in the ATHL subgroup with respect to the SED one. In the SED subgroup, but not in the ATHL one, total Aβ levels were increased by oxidative stress. Total α-syn content was lower in the ATHL subgroup with respect to the SED one and α-syn levels were increased by oxidative stress in both subgroups, with the percentage of increase higher in SED. Total tau content was comparable in both ATHL and SED and it was not affected by oxidative stress. Our data confirm previous findings evidencing that both oxidative stress and sedentary style contribute to aberrant folding and accumulation of NDs-related proteins, pointing to the importance of both anti-oxidant therapies and exercising in the prevention and treating of such diseases.


The epidemiology of alcohol consumption in Spain.
This paper is a comprehensive review of the available information about alcohol consumption in Spain. Alcohol use is the most severe drug problem among both young people and adults; almost half the Spanish population drink daily, and more than a fourth drink a quantity of alcohol sufficient to cause health problems in the long term. The consumption of alcohol may be considered to be culturally rooted when compared with other drug use which follows a more recent epidemic pattern. For those who use other drugs, for example cannabis and cocaine, alcohol is commonly used in conjunction. Clearly the level of alcohol use and abuse is high in Spain and constitutes a severe public health and socioeconomic problem.


Coincidence velocity map imaging using a single detector.
We demonstrate a single-detector velocity map imaging setup which is capable of rapidly switching between coincidence and non-coincidence measurements. By rapidly switching the extraction voltages on the electrostatic lenses, both electrons and ions can be collected in coincidence with a single detector. Using a fast camera as the 2D detector avoids the saturation problem associated with traditional delay line detectors and allows for easy transitions between coincidence and non-coincidence data collection modes. This is a major advantage in setting up a low-cost and versatile coincidence apparatus. We present both coincidence and non-coincidence measurements of strong field atomic and molecular ionization.


Meiotic inheritance of functional Gal80S gene product in Saccharomyces cerevisiae.
Transcription factors inherited during meiosis play a crucial role directing subsequent gene activity. Factors of maternal origin have been shown to influence the pattern of early zygotic transcription during Drosophila and Xenopus embryogenesis. Nevertheless, little is known regarding the meiotic inheritance of the vast majority of transcription factors. In the case of yeast meiosis, for example, it is not yet known whether any of the multitude of transcription factors expressed in the diploid are transmitted to haploid spores in functional form. Here we use a GAL1-STE4 reporter whose activity is detectable in single living cells to identify a transcription factor inherited during sporulation in Saccharomyces cerevisiae. We show that functional Gal80S repressor is meiotically inherited at levels reflecting its expression in the diploid parent.


Towards automated observational analysis of leadership in clinical networks.
Clinical networks are being increasingly employed to drive innovation in health services by encouraging multi-disciplinary clinical engagement in management processes. The effectiveness of a network, however, depends critically on the ability of its leader to coordinate group interactions. This paper discusses leadership of clinical networks, and in this context reviews technologies for analyzing the way team members interact in group conversations. This review will form the foundation for ongoing research to develop the profile of an effective clinical network leader, along with techniques and tools for evaluation and professional development.


[Neurotransmission in developmental disorders].
Attention deficit/hyperactivity disorder (AD/HD) is a heterogeneous developmental disorder with an etiology that is not fully understood. AD/HD has been considered to occur due to a disturbance in cathecholaminergic neurotransmission, with particular emphasis on dopamine. The neurotransmission of dopamine in subcortical regions such as the basal ganglia and limbic areas is synaptic; on the other hand, dopamine neurotransmission in the frontal cortex is quite different, because there are very few dopamine transporters (DAT) in the frontal cortex that allow dopamine to diffuse away from the dopamine synapse ("volume transmission"). It is now clear that noradrenergic neurons play a key regulatory role in dopaminergic function in the frontal cortex. Furthermore, serotonergic neurons exert an inhibitory effect on midbrain dopamine cell bodies, and they have an influence on dopamine release in terminal regions. There is accumulating neurobiological evidence pointing toward a role of the serotonin system in AD/HD. The etiology of autism spectrum disorders (ASD) is still unclear, but information from genetics, neuropathology, brain imaging, and basic neuroscience has provided insights into the understanding of this developmental disorder. In addition to abnormal circuitry in specific limbic and neocortical areas of the cerebral cortex, impairments in brainstem, cerebellar, thalamic, and basal ganglia connections have been reported. Numerous studies have pointed to abnormalities in serotonin and glutamate neurotransmission. Three important aspects involved in the pathophysiology of ASD have been proposed. The first is cell migration, the second is unbalanced excitatory-inhibitory networks, and the third is synapse formation and pruning, the key factors being reelin, neurexin, and neuroligin. Serotonin is considered to play an important role in all of these aspects of the pathophysiology of ASD. Finally, I would like to emphasize that it is crucial in the field of child neurology medical examination and treatment should be based on the basic neuroscience, always taking "neurons" into consideration.


Candidate genes for first flower node identified in pepper using combined SLAF-seq and BSA.
First flower node (FFN) is an important trait for evaluating fruit earliness in pepper (Capsicum annuum L.), but the genetic mechanisms that control FFN are still poorly understood. In the present study, we developed 249 F2 plants derived from an intraspecific cross between the inbred pepper lines Z4 and Z5. Thirty plants with the highest FFN and 30 plants with the lowest FFN were chosen and their DNAs were pooled according to phenotype to construct two bulked DNA pools. Specific-locus amplified fragment sequencing (SLAF-seq) was combined with bulked segregant analysis (BSA) to identify candidate regions related to FFN. According to our genetic analysis, the FFN trait is quantitatively inherited. A total of 106,848 high-quality single nucleotide polymorphism (SNP) markers were obtained, and 393 high-quality SNP markers associated with FFN were detected. Ten candidate regions within an interval of 3.98 Mb on chromosome 12 harboring 23 candidate genes were identified as closely correlated with FFN. Five genes (CA12g15130, CA12g15160, CA12g15370, CA12g15360, and CA12g15390) are predicted based on their annotations to be associated with expression of the FFN trait. The present study demonstrates an efficient genetic mapping strategy and lays a good foundation for molecular marker-assisted breeding using SNP markers linked to FFN and for cloning and functional analysis of the key genes controlling FFN.


Comparison of the characteristics of canine adipose tissue-derived mesenchymal stem cells extracted from different sites and at different passage numbers.
Mesenchymal stem cells (MSCs) have desirable characteristics for use in therapy in animal models and veterinary medicine, due to their capacity of inducing tissue regeneration and immunomodulation. The objective of this study was to evaluate the differences between canine adipose tissue-derived MSCs (AD-MSCs) extracted from subcutaneous (Sc) and visceral (Vs) sites. Surface antigenic markers, in vitro differentiation, and mineralized matrix quantification of AD-MSCs at different passages (P4, P6, and P8) were studied. Immunophenotypic analysis showed that AD-MSCs from both sites were CD44+, CD90+, and CD45-. Moreover, they were able, in vitro, to differentiate into fat, cartilage, and bone. Sc-AD-MSCs preserve in vitro multipotentiality up to P8, but Vs-AD-MSCs only tri-differentiated up to P4. In addition, compared to Vs-AD-MSCs, Sc-AD-MSCs had greater capacity for in vitro mineralized matrix synthesis. In conclusion, Sc-AD-MSCs have advantages over Vs-AD-MSCs, as Sc AD-MSCs preserve multipotentiality during a greater number of passages, have more osteogenic potential, and require less invasive extraction.


Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type II diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance.
This study was designed to quantitate glucose and FFA disposal by muscle tissue in patients with type II diabetes and to investigate the relationship between FFA metabolism and insulin resistance. The forearm perfusion technique was used in six normal subjects and two groups of normal weight diabetic patients, i.e. untreated (n = 8) and insulin-treated (n = 6). The latter received 2 weeks of intensive insulin therapy before the study. Plasma insulin levels were raised acutely [950-1110 pmol/L) (130-150 microU/mL)], while the blood glucose concentration was clamped at its basal value [4.9 +/- 0.1 (+/- SE) mmol/L in the normal subjects, 5.7 +/- 0.5 in the insulin-treated diabetic patients, and 5.5 +/- 0.3 in the untreated diabetic patients] by a variable glucose infusion. During the control period, arterial FFA concentrations were similar in the three groups, and they decreased to a comparable extent (less than 0.1 mmol/L) in response to insulin infusion. During the control period, the mean forearm FFA uptake was 2.5 +/- 0.5 mumol/L.min in the normal subjects, 2.9 +/- 0.5 in the insulin-treated patients, and 2.1 +/- 0.5 in the untreated diabetic patients. During the insulin infusion, FFA uptake was profoundly suppressed to similar levels in the normal subjects (0.9 +/- 0.1 mumol/L.min), the insulin-treated diabetic patients (1.1 +/- 0.3), and the untreated diabetic patients (0.9 +/- 0.1; P less than 0.001). Forearm glucose uptake was similar in the three groups during the control period. It increased during the insulin infusion, but the response in both diabetic groups was less than that in the normal subjects. The total amounts of glucose taken up by the forearm during the study period were 5.2 +/- 0.7, 2.6 +/- 0.5, and 2.1 +/- 0.6 mmol/L.min in the normal subjects, the insulin-treated diabetic patients, and the untreated diabetic patients, respectively (P less than 0.01). We conclude that 1) insulin-mediated glucose uptake by forearm skeletal muscle is markedly impaired in type II diabetes and improves only marginally after 2 weeks of intensive insulin therapy; 2) in contrast, no appreciable abnormality in forearm FFA metabolism is demonstrable in insulin-treated type II diabetic patients; and 3) FFA do not contribute to the insulin-treated skeletal muscle insulin resistance that occurs in patients with type II diabetes mellitus.


Final report on the safety assessment of triacetin.
Triacetin, also known as Glyceryl Triacetate, is reported to function as a cosmetic biocide, plasticizer, and solvent in cosmetic formulations, at concentrations ranging from 0.8% to 4.0%. It is a commonly used carrier for flavors and fragrances. Triacetin was affirmed as a generally recognized as safe (GRAS) human food ingredient by the Food and Drug Administration (FDA). Triacetin was not toxic to animals in acute oral or dermal exposures, nor was it toxic in short-term inhalation or parenteral studies, and subchronic feeding and inhalation studies. Triacetin was, at most, slightly irritating to guinea pig skin. However, in one study, it caused erythema, slight edema, alopecia, and desquamation, and did cause some irritation in rabbit eyes. Triacetin was not sensitizing in guinea pigs. Triacetin was not an irritant or a sensitizer in a clinical maximization study, and only very mild reactions were seen in a Duhring-chamber test using a 50% dilution. In humans, Triacetin reportedly has caused ocular irritation but no injury. Triacetin was not mutagenic. Although there were no available reproductive and developmental toxicity data, Triacetin was quickly metabolized to glycerol and acetic acid and these chemicals were not developmental toxins. Reports of 1,2-glyceryl diesters, which may be present in Triacetin, affecting cell growth and proliferation raised the possibility of hyperplasia and/or tumor promotion. The Cosmetic Ingredient Review (CIR) Expert Panel concluded, however, that the effects of 1,2-glyceryl diesters on cell growth and proliferation require longer ester chains on the glycerin backbone than are present when acetic acid is esterified with glycerin, as in Triacetin. On the basis of the available information, the CIR Expert Panel concluded that Triacetin is safe as used in cosmetic formulations.


Elevated expression of the genes for transforming growth factor-beta 1 and type VI collagen in diffuse fasciitis associated with the eosinophilia-myalgia syndrome.
Full-thickness skin biopsies obtained from four patients with rapidly progressive diffuse fasciitis associated with the Eosinophilia-Myalgia syndrome (EMS) were examined for the expression of transforming growth factor-beta 1 (TGF-beta 1), type VI collagen, and fibronectin genes employing immunohistochemistry and in situ hybridizations. The immunohistochemical studies demonstrated increased deposition of TGF-beta, type VI collagen, and fibronectin epitopes in the extracellular matrix of the fascia in comparison to the adjacent dermis in the same specimens. Increased levels of type VI collagen mRNA, as evidenced by positive in situ hybridization signals with an alpha 2(VI) collagen cDNA, were also found in the fascia in comparison with the dermis. In situ hybridizations of affected fascia with a human sequence-specific TGF-beta 1 cDNA demonstrated numerous fibroblasts displaying positive hybridization signals indicative of high levels of transcripts for this cytokine. In contrast, no hybridization signal for TGF-beta 1 was detected in fibroblasts in the adjacent dermis. These findings suggest that TGF-beta 1 may play an important role in the development of the connective tissue alterations present in EMS-associated diffuse fasciitis.


Diagnostic Accuracy of the Telephone Interview for Cognitive Status for the Detection of Dementia in Primary Care.
Cognitive diagnostic work-up in primary care is not always physically feasible, owing to chronic disabilities and/or travel restrictions. The identification of dementia might be facilitated with diagnostic instruments that are time efficient and easy to perform, as well as useful in the remote setting. We assessed whether the Telephone Interview for Cognitive Status (TICS) might be a simple and accurate alternative for remote diagnostic cognitive screening in primary care. We administered the TICS (range, 0-41) for 810 of 1,473 older people aged 84.5 (SD, 2.4) years. We scrutinized electronic health records for participants with TICS scores ≤30 and for a random sample of participants with TICS scores >30 for a dementia diagnosis using all data from the Prevention of Dementia by Intensive Vascular Care (preDIVA) trial for 8-12 years of follow-up. We used multiple imputation to correct for verification bias. Of the 810 participants, 155 (19.1%) had a TICS score ≤30, and 655 (80.9%) had a TICS score >30. Electronic health records yielded 8.4% (13/154) dementia diagnoses for participants with TICS ≤30 vs none with TICS >30. Multiple imputation for TICS >30 yielded a median of 7/655 (1.1%; interquartile range, 5-8) estimated dementia cases. After multiple imputation, the optimal cutoff score was ≤29, with mean sensitivity 65.4%, specificity 87.8%, positive predictive value 11.9%, negative predictive value 99.0%, and area under the curve 77.4% (95% CI, 56.3%-90.0%). In the present older population, the TICS performed well as a diagnostic screening instrument for excluding dementia and might be particularly useful when face-to-face diagnostic screening is not feasible in family practice or research settings. The potential reach to large numbers of people at low cost could contribute to more efficient medical management in primary care.


Inhibition of ecto-ATPase by the P2 purinoceptor agonists, ATPgammaS, alpha,beta-methylene-ATP, and AMP-PNP, in endothelial cells.
Ecto-ATPase is a plasma membrane-bound enzyme that sequentially dephosphorylates extracellular nucleotides such as ATP. This breakdown of ATP and other nucleotides makes it difficult to characterize and classify P2 purinoceptors. We have previously shown that the P2 purinergic antagonists, PPADS, suramin and reactive blue, act as ecto-ATPase inhibitors in various cell lines. Here, we show that the P2 purinergic agonists, ATPgammaS, alpha,beta-methylene ATP (alpha,beta-MeATP) and AMP-PNP, inhibit the ecto-ATPase of bovine pulmonary artery endothelial cells (CPAE), with pIC50 values of 5.2, 4.5 and 4.0, respectively. In CPAE, FPL67156, a selective ecto-ATPase inhibitor, also inhibits ecto-ATPase activity, with a pIC50 value of 4.0. In addition, alpha,beta-MeATP (3-100 microM), which itself does not induce phosphoinositide (PI) turnover, left-shifted the agonist-concentration effect (E/[A]) curves for ATP, 2MeS-ATP and UTP by approximate 100-300 fold, while those for ATPgammaS and AMP-PNP were only shifted approximately 2-3 fold. Moreover, in the presence of alpha,beta-MeATP, not only was the potentiation effect of PPADS on the UTP response lost, but a slight inhibition of the UTP response by PPADS was also seen. Thus, we conclude that the action of ATPgammaS, alpha,beta-MeATP and AMP-PNP as ecto-ATPase inhibitors account for their high agonist potency, and also provide information for the development of ecto-ATPase inhibitors of high selectivity and potency.


Ischaemic stroke: decide rapidly.
A meta-analysis of individual data for 6756 patients showed that intravenous thrombolysis with alteplase improved survival without overt neurological deficits when started within 4.5 hours of the first symptoms of ischaemic stroke, at a cost of increased mortality due to cerebral haemorrhage during the week following thrombolysis.


Galectin-3 ablation protects mice from diet-induced NASH: a major scavenging role for galectin-3 in liver.
Excess fatty acid oxidation and generation of reactive carbonyls with formation of advanced lipoxidation endproducts (ALEs) is involved in nonalcoholic steatohepatitis (NASH) by triggering inflammation, hepatocyte injury, and fibrosis. This study aimed at verifying the hypothesis that ablation of the ALE-receptor galectin-3 prevents experimental NASH by reducing receptor-mediated ALE clearance and downstream events. Galectin-3-deficient (Lgals3(-/-)) and wild type (Lgals3(+/+)) mice received an atherogenic diet or standard chow for 8 months. Liver tissue was analyzed for morphology, inflammation, cell and matrix turnover, lipid metabolism, ALEs, and ALE-receptors. Steatosis was significantly less pronounced in Lgals3(-/-) than Lgals3(+/+) animals on atherogenic diet. NASH, invariably detected in Lgals3(+/+) mice, was observed, to a lower extent, only in 3/8 Lgals3(-/-) mice, showing less inflammatory, degenerative, and fibrotic phenomena than Lgals3(+/+) mice. This was associated with higher circulating ALE levels and lower tissue ALE accumulation and expression of other ALE-receptors. Up-regulation of hepatic fatty acid synthesis and oxidation, inflammatory cell infiltration, pro-inflammatory cytokines, endoplasmic reticulum stress, hepatocyte apoptosis, myofibroblast transdifferentiation, and impaired Akt phosphorylation were also significantly attenuated in Lgals3(-/-) animals. Galectin-3 silencing in liver endothelial cells resulted in reduced N(ε)-carboxymethyllysine-modified albumin uptake and ALE-receptor expression. Galectin-3 ablation protects from diet-induced NASH by decreasing hepatic ALE accumulation, with attenuation of inflammation, hepatocyte injury, and fibrosis. It also reduced up-regulation of lipid synthesis and oxidation causing less fat deposition, oxidative stress, and possibly insulin resistance. These data suggest that galectin-3 is a major receptor involved in ALE uptake by the liver.


The LH surge in humans: its mechanism and sex difference.
There is a sex difference in the response to an estrogen challenge test in humans, but, unlike with rats, this sex difference is not permanently imprinted in the central nervous system. Estrogen is not only the important ovarian signal to trigger off the LH surge, but it also probably plays an important role in activating the positive estrogen feedback mechanism in humans. For an LH surge to occur, amplification of the hypothalamic signal (enhanced secretion of GnRH) as well as sensitization of the pituitary responsiveness to GnRH are required. It is unlikely that androgens per se are responsible for suppressing the positive estrogen feedback in humans and the possible role of another gonadal factor other than androgens remains speculative. The LH surge is a neuroendocrine phenomenon involved primarily in the process of ovulation and it is not correlated to sexual identity and orientation. Furthermore, how the hypothalamic-pituitary axis (HPA) responds to the estrogen challenge can be accounted for purely by its exposure to a different steroid milieu without reference to gender identity or sexual orientation of the subject.


Intra-articular steroid injection for osteoarthritis of the hip prior to total hip arthroplasty : is it safe? a systematic review.
Using a systematic review, we investigated whether there is an increased risk of post-operative infection in patients who have received an intra-articular corticosteroid injection to the hip for osteoarthritis prior to total hip arthroplasty (THA). Studies dealing with an intra-articular corticosteroid injection to the hip and infection following subsequent THA were identified from databases for the period between 1990 to 2013. Retrieved articles were independently assessed for their methodological quality. A total of nine studies met the inclusion criteria. Two recommended against a steroid injection prior to THA and seven found no risk with an injection. No prospective controlled trials were identified. Most studies were retrospective. Lack of information about the methodology was a consistent flaw. The literature in this area is scarce and the evidence is weak. Most studies were retrospective, and confounding factors were poorly defined or not addressed. There is thus currently insufficient evidence to conclude that an intra-articular corticosteroid injection administered prior to THA increases the rate of infection. High quality, multicentre randomised trials are needed to address this issue. Cite this article: Bone Joint J 2016;98-B:1027-35.


The expression of the follicle-stimulating hormone receptor in spermatogenesis.
Results from experiments using mouse models suggest that the role of follicle-stimulating hormone (FSH) in spermatogenesis is the regulation of Sertoli cell proliferation and, ultimately, the size and spermatogenic capacity of the testis. The regulation of the expression of the FSH receptor (FSHR) gene is very cell specific and plays an initial role in the ultimate response of the Sertoli cells to FSH. The extreme cell specificity and the importance of the FSH response to spermatogenesis have led to an extensive characterization of the promoter of the FSHR gene. Several widely expressed transcription factors - including USF 1 and 2, GATA-1, and SF-1 and potential elements such as an E2F site and an Inr region - have been shown to contribute to the maximal transcription of the transfected FSHR gene. However, these experiments have failed to provide clues as to the cell-specific expression of the FSHR gene. In both cell transfections and in transgenic mice, the promoter can direct expression of transgenes promiscuously. The rodent FSHR promoter contains conserved CpG dinucleotides that were shown to be methylated in nonexpressing cells and tissue but unmethylated in Sertoli cells. The methylated CpG sites could interfere with the binding of general transcription factors and/or lead to a repressive chromatin structure in the nonexpressing cells. While yet-undiscovered cell-specific factors may play a role in the expression of the FSHR gene, repression and activation of local chromatin structure are likely to be involved.


How an emergent cosmology of a nonlocally unified, meaningfully in-formed and holographically manifested Universe can underpin and frame the biological embodiment of quantum entanglement.
With a Nobel Prize for Physics widely viewed as only given for 'settled' science, the award then essentially accepts the validity of universal nonlocality. Other key discoveries and insights in recent years are also progressively pointing to the appearance of our Universe, its energy-matter and space-time, as not being foundational but emerging from deeper, discarnate realms of causation. as digitized and meaningful, in-formation, its manifestation pixelated at the so-named Planck scale of existence. Extending from studies of black holes to the entire Universe, a growing number of cosmologists have also developed the so-named holographic principle, to model the four-dimensional appearance of our Universe (three dimensions of space and one of time) as a holographic projection of its two- dimensional boundary. In framing the emergent cosmology of a nonlocally unified, meaningfully in-formed and holographically manifested Universe, an expansion of the three universal Laws of Thermodynamics to three Laws of Information, or Infodynamics also points the way to reconciling Quantum Theory that describes energy-matter and Relativity Theory that describes space-time and offers too an understanding of how the lifecycle of our Universe flows from its first moment until its last. Treating gravity as an emergent consequence of the in-formational and holographic structure of space- time and describing it as the consequence of the intropy associated with the positions in space-time of massive bodies, also points to the findings of the loss of phenotype identity in zero gravity and the role between gravity and cellular identity and the emergence of symbiogenesis.


A molecular, morphometric and mechanical comparison of the structural elements of byssus from Mytilus edulis and Mytilus galloprovincialis.
Marine mussels are renowned for their ability to produce an extra-organismic tendon-like structure that can withstand the wave forces associated with the intertidal habitat. Initial characterization of byssal properties has focused on Mytilus edulis, with few detailed comparisons with other mussels. M. galloprovincialis, a closely related species, provides an opportunity for a thorough comparison. Three full-length cDNA clones encoding the byssal collagens, precollagen D (preCol-D), preCol-NG and preCol-P, were isolated from M. galloprovincialis. Comparisons with M. edulis preCol-D, preCol-NG and preCol-P reveal a 91.3 %, 88.6 % and 90.1 % identity with the cDNA and an 89.0 %, 88.1 % and 89.0 % identity with the deduced protein sequences, respectively. Key elements are maintained between the species: in particular, modeled bends in the collagen helix due to breaks in the Gly-X-Y pattern and the location of cysteine and putative 3,4-dihydroxyphenylalanine (DOPA) residues. A potentially important difference between the two is that, in all cases, M. galloprovincialis byssal collagens contain additional histidine residues in their flanking domains. The significance of this may lie in the ability of M. galloprovincialis to utilize more metal chelate cross-links, which have been implicated in byssal thread stability. M. edulis threads are typically twice the length and diameter of M. galloprovincialis threads and appear to contain nearly 10 % more collagen. These differences are maintained even when the different thread portions are compared. Despite differences in a number of parameters, most notably that whole M. galloprovincialis threads are stiffer, threads whether whole or separated into proximal and distal portions, have similar mechanical behaviors. It is apparent from this comparison that M. galloprovincialis and M. edulis are seemingly interchangeable models for byssal research.


Mechanisms of eosinophil secretion: large vesiculotubular carriers mediate transport and release of granule-derived cytokines and other proteins.
Eosinophils generate and store a battery of proteins, including classical cationic proteins, cytokines, chemokines, and growth factors. Rapid secretion of these active mediators by eosinophils is central to a range of inflammatory and immunoregulatory responses. Eosinophil products are packaged within a dominant population of cytoplasmic specific granules and generally secreted by piecemeal degranulation, a process mediated by transport vesicles. Large, pleiomorphic vesiculotubular carriers were identified recently as key players for moving eosinophil proteins from granules to the plasma membrane for extracellular release. During secretion, these specialized, morphologically distinct carriers, termed eosinophil sombrero vesicles, are actively formed and direct differential and rapid release of eosinophil proteins. This review highlights recent discoveries concerning the organization of the human eosinophil secretory pathway. These discoveries are defining a broader role for large vesiculotubular carriers in the intracellular trafficking and secretion of proteins, including selective receptor-mediated mobilization and transport of cytokines.


Attention-deficit/hyperactivity disorder and occupational outcomes: The role of educational attainment, comorbid developmental disorders, and intellectual disability.
Individuals with ADHD are at increased risk for poor occupational outcomes. Educational attainment and psychiatric comorbidity may be important contributing factors for these outcomes, but the role of these factors is not well characterized. This study aimed to investigate the associations between ADHD and occupational outcomes, and to examine the influence of educational attainment, comorbid developmental disorders and intellectual disability on these associations. We linked the Swedish population graduating from compulsory school 1998-2008 (N = 1.2 millions) to population-wide register-based data on clinical psychiatric diagnoses and medications, objective annual measures of educational, and occupational outcomes. Individuals were followed for between 6 to 16 years after graduation. Individuals with ADHD had annually on average 17 percent lower income, ratio = 0.83 (95% CI 0.83-0.84), 12.19 (11.89-12.49) more days of unemployment, and a higher likelihood of receiving disability pension, odds-ratio = 19.0 (18.4-19.6), compared to controls. Comorbid diagnoses of intellectual disability and developmental disorder explained most of the association between ADHD and disability pension, while lifetime educational attainment partially explained associations between ADHD and all occupational outcomes. Analyses of occupational trajectories found that income was lower and unemployment elevated relative to controls with the same educational attainment. Higher educational attainment correlated with higher income similarly among individuals with ADHD and controls after accounting for individual background factors. The occupational burden associated with ADHD is substantial. Comorbid developmental disorders, intellectual disability and educational difficulties (e.g., failing grades) from childhood to adulthood are important factors to consider when designing interventions to improve occupational outcomes in individuals with ADHD.


Cost-effective removal of COD in the pre-treatment of wastewater from the paper industry.
The present paper reveals results of research for cost-effective removal of chemical oxygen demand (COD) contained in industrial paper mill effluent. Not only process efficiency but also wastewater treatment costs are discussed. Different pre-treatment processes are applied aiming to investigate the COD removal before discharge to the municipal sewage network. The objective of this paper is to find the optimal operating conditions for the coagulation process. The effects of key operational parameters, including the type of coagulant, initial pH, temperature and coagulant dose, on COD percentage removal were investigated. The laboratory experiments confirmed the high efficiency of chemically enhanced mechanical treatment towards COD. The data obtained show that even low dose of chemicals provides sufficient COD reduction. The initial pH of the wastewater had a significant impact on the COD removal. Under the optimal operational conditions (pH = 7.5, T = 18 °C) the treatment of wastewater from paper industries by coagulation has led to a reduction of 70% COD for wastewater discharged. In terms of the investigated paper industry wastewater, polyaluminium chloride appears to be most suitable for treatment of high COD concentration. However, in an economic evaluation of requirements for wastewater treatment, operating costs and associated saving were such that PAX was more favourable.


Strong HIV-1-specific T cell responses in HIV-1-exposed uninfected infants and neonates revealed after regulatory T cell removal.
In utero transmission of HIV-1 occurs on average in only 3%-15% of HIV-1-exposed neonates born to mothers not on antiretroviral drug therapy. Thus, despite potential exposure, the majority of infants remain uninfected. Weak HIV-1-specific T-cell responses have been detected in children exposed to HIV-1, and potentially contribute to protection against infection. We, and others, have recently shown that the removal of CD4(+) CD25(+) T-regulatory (Treg) cells can reveal strong HIV-1 specific T-cell responses in some HIV-1 infected adults. Here, we hypothesized that Treg cells could suppress HIV-1-specific immune responses in young children. We studied two cohorts of children. The first group included HIV-1-exposed-uninfected (EU) as well as unexposed (UNEX) neonates. The second group comprised HIV-1-infected and HIV-1-EU children. We quantified the frequency of Treg cells, T-cell activation, and cell-mediated immune responses. We detected high levels of CD4(+) CD25(+) CD127(-) Treg cells and low levels of CD4(+) and CD8(+) T cell activation in the cord blood of the EU neonates. We observed HIV-1-specific T cell immune responses in all of the children exposed to the virus. These T-cell responses were not seen in the cord blood of control HIV-1 unexposed neonates. Moreover, the depletion of CD4(+) CD25(+) Treg cells from the cord blood of EU newborns strikingly augmented both CD4(+) and CD8(+) HIV-1-specific immune responses. This study provides new evidence that EU infants can mount strong HIV-1-specific T cell responses, and that in utero CD4(+) CD25(+) T-regulatory cells may be contributing to the lack of vertical transmission by reducing T cell activation.


YAC-assisted cloning of transcribed sequences from the human chromosome 3p21 region.
The region surrounding the ZNF35 zinc finger protein gene on 3p21 is of particular interest, as this region of chromosome 3 is frequently involved in rearrangements and/or deletions associated with various human tumors including lung and renal carcinoma. We have analyzed yeast artificial chromosomes (YACs), identified by PCR screening, using oligonucleotides derived from the ZNF35 gene. PFGE and Southern blot/hybridization analysis revealed that the clones cover 750-kb including the ZNF35 gene. The use of specific somatic cell hybrids have allowed us to locate the YAC contig telomeric to the D3F15S2 locus, in a region which is frequently deleted in lung carcinomas. In addition, we have developed a novel cDNA hybridization protocol allowing the isolation of transcribed sequences present in the overlapping YAC clones. Using the cDNA hybridization selection, we have isolated and characterized one transcribed sequence (D3S1362E) from the 3p21 YAC contig and the corresponding cDNA has been isolated. DNA sequencing analysis indicated that the D3S1363E cDNA codes for a putative transcription factor. Northern blot analysis indicated that the D3S1362E sequence hybridized to multiple transcripts in skeletal muscle, and weakly hybridizing transcripts of similar sizes were detected in other tissues.


Natural Microbial Reactor-Based Sensing Platform for Highly Sensitive Detection of Inorganic Arsenic in Rice Grains.
Rice is a major dietary source of inorganic arsenic (iAs), a highly toxic arsenical that accumulates in rice and poses health risks to rice-based populations. However, the availability of detection methods for iAs in rice grains is limited. In this study, we developed a novel approach utilizing a natural bacterial biosensor, Escherichia coli AW3110 (pBB-ArarsR-mCherry), in conjunction with amylase hydrolysis for efficient extraction, enabling high-throughput and quantitative detection of iAs in rice grains. The biosensor exhibits high specificity for arsenic and distinguishes between arsenite [As(III)] and arsenate [As(V)] by modulating the concentration of PO43- in the detection system. We determined the iAs concentrations in 19 rice grain samples with varying total As concentrations and compared our method with the standard technique of microwave digestion coupled with HPLC-ICP-MS. Both methods exhibited comparable results, without no significant bias in the concentrations of As(III) and As(V). The whole-cell biosensor demonstrated excellent reproducibility and a high signal-to-noise ratio, achieving a limit of detection of 16 μg kg-1 [As(III)] and 29 μg kg-1 [As(V)]. These values are considerably lower than the maximum allowable level (100 μg kg-1) for infant rice supplements established by the European Union. Our straightforward sensing strategy presents a promising tool for detecting iAs in other food samples.


The predictive value of ultrasound findings in the management of thyroid nodules.
Thyroid nodules are a common medical problem, but whether fine-needle aspiration cytology (FNAC) is mandated for smaller non-palpable nodules, is controversial. To evaluate whether ultrasonographic features of thyroid nodules are associated with histological malignancy, and to identify useful criteria for clinical decision-making. Prospective observational study. From January 1991 to September 2004, 5198 patients were referred to our hospital for ultrasound evaluation of thyroid nodules. Overall, 7455 nodules (diameters from 6 to 100 mm) were examined; 2865 (38.4%) were <10 mm in diameter. All patients with suspicious or malignant cytology underwent surgery. Of the 349 nodules undergoing surgery, 284 were malignant. The prevalence of cancer was slightly higher in nodules>or=10 mm in diameter vs. those<10 mm (5.5% vs. 3.0%, p<0.01). However, histological type and local aggressiveness were largely independent of nodule size. Microcalcifications (72.2% vs. 28.7%; p<0.001; OR 6.4, 95%CI 4.9-8.4), blurred margins (52.8% vs. 18.8%; p<0.001; OR 4.8, 95%CI 3.8-6.1), solid hypoechoic appearance (80.6% vs. 52.4%; p<0.001; OR 3.8, 95%CI 2.8-5.1), size>or=10 mm (77.4% vs. 64.9%; p<0.001; OR 1.9, 95%CI 1.4-2.5) and intranodular vascular pattern type 2 (61.6% vs. 49.7%; p<0.001; OR 1.6, 95%CI 1.2-2.0) were all significantly more frequent in malignant than in benign nodules. These associations were similar when large and small nodules were analysed separately. No single parameter, including nodule size, satisfactorily identifies a subset of patients to be electively investigated by FNAC, although several may be useful in this regard.


Orbital metastases of prostatic carcinoma in a tropical African population.
We have reviewed the cases of orbital metastases from carcinoma of the prostate gland seen in the University College Hospital, Ibadan over an 11 year period, 1990-2000. During the period, seven cases of orbital metastases that presumably arose from carcinoma of the prostate were seen. Four of the patients died of progression of the primary disease over a variable period ranging between 2 weeks and 30 months of diagnosis and treatment, two were lost to follow up and one is alive 46 months after initial diagnosis of orbital metastases from carcinoma of the prostate and treatment.


How to interpret a meta-analysis?
There is an enormous and ever-growing quantity of healthcare information available and practitioners must transform it into knowledge to be able to use it in their clinical practice. Even readers who do not conduct scientific studies themselves need to understand the scientific method in detail to be able to critically evaluate scientific articles. Evidence-based healthcare (EBH) can be defined as the link between good scientific research and clinical practice and systematic reviews constitute one of the forms of research excellence proposed within EBH. Systematic reviews employ rigorous methods that reduce the occurrence of bias. Systematic reviews with meta-analyses generally optimize the results found, because quantitative analysis of the studies included in the review yields additional information. In this paper, we will discuss how to interpret a meta-analysis and how to apply subset and sensitivity analysis strategies and we will also describe possible sources of heterogeneity and common errors that can affect a meta-analysis.


Accuracy of vessel-encoded pseudocontinuous arterial spin-labeling in identification of feeding arteries in patients with intracranial arteriovenous malformations.
Identifying feeding arteries of intracranial AVMs is very important for preoperative evaluation. DSA remains the reference standard for diagnosis but is invasive. Our aim was to evaluate the diagnostic accuracy of vessel-encoded pseudocontinuous arterial spin-labeling in identifying feeding arteries of intracranial AVMs by using DSA as the criterion standard. Eighteen patients with AVMs were examined with vessel-encoded pseudocontinuous arterial spin-labeling and DSA. Three postlabeling delays (postlabeling delay = 1, 1.3, and 1.6 seconds) were applied in 6 patients, and a single postlabeling delay (1 second) was applied in the remainder. Perfusion-weighted images were decoded into individual vascular territories with standard and relative tagging efficiencies, respectively. The supply fraction of each feeding artery to the AVM was calculated. The within-subject ANOVA was applied to compare supply fractions acquired across 3 postlabeling delays. Receiver operating characteristic analysis curves were calculated to evaluate the diagnostic accuracy of vessel-encoded pseudocontinuous arterial spin-labeling for identifying the feeding arteries of AVMs. There were no significant differences in supply fractions of the 3 major arteries to AVMs acquired with 3 postlabeling delays (P > .05). For vessel-encoded pseudocontinuous arterial spin-labeling with standard labeling efficiencies, the area under the receiver operating characteristic analysis curve was 0.942. The optimal cutoff of the supply fraction for identifying feeding arteries was 15.17%, and the resulting sensitivity and specificity were 84.62% and 93.33%, respectively. For vessel-encoded pseudocontinuous arterial spin-labeling with relative labeling efficiencies, the area under the receiver operating characteristic analysis curve was 0.957. The optimal cutoff of the supply fraction was 11.73%, which yielded an 89.74% sensitivity and 93.33% specificity. The contribution fraction of each feeding artery of the AVM can be reliably estimated by using vessel-encoded pseudocontinuous arterial spin-labeling. Vessel-encoded pseudocontinuous arterial spin-labeling with either standard or relative labeling efficiencies offers a high level of diagnostic accuracy compared with DSA for identifying feeding arteries.


Inhibition of miR-92a Suppresses Oxidative Stress and Improves Endothelial Function by Upregulating Heme Oxygenase-1 in db/db Mice.
Inhibition of microRNA-92a (miR-92a) is reported to suppress endothelial inflammation and delay atherogenesis. We hypothesize that miR-92a inhibition protects endothelial function through suppressing oxidative stress in diabetic db/db mice. In this study, we found elevated expression of miR-92a in aortic endothelium from db/db mice and in renal arteries from diabetic subjects. Endothelial cells (ECs) exposed to advanced glycation end products (AGEs) and oxidized low-density lipoprotein express higher level of miR-92a. Overexpression of miR-92a impairs endothelium-dependent relaxations (EDRs) in C57BL/6 mouse aortas. Overexpression of miR-92a suppresses expression of heme oxygenase-1 (HO-1), a critical cytoprotective enzyme, whereas inhibition of miR-92a increases HO-1 expression in human umbilical vein ECs (HUVECs) and db/db mouse aortas. Importantly, miR-92a inhibition by Ad-anti-miR-92a improved EDRs and reduced reactive oxygen species (ROS) production in db/db mouse aortas. HO-1 inhibition by SnMP or HO-1 knockdown by shHO-1 reversed the suppressive effect of miR-92a inhibition on ROS production induced by AGE treatment in C57BL/6 mouse aortas. In addition, SnMP reversed miR-92a inhibition-induced improvement of EDRs in AGE-treated C57BL/6 mouse aortas and in db/db mouse aortas. Expression of miR-92a is increased in diabetic aortic endothelium and inhibition of miR-92a exerts vasoprotective effect in diabetic mice through HO-1 upregulation in ECs. MiR-92a expression is elevated in diabetic ECs. MiR-92a overexpression impairs endothelial function and suppresses HO-1 expression in ECs. Inhibition of miR-92a attenuates oxidative stress and improves endothelial function through enhancing HO-1 expression and activity in db/db mouse aortas. Antioxid. Redox Signal. 28, 358-370.


Adjusting relative survival estimates for cancer mortality in the general population.
In theory, expected survival probabilities used in the derivation of relative survival ratios (RSR) are determined from a control group free of the cancer under study. In practice, expected survival is typically estimated from general population life tables--which include people previously diagnosed with cancer--potentially leading to an overestimation of relative survival. Data are from the Canadian Cancer Registry with mortality follow-up through record linkage to the Canadian Vital Statistics Death Database. Period method RSRs for 2006-to-2008 were derived using general population life tables adjusted for cancer mortality and then compared with estimates derived using corresponding unadjusted life tables. For all cancers combined, the use of general population life tables to derive expected survival probabilities overestimated RSRs by 0.6 (1-year), 2.4 (5-year) and 4.6 (10-year) percentage units. Biases in 5-year survival were highest among males (3.0) and among people aged 75 to 99 at diagnosis (4.1). The bias was negligible for most individual cancers; biases were highest for prostate cancer, followed by colorectal and female breast cancer. Canadian estimates of relative survival for all cancers combined calculated using general life tables warrant adjustment for cancer mortality. Consideration of adjustment for cancer mortality is recommended for estimates of colorectal, female breast and especially prostate cancer.


Position-coded multivalent peptide-peptide interactions revealed by tryptophan-scanning mutagenesis.
We demonstrate in this contribution the evidence that significant cooperative binding effect can be identified for the amino acid sites that are determinant to the binding characteristics in peptide-peptide interactions. The analysis of tryptophan-scanning mutagenesis of the 14-mer peptide consisting only of glycine provides a mapping of position-dependent contributions to the binding energy. The pronounced tryptophan-associated peptide-peptide interactions are originated from the indole moieties with the main chains of 14-mer glycines containing N-H and CO moieties. Specifically, with the presence of two tryptophans as determinant amino acids, cooperative binding can be observed, which are dependent on relative positions of the two tryptophans with a "volcano"-like characteristics. An optimal separation of 6-10 amino acids between two adjacent binding sites can be identified to achieve maximal binding interactions.


Incorporating Environmental Justice into Second Generation Indices of Multiple Deprivation: Lessons from the UK and Progress Internationally.
Second generation area-based indices of multiple deprivation have been extensively used in the UK over the last 15 years. They resulted from significant developments in political, technical, and conceptual spheres for deprivation data. We review the parallel development of environmental justice research and how and when environmental data was incorporated into these indices. We explain the transfer of these methods from the UK to Germany and assess the progress internationally in developing such indices. Finally, we illustrate how billions of pounds in the UK was allocated by using these tools to tackle neighbourhood deprivation and environmental justice to address the determinants of health.


One-year Angiographic Results After pCONus Stent-Assisted Coiling of 40 Wide-Neck Middle Cerebral Artery Aneurysms.
Bifurcation middle cerebral artery (MCA) aneurysms with wide neck are amenable to endovascular coiling with pCONus stent, a recent device dedicated to wide-neck bifurcation intracranial aneurysms. To evaluate the 1-year angiographic follow-up of wide-neck MCA aneurysms treated with pCONus. Forty MCA aneurysms (mean dome size, 7.7 mm; mean neck size, 5.6 mm) coiled with pCONus were retrospectively evaluated. "Recanalization" was defined as worsening, and "progressive thrombosis" was defined as improvement on the Raymond scale. Angiographic midterm (mean, 11.9 months; range, 3-20) follow-up was obtained in all aneurysms. Retreatment was performed in 9 aneurysms (22.5%) without clinical complications, and postoperative angiographic outcome included 2 complete occlusions and 7 neck remnants. Six aneurysms were followed after retreatment (mean, 8.8 months), and presented complete occlusion in 1 case, neck remnant in 4 cases, and aneurysm remnant in 1 case. Among the 31 aneurysms, follow-up showed complete occlusion in 67.7% (21/31), neck remnants in 29% (9/31), and aneurysm remnants in 3.3% (1/31). Adequate aneurysm occlusion (total occlusion and neck remnant) was obtained in 96.7% (30/31). Among these 31 aneurysms, improvement of the rate of occlusion was observed in 15 aneurysms (48.4%), and recurrence in 2 aneurysms (6.5%). There was no 1-year angiographic recurrence of 3- or 6-month totally occluded aneurysms. pCONus stent allows a safe coiling of wide-neck MCA aneurysms usually considered as surgical with a low recanalization rate for those adequately occluded at 3 to 6 months. Angiographic results improve over time due to progressive aneurysm thrombosis in around 50% of cases.


A LINC00341-mediated regulatory pathway supports chondrocyte survival and may prevent osteoarthritis progression.
Osteoarthritis (OA) is the most common degenerative joint disease and results from progressive loss and destruction of articular cartilage and the underlying bone. The disease affects millions of people worldwide with an associated risk of mobility disability. However, the molecular basis underlying OA initiation and progression is not well understood and, currently, there is no effective intervention available to decelerate disease progression or restore degraded cartilage. We have found that lncRNA long intergenic nonprotein coding RNA 341 (LINC00341) is aberrantly downregulated in OA patient tissues and cultured OA chondrocytes. This is likely responsible for the increased apoptosis of chondrocytes and pathological destruction of cartilage. Further investigation has revealed that LINC00341 interacts with miR-141 to suppress its functional binding to the 3'-untranslated region of YY1-associated factor 2 (YAF2) messenger RNA. Aberrant downregulation of LINC00341 thus may ultimately lead to inhibition of the YAF2 protein, which has been implicated to be an antiapoptotic factor. Our study has revealed a new noncoding RNA-mediated regulatory network that highly likely protects chondrocytes by preventing apoptosis under normal conditions. The results will help further explore the molecular details pertaining to the progression of OA and stimulate efforts to develop effective therapies.


Familial mitral valve prolapse and myotonic dystrophy.
When a patient with mitral valve prolapse was found to have myotonic dystrophy, his family was studied to ascertain the occurrence of these abnormalities. Of 25 relatives screened, 8 had evidence of both myotonic dystrophy and mitral valve prolapse and 2 had evidence of myotonic dystrophy alone. Thirteen patients had evidence of neither condition and 1 had mitral valve prolapse alone. The association of these two conditions within a family has not previously been observed and valvular heart disease has not been recognized in myotonic dystrophy. This association should be looked for in other patients.


Iron species determination by task-specific ionic liquid-based in situ solvent formation dispersive liquid-liquid microextraction combined with flame atomic absorption spectrometry.
The task-specific ionic liquid (TSIL) of 1-ethyl-3-methylimidazolium bromide functionalized with 8-hydroxyquinoline was used as a chelating agent and extracting solvent for dispersive liquid-liquid microextraction and subsequent determination of Fe(III) by flame atomic absorption spectrometry. The in situ solvent formation of TSIL using KPF6 provided the desired water-immiscible ionic liquid. The total Fe concentration could be determined after pre-oxidation of Fe(II) to Fe(III). Various factors affecting the proposed extraction procedure were optimized. The proposed analytical conditions were: sample pH 5, TSIL amount 0.3% (w/v), KPF6 amount 0.15% (w/v), anti-sticking 0.1% (w/v) and salt concentration 5% (w/v). Under optimal conditions, the linear dynamic ranges for Fe(III) and total Fe were 20-80 and 20-110 ng mL-1 , respectively, with a detection limit of 6.9 ng mL-1 for Fe(III) and relative standard deviation of 2.2%. The proposed method was successfully applied to the determination of trace Fe(III) in water (underground, tap, refined water and artificial sea water) and beverage (apple, tomato, and tea) samples. The developed method offers advantages such as simplicity, ease of operation, and extraction of Fe(III) from aqueous solutions without the use of organic solvent. It was successfully applied for iron speciation in different real samples. © 2017 Society of Chemical Industry.


The ornithine decarboxylase gene is a transcriptional target of c-Myc.
Constitutive c-myc expression suppresses cell cycle arrest, promotes entry into S phase, and results in the growth factor-independent expression of ornithine decarboxylase (ODC; EC 126.96.36.199). The ODC gene contains a conserved repeat of the Myc binding site, CACGTG, in intron 1. In this report, we demonstrate that c-Myc is a potent transactivator of ODC promoter-reporter gene constructs in fibroblasts that requires the CACGTG repeat. These sites conferred Myc responsiveness on heterologous promoter constructs, suggesting that ODC is regulated by Myc at the level of transcription initiation. Analysis of deletion and point mutants of c-myc revealed that domains required for transactivation of the ODC promoter did not include the leucine zipper of the Myc protein. This suggests that Myc may interact with transcription factors other than Max to transactivate the ODC gene.


Normal Theory GLS Estimator for Missing Data: An Application to Item-Level Missing Data and a Comparison to Two-Stage ML.
Structural equation models (SEMs) can be estimated using a variety of methods. For complete normally distributed data, two asymptotically efficient estimation methods exist: maximum likelihood (ML) and generalized least squares (GLS). With incomplete normally distributed data, an extension of ML called "full information" ML (FIML), is often the estimation method of choice. An extension of GLS to incomplete normally distributed data has never been developed or studied. In this article we define the "full information" GLS estimator for incomplete normally distributed data (FIGLS). We also identify and study an important application of the new GLS approach. In many modeling contexts, the variables in the SEM are linear composites (e.g., sums or averages) of the raw items. For instance, SEMs often use parcels (sums of raw items) as indicators of latent factors. If data are missing at the item level, but the model is at the composite level, FIML is not possible. In this situation, FIGLS may be the only asymptotically efficient estimator available. Results of a simulation study comparing the new FIGLS estimator to the best available analytic alternative, two-stage ML, with item-level missing data are presented.


An evaluation of the knowledge and perceptions of pharmacy students on pharmacovigilance activities in Nigeria.
The use of the modified-prescription event monitoring technique has facilitated the understanding and reporting of pharmacovigilance (PV). However, in Nigeria, PV activities are largely misunderstood. Furthermore, there is a dearth of information on the knowledge and perceptions of pharmacy students on PV activities in relation to demographics. This study investigated and assessed the knowledge and perceptions of pharmacy students about pharmacovigilance as well as the demographic factors that are related to pharmacovigilance activities. A cross-sectional survey was conducted among final year pharmacy students in three universities in months of January and February, 2016 with permission from the institutions and with written consents from 342 respondents. Pre-tested questionnaire was used to elicit information on the study objectives. Data were analysed using appropriate descriptive and inferential statistical techniques. The study revealed that the mean score on knowledge of pharmacy students on pharmacovigilance activities was 4.3 ± 0.18 which was significant according to gender (P < 0.001), students' university (P < 0.001), and previous exposure to PV subjects (P < 0.001). Sixty-four percent of the students had positive perceptions about PV activities which was significant at P < 0.00 according to gender and their various universities. Less than half of the respondents 165 (48.2%) were able to correctly name the organisation that collates and document ADR reports in Nigeria. Only 21 (6.1%) of the respondents gave the correct answer to whether or not all possible ADRs of a drug can be determined during clinical trials or during pre-marketing phase of drug assessment. About 204 (59.7%) of the respondents erroneously believed that adverse reactions caused by cosmetics should not be reported. Respondents have inadequate knowledge of PV activities. Therefore, pharmacy student educators should enhance students' knowledge about PV through training, during clerkship, and lay more emphasis on relevant PV courses in the Pharmacy Curriculum.


Delayed-Type Hypersensitivity Reaction to Red Tattoo Ink Triggered by Ledipasvir/Sofosbuvir for Hepatitis C: A Case Report.
Tattoos have become increasingly popular worldwide making adverse effects from tattoos a growing concern. In our report, we present a 51-year-old man who developed an unusual allergic reaction to the red ink portions of his tattoos that coincided with the initiation of ledipasvir/sofosbuvir treatment for his hepatitis C. Clinical and histological features were consistent with a delayed-type hypersensitivity reaction to red ink.


[Surgical timing in bleeding liver adenoma: case report].
The diagnosis of liver adenoma, which etiopathogenesis most often involves a prolonged assumption of estrogen (90% of adenomas occurs in women after more than 5 years of estrogen therapy), always imposes a surgical resection. The reason depend from neoplasia characteristics like the malignant evolution (4%) and the high risk of abdominal/intratumoral bleeding (30-50%), that increases during pregnancy and postpartum period. Regression of lesion after discontinuation of hormone therapy is rare and does not remove the degeneration and/or haemorrhagic risk. Liver resection should be performed with appropriate selective endovascular embolization, considering that an inept emergency surgery may impose a greater risk ot the liver, exposing the patient to major risk of morbidity and mortality. The correct timing from embolization to elective surgery is not yet standardized in the literature. The surgeon's personal experience and mainly a careful patient follow-up suggest the timing of surgery after embolization. The authors relate their own experience about the therapeutic strategy and surgical timing in a case of bleeding liver adenoma.


Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.
Expanded GGGGCC (G4C2) nucleotide repeats within the C9ORF72 gene are the most common genetic mutation associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sense and antisense transcripts of these expansions are translated to form five dipeptide repeat proteins (DRPs). We employed primary cortical and motor neuron cultures, live-cell imaging, and transgenic fly models and found that the arginine-rich dipeptides, in particular Proline-Arginine (PR), are potently neurotoxic. Factors that anticipated their neurotoxicity included aggregation in nucleoli, decreased number of processing bodies, and stress granule formation, implying global translational dysregulation as path accountable for toxicity. Nuclear PR aggregates were also found in human induced motor neurons and postmortem spinal cord tissues from C9ORF72 ALS and ALS/FTD patients. Intronic G4C2 transcripts, but not loss of C9ORF72 protein, are also toxic to motor and cortical neurons. Interestingly, G4C2 transcript-mediated neurotoxicity synergizes with that of PR aggregates, suggesting convergence of mechanisms.


[Combination treatment of depression].
Severe depression is a common diagnosis and a number of studies have demonstrated the superiority of antidepressants to placebos. More than half of the patients remain depressed despite initial treatment. If reasons like incorrect diagnosis and non-optimal choice of drug or doses are excluded, combination therapy may be considered. Augmentation of antidepressants with lithium or the thyroid hormone T3 has documented effectiveness, mainly with tricyclic antidepressants, but is not frequently used. Less documentation exists for a combination of two antidepressant drugs, but their use is relatively common.


Dynamic Equilibrium of the Aurora A Kinase Activation Loop Revealed by Single-Molecule Spectroscopy.
The conformation of the activation loop (T-loop) of protein kinases underlies enzymatic activity and influences the binding of small-molecule inhibitors. By using single-molecule fluorescence spectroscopy, we have determined that phosphorylated Aurora A kinase is in dynamic equilibrium between a DFG-in-like active T-loop conformation and a DFG-out-like inactive conformation, and have measured the rate constants of interconversion. Addition of the Aurora A activating protein TPX2 shifts the equilibrium towards an active T-loop conformation whereas addition of the inhibitors MLN8054 and CD532 favors an inactive T-loop. We show that Aurora A binds TPX2 and MLN8054 simultaneously and provide a new model for kinase conformational behavior. Our approach will enable conformation-specific effects to be integrated into inhibitor discovery across the kinome, and we outline some immediate consequences for structure-based drug discovery.


Activation of carbon-hydrogen bonds via 1,2-addition across M-X (X = OH or NH(2)) bonds of d(6) transition metals as a potential key step in hydrocarbon functionalization: a computational study.
Recent reports of 1,2-addition of C-H bonds across Ru-X (X = amido, hydroxo) bonds of TpRu(PMe3)X fragments {Tp = hydridotris(pyrazolyl)borate} suggest opportunities for the development of new catalytic cycles for hydrocarbon functionalization. In order to enhance understanding of these transformations, computational examinations of the efficacy of model d6 transition metal complexes of the form [(Tab)M(PH3)2X]q (Tab = tris-azo-borate; X = OH, NH2; q = -1 to +2; M = TcI, Re(I), Ru(II), Co(III), Ir(III), Ni(IV), Pt(IV)) for the activation of benzene C-H bonds, as well as the potential for their incorporation into catalytic functionalization cycles, are presented. For the benzene C-H activation reaction steps, kite-shaped transition states were located and found to have relatively little metal-hydrogen interaction. The C-H activation process is best described as a metal-mediated proton transfer in which the metal center and ligand X function as an activating electrophile and intramolecular base, respectively. While the metal plays a primary role in controlling the kinetics and thermodynamics of the reaction coordinate for C-H activation/functionalization, the ligand X also influences the energetics. On the basis of three thermodynamic criteria characterizing salient energetic aspects of the proposed catalytic cycle and the detailed computational studies reported herein, late transition metal complexes (e.g., Pt, Co, etc.) in the d6 electron configuration {especially the TabCo(PH3)2(OH)+ complex and related Co(III) systems} are predicted to be the most promising for further catalyst investigation.


[The CD45-positive thrombocytes and neutrophils/lymphocytes level ratio in evaluation of risk of development of re-stenosis шт patients with chronic ischemic heart disease and diabetes mellitus type II.]
The purpose of study is to investigate significance of detection of number of CD45-positive thrombocytes and ratio neutrophils/lymphocytes in evaluation of risk of development of re-stenosis after implantation of drug-eluting stents in patients with chronic ischemic heart disease and diabetes mellitus type II. The examination was applied to 126 patients with chronic forms of ischemic heart disease who passed through repeat coronary angiography during first year after implantation of drug-eluting stents. The patients were separated on two groups depending on availability of diabetes mellitus type II. In both groups, the patients passed through comparing of angiography and clinical characteristics. Also, a logistic model was developed prognosticating development of re-stenosis. The re-stenosis developed more often in patients with diabetes mellitus type II (54.5%) than in patients without diabetes mellitus type II (32.4%; p=0.01). The comparative analysis of more than 35 characteristics permitted to establish risk factors of development of re-stenosis with the highest prognosticating capacity among patients with diabetes mellitus type II. These risk factors were CD45-positive thrombocytes and ratio neutrophils/lymphocytes. To prognosticate development of re-stenosis a logistic regression model was developed comprising number of circulating CD45-positive thrombocytes, ratio neutrophils/lymphocytes and availability of diabetes mellitus type II. The model demonstrated high prognosticating value as regards development of re-stenosis: OR = 15.1 (95% CI 4.81-31, p < 0.001). The square under ROC-curve: AUC = 0.83 (95% CI 0,72-0,92; р < 0,001). The increasing of number of circulating CD45-positive thrombocytes and ratio neutrophils/lymphocytes can be considered as a valuable risk factors of development of re-stenosis in case of diabetes mellitus type II.


Correlates of aggression in African American and Puerto Rican children.
The authors examined a cross-sectional interrelationship of psychosocial domains as they relate to aggression in a group of African American and English-speaking Puerto Rican children living in New York City. The population included 80 biological children of African American and Puerto Rican young adults who had been participating in the authors' ongoing longitudinal study, and 77 mothers or mother substitutes (rearing mothers) of those children. The authors performed hierarchical multiple regression analysis. The results indicated that (a) the child's personality and maternal attributes were significantly related to the child's aggression, despite control on all of the other domains and (b) the ethnic identification and discrimination domain was no longer related to the child's aggression with control on the mother-child relationship domain or on the child's personality domain. The findings have implications for clinical practice and public policy.


Volumetric absorptive microsampling as an alternative tool for therapeutic drug monitoring of first-generation anti-epileptic drugs.
Dosage adjustment of anti-epileptic drugs by therapeutic drug monitoring (TDM) is very useful, especially for the first-generation anti-epileptic drugs (AEDs). Microsampling-the collection of small volumes of blood-is increasingly considered a valuable alternative to conventional venous sampling for TDM. Volumetric absorptive microsampling (VAMS) allows accurate and precise collection of a fixed volume of blood, eliminating the volumetric blood hematocrit bias coupled to conventional dried blood spot collection. The aim of this study was to develop and validate an LC-MS/MS method for the determination and quantification of four anti-epileptic drugs (carbamazepine, valproic acid, phenobarbital, and phenytoin) and one active metabolite (carbamazepine-10,11-epoxide) in samples collected by VAMS. The method was fully validated based on international guidelines. Precision (%RSD) was below 10%, while, with a single exception, accuracy (%bias) met the acceptance criteria. Neither carry-over nor unacceptable interferences were observed, the method being able to distinguish between the isomers oxcarbazepine and carbamazepine-10,11-epoxide. All compounds were stable in VAMS samples for at least 1 month when stored at room temperature, 4 °C, and - 20 °C and for at least 1 week when stored at 60 °C. Internal standard-corrected matrix effects were below 10%, with %RSDs below 4%. High (> 85%) recovery values were obtained and the effect of the hematocrit on the recovery was overall limited. Successful application on external quality control materials and on left-over patient samples demonstrated the validity and applicability of the developed procedure. Graphical abstract Graphical representation of the sampling, chemical structures, and the resulting chromatogram for volumetric absorptive microsampling (VAMS)-based therapeutic drug monitoring of first-generation anti-epileptic drugs by liquid chromatography with tandem mass spectrometric detection.


Deep learning for computational chemistry.
The rise and fall of artificial neural networks is well documented in the scientific literature of both computer science and computational chemistry. Yet almost two decades later, we are now seeing a resurgence of interest in deep learning, a machine learning algorithm based on multilayer neural networks. Within the last few years, we have seen the transformative impact of deep learning in many domains, particularly in speech recognition and computer vision, to the extent that the majority of expert practitioners in those field are now regularly eschewing prior established models in favor of deep learning models. In this review, we provide an introductory overview into the theory of deep neural networks and their unique properties that distinguish them from traditional machine learning algorithms used in cheminformatics. By providing an overview of the variety of emerging applications of deep neural networks, we highlight its ubiquity and broad applicability to a wide range of challenges in the field, including quantitative structure activity relationship, virtual screening, protein structure prediction, quantum chemistry, materials design, and property prediction. In reviewing the performance of deep neural networks, we observed a consistent outperformance against non-neural networks state-of-the-art models across disparate research topics, and deep neural network-based models often exceeded the "glass ceiling" expectations of their respective tasks. Coupled with the maturity of GPU-accelerated computing for training deep neural networks and the exponential growth of chemical data on which to train these networks on, we anticipate that deep learning algorithms will be a valuable tool for computational chemistry. © 2017 Wiley Periodicals, Inc.


Characterization and preparation of oligomeric procyanidins from Litchi chinensis pericarp.
The main purpose of this study is to characterize and prepare A-type oligomeric procyanidins from litchi pericarp (Litchi chinensis Baila). The variety of oligomeric procyanidins was characterized by LC-ESI-MS analysis. There were (+)-catechin, (-)-epicatechin, twelve dimers and six trimers of procyanidins were found in litchi pericarp extracts, and A-type procyanidins were much more abundant than B-type procyanidins. The main flavan-3-ol monomer and oligomeric procyanidins in litchi pericarp were (-)-epicatechin, A-type dimers (A1 and A2) and trimer (epicatechin-(4β-8, 2β-O-7)-epicatechin- (4β-8)-epicatechin). Procyanidin A1 (epicatechin-(4β-8, 2β-O-7)-catechin) was identified by NMR in litchi pericarp for the first time. (-)-Epicatechin and oligomeric procyanidins were prepared by the combination of AB-8 column chromatography and Toyopearl HW-40S column chromatography. The results showed that each fraction predominantly owned a single compound and gave a high yield with (-)-epicatechin, A-type dimers (A1 and A2) and trimer, suggesting a useful method to obtain pure (-)-epicatechin and A-type oligomeric procyanidins.


Recovering FICA tax paid on resident stipends: 2010 update.
Recently, the IRS announced that it would cease contesting timely filed refund claims for taxable quarters before April 1, 2005, although the details that apply to its processing of those claims were not available as this article went to press. The IRS will continue to contest refund claims filed for taxable quarters after March 31, 2005, so those claims will have to be litigated to a conclusion. Financial officials at teaching hospitals should consult with advisers who are knowledgeable about the litigation against, and the settlement practices of, the Department of Justice.


Cellular stress response mechanisms as therapeutic targets of ginsenosides.
Ginseng, one of the most widely used traditional herbal medicines and dietary supplements, has historically been recognized as a tonic herb and adaptogen that can enhance the body's tolerance to various adversities. Ginsenosides are a diverse group of steroidal saponins that comprise the major secondary metabolites of ginseng and are responsible for its multiple pharmacological effects. Emerging evidence suggests that hormetic phytochemicals produced by environmentally stressed plants can activate the moderate cellular stress response mechanisms at a subtoxic level in humans, which may enhance tolerance against severe dysfunction or disease. In this review, we initially describe the role of ginsenosides in the chemical defense of plants from the genus Panax suffering from biotic and abiotic stress. Next, we summarize the diverse evolutionarily conserved cellular stress response pathways regulated by ginsenosides and the subsequent stress tolerance against various dysfunctions or diseases. Finally, the structure-activity relationship involved in the effect of ginsenosides is also analyzed. The evidence presented in this review implicates that ginseng as "the King of all herbs" could be regarded as a well-characterized example of the critical role of cellular stress response mechanisms in understanding the health benefits provided by herbal medicines from an evolutionary and ecological perspective.


Retrospective review of Surgical Availability and Readiness in 8 African countries.
The purpose of this study was to assess surgical availability and readiness in 8 African countries using the WHO's Service Availability and Readiness Assessment (SARA) tool. We analysed data for surgical services, including basic and comprehensive surgery, comprehensive obstetric care, blood transfusion, and infection prevention, obtained from the WHO's SARA surveys in Sierra Leone, Uganda, Mauritania, Benin, Zambia, Burkina Faso, Democratic Republic of Congo and Togo. Among the facilities that were expected to offer surgical services (N=3492), there were wide disparities between the countries in the number of facilities per 100 000 population that reported offering basic surgery (1.0-12.1), comprehensive surgery (0.1-0.8), comprehensive obstetric care (0.1-0.8) and blood transfusion (0.1-0.8). Only 0.1-0.3 facilities per 100 000 population had all three bellwether procedures available, namely laparotomy, open fracture management and caesarean section. In all the countries, the facilities that reported offering surgical services generally had a shortage of the necessary items for offering the services and this varied greatly between the countries, with the facilities having on average 27-53% of the items necessary for offering basic surgery, 56-83% for comprehensive surgery, 49-72% for comprehensive obstetric care and 54-80% for blood transfusion. Furthermore, few facilities had all the necessary items present. However, facilities that reported offering surgical services had on average most of the necessary items for the prevention of infection. There are important gaps in the surgical services in the 8 African countries surveyed. Efforts are therefore urgently needed to address deficiencies in the availability and readiness to deliver surgical services in these nations, and this will require commitment from multiple stakeholders. SARA may be used to monitor availability and readiness at regular intervals, which will enable stakeholders to evaluate progress and identify gaps and areas for improvement.


Possession, use, and transfer of select agents and toxins. Final rule.
This document completes the biennial review and republication of the lists of biological agents and toxins regulated by the U.S. Department of Health and Human Services (HHS), as well as those biological agents and toxins regulated by both HHS and the U.S. Department of Agriculture (USDA). Because USDA has chosen to no longer regulate ten biological agents and toxins which HHS still believes have the potential to pose a severe threat to public health and safety, we have moved those ten biological agents and toxins from the overlap select agents and toxins section to the HHS select agents and toxins section of the select agent regulations. In a companion document published in this issue of the Federal Register, the USDA has established corresponding final rules regarding the select agents and toxins regulated only by the USDA, as well as those overlap select agents and toxins regulated by both agencies.


Snap-through inversion of elastic shells swelling via solvent diffusion.
Snap-through buckling instability of elastic shells can provide a variety of biological and artificial mechanical systems with an efficient strategy to generate rapid and powerful actuation. However, snapping spherical shells studied to date have typically been shallow and thus are dominantly prone to axisymmetric inversions. Here, we study diffusion-swelling stimulated snap-through inversion of bilayer shells of a wide range of depth to cover non-axisymmetric as well as axisymmetric modes. We first establish an analytical model of strain energy stored in axisymmetrically swelling shells, in order to predict the snap-through conditions based on energy minimization. Confirming that the strain energy can indicate the critical conditions for snap-through, we compare the conditions of axisymmetric and non-axisymmetric snap-through inversion using both experiments and numerical simulations. We find that differentially swelling bilayer shells snap-through with a time-lagged but increased energy release during inversion when buckled non-axisymmetrically rather than axisymmetrically.


Special coverage: 9th Conference on Retroviruses. New drugs, new data hold promise for next decade of HIV treatment.
Antiretroviral research presented recently at the 9th Conference on Retroviruses and Opportunistic Infections demonstrates that investigators and pharmaceutical companies continue to strive for the next highly potent and easily tolerated anti-HIV drug. Among the new approaches are entry inhibitor drug and second-generation non-nucleoside reverse transcriptase inhibitors. New studies also looked into potency against multidrug-resistant virus and medication regimens that are simpler to take and have fewer side effects.


Application of Polysaccharide-Based Hydrogels as Probiotic Delivery Systems.
Polysaccharide hydrogels have been increasingly utilized in various fields. In this review, we focus on polysaccharide-based hydrogels used as probiotic delivery systems. Probiotics are microorganisms with a positive influence on our health that live in the intestines. Unfortunately, probiotic bacteria are sensitive to certain conditions, such as the acidity of the gastric juice. Polysaccharide hydrogels can provide a physical barrier between encapsulated probiotic cells and the harmful environment enhancing the cells survival rate. Additionally, hydrogels improve survivability of probiotic bacteria not only under gastrointestinal track conditions but also during storage at various temperatures or heat treatment. The hydrogels described in this review are based on selected polysaccharides: alginate, κ-carrageenan, xanthan, pectin and chitosan. Some hydrogels are obtained from the mixture of two polysaccharides or polysaccharide and non-polysaccharide compounds. The article discusses the efficiency of probiotic delivery systems made of single polysaccharide, as well as of systems comprising more than one component.


[Why Switzerland needs evidence-based guidelines for its general practice medicine].
Medical guidelines summarize evidence based knowledge and give helpful recommendations for diagnostics and therapy in daily practice. Most Swiss medical societies therefore adapt international guidelines for the Swiss setting. In primary care this adaption must not only take into account the specific Swiss healthcare system, but also the specific setting of primary care, which is characterized by a low prevalence of most diseases as well as by chronic conditions and multimorbidity. Exactly these multimorbid patients are underrepresented in the studies, which underline the current guidelines of medical societies. The institute of primary care at the university of Zurich, IHAMZ, therefore creates evidence based guidelines according to international established quality criteria for the Swiss primary care setting.


Immune activation and target organ damage are consequences of hydrodynamic treatment but not delivery of naked siRNAs in mice.
Short-interfering RNAs (siRNAs), key mediators of RNA interference comprise a promising therapeutic tool, although side effects such as interferon (IFN) response are still not perfectly understood. Further, delivery to target organs is a major challenge, possibly associated with side effects including immune activation or organ damage. We investigated whether immune activation as a consequence of double-stranded RNA induced IFN response (Jak/STAT pathway activation or cytokine production) or target organ damage is induced by in vivo low-volume (LV) or high-volume (HV) hydrodynamic delivery or treatment with naked siRNA. NMRI mice were injected with naked siRNAs or saline by hydrodynamic injection (HDI) and positive control mice received polyinosinic-polycytidilic acid (poly I:C). LV (1 mL/mouse) and HV (10% of body weight) HDI were compared. After LV HDI, STAT1 and OAS1 gene expression inflammatory cytokine plasma levels and target organ injury were assessed. LV HDI induced slight alanine aminotransferase elevation and mild hepatocyte injury, whereas HV HDI resulted in high ALAT level and extensive hepatocyte necrosis. STAT1 or OAS1 was not induced by LV siRNA; however, HV saline led to a time-dependent slight increase in gene expression. Inflammatory cytokine plasma level and organ histology and functional parameters demonstrated no damage following LV HDI with or without siRNA. Our data demonstrate that naked siRNAs may be harnessed, without the induction of IFN response or immune activation, and that LV HDI is preferable, because HV HDI may cause organ damage.


Bivalent ligation of the collagen-binding modules of fibronectin by SFS, a non-anchored bacterial protein of Streptococcus equi.
SFS is a non-anchored protein of Streptococcus equi subspecies equi that causes upper respiratory infection in horses. SFS has been shown to bind to fibronectin (FN) and block interaction of FN with type I collagen. We have characterized interactions of a recombinant 60-mer polypeptide, R1R2, with FN. R1R2 contains two copies of collagen-like 19-residue repeats. Experiments utilizing various FN fragments and epitope-mapped anti-FN monoclonal antibodies located the binding site to (8-9)FNI modules of the gelatin-binding domain. Fluorescence polarization and competitive enzyme-linked assays demonstrated that R1R2 binds preferentially to compact dimeric FN rather than monomeric constructs containing (8-9)FNI or a large dimeric FN construct that is constitutively in an extended conformation. In contrast to bacterial peptides that bind (2-5)FNI in addition to (8-9)FNI, R1R2 did not cause conformational extension of FN as assessed by a conformationally sensitive antibody. Equilibrium and stopped-flow binding assays and size exclusion chromatography were compatible with a two-step binding reaction in which each of the repeats of R1R2 interacts with one of the subunits of dimeric FN, resulting in a stable complex with a slow koff. In addition to not binding to type I collagen, the R1R2·FN complex incorporated less efficiently into extracellular matrix than free FN. Thus, R1R2 binds to FN utilizing features of compact soluble FN and in doing so interferes with the organization of the extracellular matrix. A similar bivalent binding strategy may underlie the collagen-FN interaction.


[Transient Femoral Nerve Palsy after Ilioinguinal-Iliohypogastric Nerve Block: Comparison of Ultrasound-guided and Landmark-based Techniques in Adult Inguinal Hernia Surgery].
Transient femoral nerve palsy (TFNP) is a well-known complication associated with ilioinguinal-iliohypogastric nerve block (IINB). We compared the incidence of TFNP after ultrasound-guided IINB and that after anatomical landmark-based IINB. We reviewed medical records of adult patients (ASA-PS 1-3, Age 21-87) who had received inguinal hernia surgery under general anesthesia and LINB retrospectively. IINB was performed using 0.5% ropivacaine either by ultrasound-guidance (US group, n = 16) or by landmark-based technique (LM group, n =17). TFNP was defined as sensory loss in the anterior aspect of the thigh or weakness of quadriceps femoris muscle in the nerve-blocked side. The frequency of TFNP in US group (6%) was lower than that in LM group (41%) in the post-anesthesia care unit (P = 0.019). TFNP symptom was resolved completely on the morning after surgery. The incidence of severe-intermediate postoperative pain and analgesic requirement were not different between the two groups. This study revealed that ultrasound-guided technique is effective to lower the incidence of TFNP after IINB in adult inguinal hernia surgery.


Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15.
The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3+CD4-CD8- double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms. DNTs were enriched and expanded ex vivo from healthy donors and phenotyped by flow cytometry. Functionally, their cytotoxicity was determined against primary and established non-small-cell lung cancer (NSCLC) cell lines in vitro or through in vivo adoptive transfer into xenograft models. Mechanistic analysis was performed using blocking antibodies against various cell surface and soluble markers. Furthermore, the role of IL-15 on DNT function was determined. We demonstrated that ex vivo expanded DNTs can effectively lyse various human NSCLC cells in vitro and inhibit tumor growth in xenograft models. Expanded DNTs have a cytotoxic phenotype, as they express NKp30, NKG2D, DNAM-1, membrane TRAIL (mTRAIL), perforin and granzyme B, and secrete IFNγ and soluble TRAIL (sTRAIL). DNT-mediated cytotoxicity was dependent on a combination of tumor-expressed ligands for NKG2D, DNAM-1, NKp30 and/or receptors for TRAIL, which differ among different NSCLC cell lines. Furthermore, stimulation of DNTs with IL-15 increased expression of effector molecules on DNTs, their TRAIL production and cytotoxicity against NSCLC in vitro and in vivo. Healthy donor-derived DNTs can target NSCLC in vitro and in vivo. DNTs recognize tumors via innate receptors which can be up-regulated by IL-15. DNTs have the potential to be used as a novel adoptive cell therapy for lung cancer either alone or in combination with IL-15.


[Effects of copper on rhizobia-Acacia auriculaeformis symbiotic association].
The effects of different levels of Cu2+ were studied individually on the growth of two Rhizobium strains and host plant growth, nodulation(%) and nitrogen fixation activity in A. auriculaeformis under solution culture conditions so as to explore a probability of utilization of the genus Acacia in revegetation of Cu(2+)-contaminated land. The results shows that Rhizobium sp. (Acacia auriculaeformis) had more stronger tolerance to Cu2+ iron than Rhizobium sp(Lespedeza formosa). The values of EC50 respectively achieved 0.129 mmol for Rhizobium sp. and 0.151 mmol for the N2-fixation activity. When the concentration of Cu2+ was over 0.50 mmol, N2-fixation activity had been inhabited thoroughly. Although the formation of nodules of Acacia auriculaeformis could continued, the growth of host plant had been inhibited with the appearance such as stunting, chlorosis. Between the noinodulating but adding nitrogen treat group and the inodulating without any nitrogen resource treat group, when Cu2+ < 0.125 mmol, the latter group showed better growth for A. auriculaeformis. There were higher contents of Cu in the underground tissues than in aboveground tissues.


Effect of filler particles morphology of resin-composites on cavity packing force for repeated condensation.
Effect of variation in morphology and size of filler particles, temperature and increase in condensation speed on packability of resincomposites was investigated. Eight experimental light-cured resin-composites (RZDn series) were tested. Each material was placed in a cylindrical mould at 26 or 32ºC. A flat-ended stainless-steel probe (φ=6 mm) was mechanically lowered with two different speeds 2 and 8 mm/s onto and into at the surface of the unset sample until a compressive force of 1 N was reached. This was repeated for five cycles, and from each cycle Fp was calculated. All spherical and irregular filler particle resin-composites showed a decrease in Fp with increase in number of compressions. Increase in temperature also decreased Fp, but this effect was not very prominent in the case of irregular filler resin-composites. Filler particle morphology, increase in temperature and compression cycle speed has a prominent effect on packability of resin-composites.


Headache diagnoses in patients with treated idiopathic intracranial hypertension.
The authors reviewed medical records of 82 patients with idiopathic intracranial hypertension (IIH) to determine the frequency of headaches occurring after initial diagnosis and treatment of IIH, classifiable by the International Headache Society guidelines. Sixty-eight percent of patients had definable headache disorders, including episodic tension type headache (30%) and migraine without aura (20%). Patients with IIH frequently have other types of headaches, not necessarily related to increased intracranial pressure.


The Integrative Method Based on the Module-Network for Identifying Driver Genes in Cancer Subtypes.
With advances in next-generation sequencing(NGS) technologies, a large number of multiple types of high-throughput genomics data are available. A great challenge in exploring cancer progression is to identify the driver genes from the variant genes by analyzing and integrating multi-types genomics data. Breast cancer is known as a heterogeneous disease. The identification of subtype-specific driver genes is critical to guide the diagnosis, assessment of prognosis and treatment of breast cancer. We developed an integrated frame based on gene expression profiles and copy number variation (CNV) data to identify breast cancer subtype-specific driver genes. In this frame, we employed statistical machine-learning method to select gene subsets and utilized an module-network analysis method to identify potential candidate driver genes. The final subtype-specific driver genes were acquired by paired-wise comparison in subtypes. To validate specificity of the driver genes, the gene expression data of these genes were applied to classify the patient samples with 10-fold cross validation and the enrichment analysis were also conducted on the identified driver genes. The experimental results show that the proposed integrative method can identify the potential driver genes and the classifier with these genes acquired better performance than with genes identified by other methods.


Repeated mechanical thrombectomy in short-term large vessel occlusion recurrence: multicenter study and systematic review of the literature.
Data on the frequency and outcome of repeated mechanical thrombectomy (MT) in patients with short-term re-occlusion of intracranial vessels is limited. Addressing this subject, we report our multicenter experience with a systematic review of the literature. A retrospective analysis was conducted of consecutive acute stroke patients treated with MT repeatedly within 30 days at 10 tertiary care centers between January 2007 and January 2020. Baseline demographics, etiology of stroke, angiographic outcome and clinical outcome evaluated by the modified Rankin Scale (mRS) at 90 days were noted. Additionally, a systematic review of reports with repeated MT due to large vessel occlusion (LVO) recurrence was performed. We identified 30 out of 7844 (0.4%) patients who received two thrombectomy procedures within 30 days due to recurrent LVO. Through systematic review, three publications of 28 participants met the criteria for inclusion. Combined, a total of 58 participants were analyzed: cardioembolic events were the most common etiology for the first (65.5%) and second LVO (60.3%), respectively. Median baseline NIHSS (National Institutes of Health Stroke Scale) was 13 (IQR 8-16) before the first MT and 15 (IQR 11-19) before the second MT (p=0.031). Successful reperfusion was achieved in 91.4% after the first MT and in 86.2% patients after the second MT (p=0.377). The rate of functional independence (mRS 0-2) was 46% at 90 days after the second procedure. Repeated MT in short-term recurrent LVO is a rarity but appears to be safe and effective. The second thrombectomy should be pursued with the same extensive effort as the first procedure as these patients may achieve similar good outcomes.


The journey to multiple sclerosis: a qualitative study.
The diagnosis of multiple sclerosis (MS) often creates more questions than answers. It is not uncommon to hear about individuals who receive the diagnosis with relief and surprise, However, the implications of being diagnosed with a chronic illness like MS is complex. There is no known cure for this disease that has remissions, relapses and possible continued progression. For individuals diagnosed with MS, responding to the physical and psychological stresses of a condition with an unknown cause and no cure is challenging. The purpose of this study was to explore the individual's experience of having symptoms for a period of time and then to be told they have MS. The phenomenological qualitative research method was used to illuminate the nature of their experiences. The time course spanned before diagnosis, at diagnosis and following diagnosis. Interviews were conducted with five purposefully selected participants. The process of data analysis highlighted common threads and patterns among informants. Four major themes emerged: Whispered Beginnings, Echoes of Silence, The Spoken Words, and Recreating Voice. The experiences of individuals recently diagnosed with MS are illuminated in order to provide insight and information to health care providers who are faced with telling a person the diagnosis of MS.