Familial KANK1 deletion that does not follow expected imprinting pattern.
Deletion of the KANK1 gene (also called ANKRD15), located at chromosome position 9p24.3, has been associated with neurodevelopmental disease including congenital cerebral palsy, hypotonia, quadriplegia, and intellectual disability in a four-generation family. The inheritance pattern in this family was suggested to be maternal imprinting, as all affected individuals inherited the deletion from their fathers and monoallelic protein expression was observed. We present a family in which the proband's phenotype, including autism spectrum disorder, motor delay, and intellectual disability, is consistent with this previous report of KANK1 deletions. However, a paternally inherited deletion in the proband's unaffected sibling did not support maternal imprinting. This family raises consideration of further complexity of the KANK1 locus, including variable expressivity, incomplete penetrance, and the additive effects of additional genomic variants or the potential benign nature of inherited copy number variations (CNVs). However, when considered with the previous publication, our case also suggests that KANK1 may be subject to random monoallelic expression as a possible mode of inheritance. It is also important to consider that KANK1 has two alternately spliced transcripts, A and B. These have differential tissue expression and thus potentially differential clinical significance. Based upon cases in the literature, the present case, and information in the Database of Genomic Variants, it is possible that only aberrations of variant A contribute to neurodevelopmental disease. The familial deletion in this present case does not support maternal imprinting as an inheritance pattern. We suggest that other inheritance patterns and caveats should be considered when evaluating KANK1 deletions, which may become increasingly recognized through whole genome microarray testing, whole genome sequencing, and whole exome sequencing techniques.


Towards elimination of hepatitis B and C in European Union and European Economic Area countries: monitoring the World Health Organization's global health sector strategy core indicators and scaling up key interventions.
The World Health Organization 'Global Health Sector Strategy on Viral Hepatitis 2016-2021' aimed at the elimination of viral hepatitis as a public health threat provides a significant opportunity to increase efforts for tackling the epidemics of hepatitis B and hepatitis C virus infections across Europe. To support the implementation and monitoring of this strategy, core epidemiological and programmatic indicators have been proposed necessitating specific surveys, the systematic collection of programmatic data and the establishment of monitoring across the care pathway. European Union and European Economic Area countries already made progress in recent years implementing primary and secondary prevention measures. Indeed, harm reduction measures among people who inject drugs reach many of those who need them and most countries have a universal hepatitis B vaccination programme with high coverage above 95%. However, while a further scaling up of prevention interventions will impact on incidence of new infections, treating those already infected is necessary to achieve reductions in mortality. The epidemiological, demographic and socio-political situation in Europe is complex, and considerable diversity in the programmatic responses to the hepatitis epidemic exists. Comprehension of such issues alongside collaboration between key organisations and countries will underpin any chance of successfully eliminating hepatitis.


A case of patellar fractures in monozygotic twin gymnasts.
We present a case of near identical patellar fractures in adolescent monozygotic twins who are both high-level competitive gymnasts. These patients presented 14 months apart with almost identical history and clinical findings. Both had an intense training regime involving over 30 hours per week of load-bearing exercise. Clinical and radiological examinations suggested avulsion or sleeve fracture of the inferior pole of the patella with minimal displacement. Diagnoses of patellar stress fracture with avulsion of the distal pole and symptomatic bipartite patella could not be reliably excluded. Both fractures were treated conservatively with immobilisation of the knee in extension. An excellent functional result was observed in both patients with return to full activity at 8 weeks.This is the first published case of identical injury to the patella in monozygotic twins. A significant genetic influence on bone mineral density (BMD) has been reported and low BMD is associated with increased susceptibility to fracture. These injuries corroborate a genetic influence on susceptibility to fracture. There is a requirement for further work to investigate genetic factors influencing susceptibility to fracture.


Platelet protective effect of TAK-029, a novel glycoprotein IIb/IIIa antagonist: an in vitro study.
Previous studies have indicated that exposure of fibrinogen receptors associated with the glycoprotein IIb/IIIa complex contributes to platelet loss during cardiopulmonary bypass. TAK-029 is a newly developed reversible, nonpeptide inhibitor of platelet glycoprotein IIb/IIIa receptors. In this study, we tested the platelet preserving effect of TAK-029 in an in vitro model. The methods included the comparison of the release of beta-thromboglobulin (beta-TG) between a TAK-029 group (n = 5) and a control group (n = 5) in a mock circulation under a shear force generated by a centrifugal pump. To evaluate the degree of beta-TG release, deltabeta-TG/deltaT was calculated where deltabeta-TG is the increase in beta-TG and deltaT is the time. The results showed that the value of deltabeta-TG/deltaT in the TAK-029 group was significantly lower than it was in the control group (4.22 +/- 0.27 x 10(2) ng/ml vs. 7.33 +/- 0.66 x 10(2) ng/ml, respectively). In conclusion, TAK-029 reduced the platelet activation under the shear forces of an in vitro model, suggesting that TAK-029 is a potential candidate for platelet protection during cardiopulmonary bypass.


Concentration of Thyrotropic Hormone in Persons Occupationally Exposed to Lead, Cadmium and Arsenic.
Thyroid hormones are essential for body homeostasis. The scientific literature contains restricted proofs for effects of environmental chemical factors on thyroid function. The present study aimed at evaluating the relationship between toxicological parameters and concentration of thyrotropic hormone in persons occupationally exposed to lead, cadmium and arsenic. The studies were conducted on 102 consecutive workers occupationally exposed to lead, cadmium and arsenic (mean age 45.08 ± 9.87 years). The estimated parameters characterizing occupational exposure to metals included blood cadmium concentration (Cd-B), blood lead concentration (Pb-B), blood zinc protoporphyrin concentration (ZnPP) and urine arsenic concentration (As-U). Thyroid function was evaluated using the parameter employed in screening studies, the blood thyrotropic hormone concentration (TSH). No differences were disclosed in mean values of toxicological parameters between the subgroup of persons occupationally exposed to lead, cadmium and arsenic with TSH in and out of the accepted normal values. Logistic regression demonstrated that higher blood total bilirubin concentrations (ORu = 4.101; p = 0.025) and higher Cd-B (ORu = 1.532; p = 0.027) represented independent risk factors of abnormal values of TSH in this group. In conclusion, in the group of workers exposed to lead, cadmium and arsenic, higher blood cadmium concentration seems to augment the risk of abnormal hormonal thyroid function.


The domain management model: organizing care for stroke survivors and other persons with chronic diseases.
The US health care system is poorly designed to help patients with stroke and chronic health conditions and their functional consequences. These patients face multiple clinical problems. The Domain Management Model (DMM), based on the biopsychosocial model, describes four domains into which all patient and family problems can be classified. These problems are then managed over time through attention to care processes and outcomes. The use of the DMM in health care may help relieve patient and family suffering, guide resource use more efficiently, and improve satisfaction of health care providers (clinical, administrative, and financial) in treating complex patients with chronic health conditions.


The PHR Family: The Role of Extracellular Transglycosylases in Shaping Candida albicans Cells.
Candida albicans is an opportunistic microorganism that can become a pathogen causing mild superficial mycosis or more severe invasive infections that can be life-threatening for debilitated patients. In the etiology of invasive infections, key factors are the adaptability of C. albicans to the different niches of the human body and the transition from a yeast form to hypha. Hyphal morphology confers high adhesiveness to the host cells, as well as the ability to penetrate into organs. The cell wall plays a crucial role in the morphological changes C. albicans undergoes in response to specific environmental cues. Among the different categories of enzymes involved in the formation of the fungal cell wall, the GH72 family of transglycosylases plays an important assembly role. These enzymes cut and religate β-(1,3)-glucan, the major determinant of cell shape. In C. albicans, the PHR family encodes GH72 enzymes, some of which work in specific environmental conditions. In this review, we will summarize the work from the initial discovery of PHR genes to the study of the pH-dependent expression of PHR1 and PHR2, from the characterization of the gene products to the recent findings concerning the stress response generated by the lack of GH72 activity in C. albicans hyphae.


Spectroscopic Indicators for Cytotoxicity of Chlorinated and Ozonated Effluents from Wastewater Stabilization Ponds and Activated Sludge.
We investigated chronic mammalian cell cytotoxicity of wastewaters from four sources and their optical spectroscopic properties with or without chlorination or ozonation. Samples from effluents of activated sludge, nitrification tower, facultative waste stabilization pond, and maturation waste stabilization pond were either chlorinated or ozonated. The wastewater samples were analyzed for fluorescence excitation emission matrix, specific fluorescence index (SFI), and specific UV absorbance at 254 nm (SUVA). Before and after disinfection the wastewater samples were quantitatively analyzed for in vitro mammalian cell cytotoxicity. We found that the organic extracts from the ozonated samples induced lower cytotoxicity responses than those from the chlorinated or the nondisinfected samples. To develop correlations between SFI, SUVA, and cytotoxicity, we analyzed 21 independent samples. Significant linear correlations found among these samples suggest that under the tested conditions, cytotoxicity was preferentially influenced by the fluorescence and SUVA of their composite organic agents. These two spectroscopic parameters may be used as indicators for the potential cytotoxicity of nondisinfected, ozonated, or chlorinated municipal wastewaters.


Longitudinal demographic study of wild populations of African annual killifish.
The natural history of model organisms is often overlooked despite its importance to correctly interpret the outcome of laboratory studies. Ageing is particularly understudied in natural populations. To address this gap, we present lifetime demographic data from wild populations of an annual species, the turquoise killifish, Nothobranchius furzeri, a model species in ageing research, and two other species of coexisting annual killifishes. Annual killifish hatch synchronously, have non-overlapping generations, and reproduce daily after reaching sexual maturity. Data from 13 isolated savanna pools in southern Mozambique demonstrate that the pools supporting killifish populations desiccated 1-4 months after their filling, though some pools persisted longer. Declines in population size over the season were stronger than predicted, because they exceeded the effect of steady habitat shrinking on population density that, contrary to the prediction, decreased. Populations of N. furzeri also became more female-biased with progressing season suggesting that males had lower survival. Nothobranchius community composition did not significantly vary across the season. Our data clearly demonstrate that natural populations of N. furzeri and its congeners suffer strong mortality throughout their lives, with apparent selective disappearance (condition-dependent mortality) at the individual level. This represents selective force that can shape the evolution of lifespan, and its variation across populations, beyond the effects of the gradient in habitat persistence.


Identifying bipolar knapping in the Mesolithic site of Font del Ros (northeast Iberia).
Despite recent advances in the identification of bipolar knapping, its role in many sites is not well known. We propose to assess the significance of this technique in the context of changes that occur in the Mesolithic. A lithic assemblage was recovered from unit SG at Font del Ros (Catalunya, Spain) in which pitted stones, cores and products arising from bipolar reduction (flakes, fragments and splintered pieces) were identified. This study indicates that the bipolar technique is fundamental in the settlement. These results are key to defining the organization of Holocene hunter-gatherer subsistence in northeast Iberia.


Elevation of plasma von Willebrand factor and tumor necrosis factor-a in obese subjects and their reduction by the low molecular weight heparin tinzaparin.
Increased plasma-soluble von Willebrand factor (vWF) level, a marker of vascular endothelial cell dysfunction, is a predictor of atherosclerotic cardiovascular disease. We compared associations between vWF level and markers of inflammation as well as the effects of LMWH in obese as compared to healthy human subjects. Plasma samples were obtained from healthy volunteers (n=32) and obese subjects (n=12) before and after administration of a single subcutaneous dose of tinzaparin, given at 75 IU/kg once a day, a deep vein thrombosis prophylaxis dose. Plasma samples were analyzed for vWF and tumor necrosis factor-alfa (TNF-alfa) using specific and sensitive ELISA. Obese subjects showed relatively higher plasma levels of TNF-alfa compared with normal-weight subjects. Regression analysis showed that plasma vWF levels to be directly associated with the presence of higher plasma levels of TNF-alfa in these obese subjects. Tinzaparin significantly reduced elevated plasma levels of both vWF and TNF-a levels (P<0.01). Plasma values of vWF and TNF-alfa are higher in obese than in normal-weight individuals. Treatment with tinzaparin lowers plasma levels of TNF-alfa in both obese and normal-weight subjects. The levels of vWF were higher in obese subjects than in normal-weight ones, which might be due to the higher levels of circulating TNF-alfa. Tinzaparin reduced vWF levels in these obese subjects.


Graphene enhanced evanescent field in microfiber multimode interferometer for highly sensitive gas sensing.
Graphene based new physics phenomena are leading to a variety of stimulating graphene-based photonic devices. In this study, the enhancement of surface evanescent field by graphene cylindrical cladding is observed, for the first time, by using a graphene-coated microfiber multi-mode interferometer (GMMI). It is found theoretically and experimentally that the light transmitting in the fiber core is efficiently dragged by the graphene, hence significantly enhancing the evanescent fields, and subsequently improving the sensitivity of the hybrid waveguide. The experimental results for gas sensing verified the theoretical prediction, and ultra-high sensitivities of ~0.1 ppm for NH(3) gas detection and ~0.2 ppm for H(2)O vapor detection are achieved, which could be used for trace analysis. The enhancement of surface evanescent field induced by graphene may pave a new way for developing novel graphene-based all-fiber devices with compactness, low cost, and temperature immunity.


Comparison of Different Magnitudes of Applied Syndesmotic Clamp Force: A Cadaveric Study.
Overcompression of the ankle syndesmosis was once thought to be improbable. Recent studies using computerized tomography (CT) however, have demonstarted otherwise; raising pertinent questions regarding the factors associated with and consequences of syndesmotic overcompression. The purpose of the present study was to directly compare different magnitudes of applied clamp force on the coronal reduction of ankle syndesmosis. Eight through-the-knee cadaveric specimens were obtained. Fiducial cannulated screws were placed in the tibia and fibula to standardize placement of the reduction clamp's tines. CT scans were obtained as baseline controls, followed by destabilization of the syndesmosis. Reductions were then performed using a clamp equipped with an inline load cell, and objective forces (60, 80, 100, 120, 140, and 160 N) applied sequentially to each of the specimens. The syndesmosis was fixed with a single quadricortical screw, and CT were scans repeated. Applied clamp forces of 60 and 80 N resulted in lateral fibular displacement and undercompression (42.9% and 57.1%, respectively), whereas forces of 140 and 160 N resulted in medial fibular displacement (p = .011 and p = .001) and overcompression (100%). The smallest mediolateral displacements were observed with 100 and 120 N, respectively. Malreduction assessment with CT was superior to traditional radiographs [r(54) = 0.22; 95% confidence interval -0.04 to 0.45; p = .101]. In our cadaveric model, an applied clamp force of 100 N most effectively mitigated iatrogenic coronal syndesmotic malreduction from under- or overcompression. Although additional research is warranted, based on the data, inherent variabilities in the applied clamp force by surgeons appear to contribute to the unacceptably high coronal syndesmotic malreduction rate.


Comparative analysis of Diospyros (Ebenaceae) plastomes: Insights into genomic features, mutational hotspots, and adaptive evolution.
Diospyros (Ebenaceae) is a widely distributed genus of trees and shrubs from pantropical to temperate regions, with numerous species valued for their fruits (persimmons), timber, and medicinal values. However, information regarding their plastomes and chloroplast evolution is scarce. The present study performed comparative genomic and evolutionary analyses on plastomes of 45 accepted Diospyros species, including three newly sequenced ones. Our study showed a highly conserved genomic structure across the Diospyros species, with 135-136 encoding genes, including 89 protein-coding genes, 1-2 pseudogenes (Ψycf1 for all, Ψrps19 for a few), 37 tRNA genes and 8 rRNA genes. Comparative analysis of Diospyros identified three intergenic regions (ccsA-ndhD, rps16-psbK and petA-psbJ) and five genes (rpl33, rpl22, petL, psaC and rps15) as the mutational hotspots in these species. Phylogenomic analysis identified the phylogenetic position of three newly sequenced ones and well supported a monophylogenetic (sub)temperate taxa and four clades in the pantropical taxa. The analysis codon usage identified 30 codons with relative synonymous codon usage (RSCU) values >1 and 29 codons ending with A and U bases. A total of three codons (UUA, GCU, and AGA) with highest RSCU values were identified as the optimal codons. Effective number of codons (ENC)-plot indicated the significant role of mutational pressure in shaping codon usage, while most protein-coding genes in Diospyros experienced relaxed purifying selection (d N/d S < 1). Additionally, the psbH gene showed positive selection (d N/d S > 1) in the (sub)temperate species. Thus, the results provide a meaningful foundation for further elaborating Diospyros's genetic architecture and taxonomy, enriching genetic diversity and conserving genetic resources.


Theoretical study of oxygen adsorption on pure Au(n+1)+ and doped MAu(n)+ cationic gold clusters for M = Ti, Fe and n = 3-7.
A comparative study of the adsorption of an O2 molecule on pure Au(n+1)+ and doped MAu(n)+ cationic gold clusters for n = 3-7 and M = Ti, Fe is presented. The simultaneous adsorption of two oxygen atoms also was studied. This work was performed by means of first principles calculations based on norm-conserving pseudo-potentials and numerical basis sets. For pure Au4 +, Au6+, and Au7+ clusters, the O2 molecule is adsorbed preferably on top of low coordinated Au atoms, with an adsorption energy smaller than 0.5 eV. Instead, for Au5+ and Au8+, bridge adsorption sites are preferred with adsorption energies of 0.56 and 0.69 eV, respectively. The ground-state geometry of Au(n)+ is almost unperturbed after O2 adsorption. The electronic charge flows towards O2 when the molecule is adsorbed in bridge positions and towards the gold cluster when O2 is adsorbed on top of Au atoms, and both the adsorption energy and the O-O bond length of adsorbed oxygen increase when the amount of electronic charge on O2 increases. On the other hand, we studied the adsorption of an O2 molecule on doped MAu(n)+ clusters, leading to the formation of (MAu(n)O2+) ad complexes with different equilibrium configurations. The highest adsorption energy was obtained when both atoms of O2 bind on top of the M impurity, and it is larger for Ti doped clusters than for Fe doped clusters, showing an odd-even effect trend with size n, which is opposite for Ti as compared to Fe complexes. For those adsorption configurations of (MAu(n)O2+) ad involving only Au sites, the adsorption energy is similar to or smaller than that for similar configurations of Au(n)+1O2 + complexes. However, the highest adsorption energy of (MAu(n)O2+) ad is higher than that for (Au(n)+1O2+) ad by a factor of approximately 4.0 (1.2) for M = Ti (M = Fe). The trends with size n are rationalized in terms of O-O and O-M bond distances, as well as charge transfer between oxygen and cluster substrates. The spin multiplicity of those (MAu(n)O2+) ad complexes with the highest O2 adsorption energy is a maximum (minimum) for M = Fe (Ti), corresponding to parallel (anti-parallel) spin coupling of MAu(n)+ clusters and O2 molecules. Finally, we obtained the minimum energy equilibrium structure of complexes (Au(n)O2+) dis and (MAu(n)O2+) dis containing two separated O atoms bonded at different sites of Au(n)+ and MAu(n)+ clusters, respectively. For (MAu(n)O2 (+)) dis, the equilibrium configuration with the highest adsorption energy is stable against separation in MAu(n)+ and O2 fragments, respectively. Instead, for (Au(n)O2+) dis, only the complex n = 6 is stable against separation in Au(n)+ and O2 fragments. The maximum separation energy of (MAu(n)O2+) dis is higher than the O2 adsorption energy of (MAu(n)O2+) ad complexes by factors of approximately 1.6 (2.5), 1.6 (1.7), 1.5 (2.4), 1.5 (1.3), and 1.6 (1.8) for M = Ti (Fe) complexes in the range n = 3-7, respectively.


Advances in quantifying air-sea gas exchange and environmental forcing.
The past decade has seen a substantial amount of research on air-sea gas exchange and its environmental controls. These studies have significantly advanced the understanding of processes that control gas transfer, led to higher quality field measurements, and improved estimates of the flux of climate-relevant gases between the ocean and atmosphere. This review discusses the fundamental principles of air-sea gas transfer and recent developments in gas transfer theory, parameterizations, and measurement techniques in the context of the exchange of carbon dioxide. However, much of this discussion is applicable to any sparingly soluble, non-reactive gas. We show how the use of global variables of environmental forcing that have recently become available and gas exchange relationships that incorporate the main forcing factors will lead to improved estimates of global and regional air-sea gas fluxes based on better fundamental physical, chemical, and biological foundations.


Does intensity modulation increase target dose calculation errors of conventional algorithms for lung SBRT?
Conventional dose algorithms (Type A and Type B) for lung SBRT can display considerable target dose errors compared to Type-C algorithms. Intensity-modulated techniques (IMRT/VMAT) are increasingly being utilized for lung SBRT. Therefore, our study aimed to assess whether intensity modulation increased target dose calculation errors by conventional algorithms over conformal techniques. Twenty lung SBRT patients were parallely planned with both IMRT and dynamic conformal arc (DCA) techniques using a Type-A algorithm, and another 20 patients were parallely planned with IMRT, VMAT, and DCA using a Type-B algorithm. All 100 plans were recalculated with Type-C algorithms using identical beam and monitor unit settings, with the Type-A/Type-B algorithm dose errors defined using Type-C recalculation as the ground truth. Target dose errors for PTV and GTV were calculated for a variety of dosimetric end points. Using Wilcoxon signed-rank tests (p < 0.05 for statistical significance), target dose errors were compared between corresponding IMRT/VMAT and DCA plans for the two conventional algorithms. The levels of intensity modulation were also evaluated using the ratios of MUs in the IMRT/VMAT plans to those in the corresponding DCA plans. Linear regression was used to study the correlation between intensity modulation and relative dose error magnitudes. Overall, larger errors were found for the Type-A algorithm than for the Type-B algorithm. However, the IMRT/VMAT plans were not found to have statistically larger dose errors from their corresponding DCA plans. Linear regression did not identify a significant correlation between the intensity modulation level and the relative dose error. Intensity modulation did not appear to increase target dose calculation errors for lung SBRT plans calculated with conventional algorithms.


Regional chemotherapy for melanoma. A 35-year experience.
The authors present their 35-year experience with intra-arterial chemotherapeutic regional perfusion of 1139 patients with melanomas, using an extracorporeal oxygenated circuit and heart-lung apparatus. Intra-arterial chemotherapy produces improved responses in many tumors. By isolating and sustaining the area with extracorporeal oxygenated circulation, high doses can be delivered to the tumor area, limited only by local toxicity. Drug levels up to 10 times those achieved by systemic administration are obtained. Techniques for hyperthermic perfusion were developed for limbs, pelvis, head, neck, and skin of the breast. Melphalan (Burroughs Wellcome, Research Triangle Park, NC) was used in 753 patients. Combinations with melphalan or other drugs were used in remaining cases at temperature of 38 to 40 C for 30 to 60 minutes. Chemotherapy perfusion followed by tumor excision or node dissection, was performed where indicated. The cumulative 10-year survival for patients with localized melanomas was 70%. For patients with local recurrences or satellites within 3 cm, survival was 61%. For those with regionally confined intransit tumors, survival was 30%; for those with regional node involvement, 38%; for those with intransit and nodal metastases, 16%; for those with distant metastases and perfusion--mainly to save functional limbs--survival was 7%. Multiple perfusions were performed in 158 patients with recurrent disease on 366 occasions. Patients with indolent regionally confined melanomas were benefited by prolongation of useful life. Safe perfusion techniques are available for most anatomic regions. Increased chemotherapeutic doses are delivered to isolated areas limited only by local toxicity. Adjunct perfusion in poor prognosis stage I cases is useful in reducing local recurrence, and intransit or lymph node metastases. Regional perfusion reduces the need for major amputation. Multiple perfusion can be useful in treating recurrent chronic melanoma.


Relationship between digital exclusion and cognitive impairment in Chinese adults.
We aimed to evaluate the relationship between digital exclusion, such as neither mobile payments nor WeChat use, and cognitive impairment in Chinese individuals aged 45 and older. A population-based cross-sectional study utilizing data from the fourth national survey of the China Health and Retirement Longitudinal Study (CHARLS). In the fourth wave of CHARLS, 10,325 participants aged 45 and older with complete information were included in this analysis. Self-reported mobile payments and WeChat usage constituted our exposure. Cognitive impairment was the primary outcome. Univariate and multivariate logistic regression were used to assess the relationships between cognitive impairment risk and digital exclusion. Data were analyzed from 10,325 participants [mean (SD) age, 60.3 (9.1) years; 44.8% women], including 1,232 individuals with cognitive impairment and 9,093 cognitively normal individuals. The overall proportion of users who did not use either mobile payment or WeChat and those who only used WeChat were 81.3 and 6.7%, for cognitively impaired individuals 95.0 and 3.1%, and for cognitively normal individuals 79.5 and 7.2% [neither WeChat nor mobile payments vs. control unadjusted odds ratio (OR), 8.16; P < 0.001; only WeChat use vs. control unadjusted OR, 2.91; P < 0.001]. Participants who did not use either WeChat or mobile payments had an elevated risk for cognitive impairment after adjusting for a number of covariates (neither WeChat nor mobile payments vs. control adjusted OR, 3.48; P < 0.001; only WeChat use vs. control adjusted OR, 1.86; P = 0.021). Our study reveals a positive correlation between digital exclusion and cognitive impairment in Chinese adults, providing insights for promoting active digital integration among older adults. Further longitudinal research is needed to further validate this hypothesis.


Para-aminobenzoate synthase gene of Saccharomyces cerevisiae encodes a bifunctional enzyme.
The Saccharomyces cerevisiae gene for para-aminobenzoate (PABA) synthase has been identified based upon its ability to confer sulfonamide resistance when present on a multicopy episomal vector. The 3840 bp DNA sequence fragment reported here contains a 2199 bp open reading frame encoding a 733 amino acid protein with similarity to the two components of PABA synthase described for prokaryotes (Escherichia coli PabA and PabB), suggesting that PABA synthase is bifunctional in yeast. The cloned sequence was confirmed to be PABA synthase by gene disruption. Chromosome gel analysis places the gene for PABA synthase on chromosome XIV.


Association between child and adolescent television viewing and adult health: a longitudinal birth cohort study.
Watching television in childhood and adolescence has been linked to adverse health indicators including obesity, poor fitness, smoking, and raised cholesterol. However, there have been no longitudinal studies of childhood viewing and adult health. We explored these associations in a birth cohort followed up to age 26 years. We assessed approximately 1000 unselected individuals born in Dunedin, New Zealand, in 1972-73 at regular intervals up to age 26 years. We used regression analysis to investigate the associations between earlier television viewing and body-mass index, cardiorespiratory fitness (maximum aerobic power assessed by a submaximal cycling test), serum cholesterol, smoking status, and blood pressure at age 26 years. Average weeknight viewing between ages 5 and 15 years was associated with higher body-mass indices (p=0.0013), lower cardiorespiratory fitness (p=0.0003), increased cigarette smoking (p<0.0001), and raised serum cholesterol (p=0.0037). Childhood and adolescent viewing had no significant association with blood pressure. These associations persisted after adjustment for potential confounding factors such as childhood socioeconomic status, body-mass index at age 5 years, parental body-mass index, parental smoking, and physical activity at age 15 years. In 26-year-olds, population-attributable fractions indicate that 17% of overweight, 15% of raised serum cholesterol, 17% of smoking, and 15% of poor fitness can be attributed to watching television for more than 2 h a day during childhood and adolescence. Television viewing in childhood and adolescence is associated with overweight, poor fitness, smoking, and raised cholesterol in adulthood. Excessive viewing might have long-lasting adverse effects on health.


Medical nanotechnology: how small can we go?
Medical devices are becoming more sophisticated and, in common with instrumentation in many other disciplines, are becoming more compact. This article addresses the question of how small these devices need to be for them to have a significant impact on our ability to provide functioning interfaces with tissues. The significance of recent developments in materials and materials fabrication is also highlighted.


Probing conformational dynamics to understand kinase inhibition.
Why do some inhibitors select the on-state in ERK2, a kinase that is involved in many signaling pathways in cells, whereas others bind to more than one conformation?


Patient compliance and angiotensin converting enzyme inhibitors in hypertension.
Patient compliance is crucial to successful medical treatment. Many factors contribute to compliance, including age, sex, other sociodemographic factors, finances, intelligence, complexity of therapeutic regimen, and patient-physician rapport. Compliance is especially critical in medical conditions requiring prolonged therapy, such as hypertension. Historically, compliance among hypertensive patients has been alarmingly poor, with a 50% drop-off after 1 year and fewer than 20% still in therapy after 5 years. The use of enalapril, the long-acting angiotensin converting enzyme (ACE) inhibitor that allows for a once-daily regimen, has improved treatment success and compliance. This probably is due to the efficacy of the drug, coupled with a low incidence of side effects.


Structural characterization of chaos game fractals using small-angle scattering analysis.
Small-angle scattering (SAS) technique is applied to study the nano and microstructural properties of spatial patterns generated from chaos game representation (CGR). Using a simplified version of Debye formula, we calculate and analyze in momentum space, the monodisperse scattering structure factor from a system of randomly oriented and non-interacting 2D Sierpinski gaskets (SG). We show that within CGR approach, the main geometrical and fractal properties, such as the overall size, scaling factor, minimal distance between scattering units, fractal dimension and the number of units composing the SG, can be recovered. We confirm the numerical results, by developing a theoretical model which describes analytically the structure factor of SG. We apply our findings to scattering from single scale mass fractals, and respectively to a multiscale fractal representing DNA sequences, and for which an analytic description of the structure factor is not known a priori.


Cardiovascular health in pediatric heart transplant patients.
Ideal "cardiovascular health" (CVH)-optimal diet, exercise, nonsmoking, BMI, BP, lipids, and glucose-is associated with healthy longevity in adults. Pediatric heart transplant (HT) patients may be at risk for suboptimal CVH. Single-center retrospective study of HT patients 2003-2014 who survived 1 year post-transplant. Five CVH metrics were collected at listing, 1, 3 and 5 years post-transplant (diet and exercise were unavailable). CVH was scored by summing individual metrics: ideal = 2, intermediate = 1, and poor = 0 points; total scores of 8-10 points were considered high (favorable). CVH was compared between HT patients and the US pediatric population (GP) utilizing NHANES 2007-2016. Logistic regression was performed to examine the association of CVH 1 year post-transplant with a composite adverse outcome (death, re-listing, coronary vasculopathy, or chronic kidney disease) 3 years post-transplant. We included 110 HT patients (median age at HT: 6 years [range 0.1-21]) and 19,081 NHANES participants. CVH scores among HT patients were generally high at listing (75%), 1 (74%), 3 (87%) and 5 (76%) years post-transplant and similar to GP, but some metrics (e.g., glucose) were worse among HT patients. Among HT patients, CVH was poorer with older age and non-Caucasian race/ethnicity. Per 1-point higher CVH score, the demographic-adjusted OR for adverse outcomes was 0.95 (95% CI, 0.7-1.4). HT patients had generally favorable CVH, but some metrics were unfavorable and CVH varied by age and race/ethnicity. No significant association was detected between CVH and adverse outcomes in this small sample, but study in a larger sample is warranted.


Association of homocysteine with global DNA methylation in vegetarian Indian pregnant women and neonatal birth anthropometrics.
The present study was designed to evaluate if plasma maternal folate, vitamin B-12 and homocysteine levels had an effect on maternal global DNA methylation and neonatal anthropometrics in Indian pregnant women. A total of 49 participants having completed ≥36 weeks of pregnancy were enrolled in the study. Estimation of folate was by Ion capture assay, vitamin B-12 by microparticle enzyme immunoassay, total homocysteine by fluorescence polarization immunoassay and global DNA methylation using Cayman's DNA methylation enzyme immunoassay (EIA) kit. Folate and vitamin B-12 were inversely correlated to homocysteine in pregnant women consuming vegetarian and non-vegetarian diet. No difference in global DNA methylation was found between the vegetarian and non-vegetarian pregnant women. Folate and vitamin B-12 did not show association with global DNA methylation, however plasma total homocysteine of the vegetarian group showed significant correlation to global DNA methylation (r(2 )= 0.49, p = 0.011). Plasma total homocysteine was inversely related to tricep skinfold (r(2 )= -0.484, p = 0.01) and chest circumference (r(2 )= -0.104, p = 0.04) of neonates in vegetarian group. Moderate vitamin B-12 deficiency in vegetarian pregnant women might be the cause of hyperhomocystinemia, hypermethylation when compared to vitamin B-12 sufficient non-vegetarian group.


[Water and electrolytes disorders after brain injury: mechanism and treatment].
Electrolyte disturbances are frequent after brain injuries, especially dysnatremia and dyskalemia. In neurological patients, usual clinical signs of hyponatremia are frequently confounded with clinical signs of the underlying disease. Natremia absolute value is less important than speed of onset of the trouble. Most often, hyponatremia is associated with hypotonicity and intracellular hyperhydration, which may exacerbate a cerebral edema. Distinction between inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt wasting syndrome (CSWS) may be difficult and is mainly based on assessment of patient's volemia, SIADH being associated with normal or hypervolemia and CSWS with hypovolemia. After subarachnoid haemorrhage, the most common disorder is CSWS. In this case, fluid restriction is strictly prohibited. Treatment of CSWS needs to compensate for the natriuresis and may justify the use of mineralocorticoid. It is important to avoid excessively rapid correction of hypernatremia, with a maximal speed of correction of 0.5 m mol/l/h. Serum sodium monitoring should be mandatory for the first ten postoperative days after pituitary adenoma surgery. Therapeutic barbiturate may be responsible for life threatening dyskalemia.


Cardiac Magnetic Resonance Imaging at 7 Tesla.
CMR at an ultra-high field (magnetic field strength B0 ≥ 7 Tesla) benefits from the signal-to-noise ratio (SNR) advantage inherent at higher magnetic field strengths and potentially provides improved signal contrast and spatial resolution. While promising results have been achieved, ultra-high field CMR is challenging due to energy deposition constraints and physical phenomena such as transmission field non-uniformities and magnetic field inhomogeneities. In addition, the magneto-hydrodynamic effect renders the synchronization of the data acquisition with the cardiac motion difficult. The challenges are currently addressed by explorations into novel magnetic resonance technology. If all impediments can be overcome, ultra-high field CMR may generate new opportunities for functional CMR, myocardial tissue characterization, microstructure imaging or metabolic imaging. Recognizing this potential, we show that multi-channel radio frequency (RF) coil technology tailored for CMR at 7 Tesla together with higher order B0 shimming and a backup signal for cardiac triggering facilitates high fidelity functional CMR. With the proposed setup, cardiac chamber quantification can be accomplished in examination times similar to those achieved at lower field strengths. To share this experience and to support the dissemination of this expertise, this work describes our setup and protocol tailored for functional CMR at 7 Tesla.


Serum periplakin as a potential biomarker for urothelial carcinoma of the urinary bladder.
The objectives of this study were to examine serum periplakin expression in patients with urothelial carcinoma of the urinary bladder and in normal controls, and to examine relationships with clinicopathological findings. Detection of serum periplakin was performed in 50 patients and 30 normal controls with anti-periplakin antibodies using the automatic dot blot system, and a micro-dot blot array with a 256 solid-pin system. Levels in patients with urothelial carcinoma of the urinary bladder were significantly lower than those in normal controls (0.31 and 5.68, respectively; p<0.0001). The area under the receiver-operator curve level for urothelial carcinoma of the urinary bladder was 0.845. The sensitivity and specificity, using a cut-off point of 4.045, were 83.7% and 73.3%, respectively. In addition, serum periplakin levels were significantly higher in patients with muscle-invasive cancer than in those with nonmuscle-invasive cancer (P=0.03). In multivariate Cox proportional hazards regression analysis, none of the clinicopathological factors was associated with an increased risk for progression and cancer-specific survival. Examination of the serum periplakin level may play a role as a non- invasive diagnostic modality to aid urine cytology and cystoscopy.


A novel hinge system and incubation chamber for emulsion-coated coverslip autoradiography.
We describe an emulsion-coated coverslip autoradiographic technique for large (50 x 50 mm) sections of monkey or human brain. The technique uses adhesive-backed, teflon-reinforced aluminum foil as a flexible hinge that allows the coverslip to swing away from the slide so that the emulsion and tissue can be processed independently. We also describe a plexiglas incubation chamber that allows two slides with coverslips folded away to be processed back-to-back in 5 ml of reagent solution. In general use, the chamber minimizes the volume of solution needed to cover large slide-mounted sections and is ideal for radioligand or immunohistochemical reactions that use expensive reagents. For autoradiography, the chamber greatly facilitates independent processing of the emulsion and tissue section. Together, the foil-hinge method and incubation chamber virtually eliminate the major technical pitfalls of previous emulsion-coated coverslip methods. Moreover, they facilitate combination of histochemical or immunocytochemical staining with autoradiographic localization of neurotransmitter receptors in the same tissue section. This is demonstrated by thioflavin S staining of neuritic plaques and tangles and autoradiographic localization of serotonin 1A receptors in sections of Alzheimer disease brain.


Post-transcriptional regulation in metabolic diseases.
Post-transcriptional gene regulation by microRNAs (miRNAs) and RNA-binding proteins (RBPs) is central to many biological functions. Aberrant gene expression patterns underlie many metabolic diseases that represent major public health concerns and formidable therapeutic challenges. Several studies have established a number of post-transcriptional regulators implicated in metabolic diseases such as diabetes and obesity. In addition, emerging knowledge of metabolically active and insulin-sensitive organs, such as the pancreas, liver, muscle and adipose compartment, is rapidly expanding the panel of potential therapeutic targets for the treatment of metabolic diseases. Here, we review our current understanding of miRNAs and RBPs that affect glucose and lipid homeostasis, and their roles in normal physiology and metabolic disorders, especially type 2 diabetes and obesity.


Sealworm Pseudoterranova decipiens s.s. infection of European smelt Osmerus eperlanus in German coastal waters: ecological implications.
European smelt Osmerus eperlanus (n = 501) from the German Wadden Sea (North Sea) near the city of Cuxhaven were examined for their infestation with parasitic anisakid nematodes, especially with sealworms of the genus Pseudoterranova. The distribution of third-stage larvae (L3) in the musculature and viscera of the fish was analyzed. In total, we isolated 543 L3 from the hosts' body cavity and musculature. A subsample of 105 larvae were identified as the (sibling) species P. decipiens s.s. using direct sequencing of the highly variable ribosomal ITS1-5.8S-ITS2 genetic marker. The mean abundance was 1.1, the mean intensity was 2.3 P. decipiens s.s. and the prevalence was 47.3%. Total length and total weight, but not Fulton's condition factor (K), were significantly different in infected compared to uninfected smelt. No correlation was found between the total length of infected fish and the intensity of anisakid nematodes. The vast majority of P. decipiens s.s. was found in the musculature of the smelt. More than half (55.7%) of all nematodes were located in the 3 parts of the epaxial musculature, whereas 18.4 and 26.0% were found in the hypaxial musculature and the compartments of the tail muscles, respectively.


Factors affecting pregnancy loss from gestation Day 38 to 90 in lactating dairy cows from a single herd.
The present study was designed to establish whether factors such as previous estrus synchronization, corpus luteum and embryo number at the time of pregnancy diagnosis, changes in body condition score, milk production, clinical disease (mastitis or lameness) and the inseminating bull affect pregnancy loss from 38 to 90 days of gestation. We derived data from 601 pregnant lactating dairy cows from a single herd. Pregnancy diagnosis was performed by ultrasonography between Day 38 and 44 following insemination. We also recorded corpus luteum and embryo number at this time. Pregnancy loss was defined as a negative pregnancy diagnosis on the second palpation per rectum undertaken between 90 and 96 days after insemination. Data were analyzed using multiple logistic regression methods. Cows that had an additional corpus luteum were eight times less likely to miscarry. The risk of pregnancy loss was 3.1 times higher in cows bearing twins. A one unit reduction in body condition score from previous partum to 30 days postpartum resulted in a 2.4-fold increase in pregnancy loss. We noted a higher incidence of pregnancy loss in cows inseminated using semen from one of the six bulls used. This particular bull led to a 3.4-fold increase in the rate of pregnancy loss. Logistic regression analysis showed no significant effects of previous estrus synchronization, milk production, clinical disease, body condition at previous partum or at pregnancy diagnosis, or body condition change between previous partum and pregnancy diagnosis. Our findings indicate a positive relationship between the presence of an additional corpus luteum and the maintenance of gestation. Risk factors for pregnancy loss were twin pregnancy, reduced body condition after previous parturition and the inseminating bull.


Fine structure of the testis and epididymis of rats treated with cyproterone acetate.
Adult male rats were administered the antiandrogen, cyproterone acetate, for 4, 8 or 12 weeks, and the histology and fine structure of the testis and several parts of the epididymis were studied. After treatment for 8 or 12 weeks, the testes of treated animals displayed a great reduction in the abundance of late spermatids. Necrotic cells, many of which were identified as cap-phase spermatids, were present in the seminiferous epithelium. Sertoli cells contained many large lipid droplets and lysosome-like structures with a content of cellular debris, including parts of spermatids. Leydig cells of treated rats were smaller than those of control animals at all the intervals studied. Sperm were absent from the lumen of the middle segment, or caput epididymidis, of severely affected specimens. In the terminal segment, or cauda epididymidis, the microscopic appearance varied in different regions. In the proximal part of the cauda epididymidis, the lumen was usually clear of sperm. The epithelium was tall and the light cells were very large and distended with many dense bodies resembling lysosomes. In contrast, in the distal part of the cauda epididymidis, the lumen was filled with sperm and debris, which appeared to be derived from germ cells. It is suggested that the light cells of the epididymal epithelium may have a role in clearing the lumen in the proximal part of the cauda epididymidis, in which they are particularly large and numerous. The results suggest that in the presence of cyproterone acetate, germ cells develop up to a cap-phase spermatids and then begin to undergo degeneration and death. This alteration may have an important role in the antifertility effect of the drug, but changes in the epididymis may contribute also.


A novel instrument and technique for using Seprafilm hyaluronic acid/carboxymethylcellulose membrane during laparoscopic myomectomy.
Myomectomy is associated with the development of adhesions, and even when the patient is operated on laparoscopically, postoperative adhesions can often occur. Seprafilm is an effective and highly safe barrier to postoperative adhesions. However, it is vulnerable to tears and difficult to handle. We developed a device to introduce Seprafilm into the abdominal cavity during the laparoscopic procedure. Seprafilm is divided into 6 pieces and the pieces are rolled and inserted into the purpose-built introducer to be guided into the abdominal cavity. The inner syringe is pushed in and Seprafilm is applied onto the uterine wound with two grasping forceps. Of 117 patients in our study, we were able to use Seprafilm on 114 patients (97.4%). In total, 221 pieces of Seprafilm were used, and 87 pieces were damaged during the operation. Of these 87 pieces, 58 were damaged when inserted into the introducer, though this kind of loss tended to decrease with training, and 29 pieces were damaged during application to the wound. Seprafilm can be used safely and efficiently during laparoscopic surgery.


Structure-switching aptasensors for sensitive detection of ochratoxin A.
Ochratoxin A (OTA) is a toxic metabolite commonly found in various foods and feedstuffs. Accurate and sensitive detection of OTA is needed for food safety and human health. Based on a common OTA-binding aptamer (OTABA), two structure-switching OTABAs, namely OTABA4 and OTABA3, were designed by configuring a split G-quadruplex and a split G-triplex, respectively, at the two ends of OTABA to construct aptasensors for the detection of OTA. The OTABA, G-quadruplex, and G-triplex all can capture the thioflavin T (ThT) probe, thereby enhancing the fluorescence intensity of ThT. Bonding with OTA could change the conformations of OTABA and G-quadruplex or G-triplex regions, resulting in the release of the captured ThT and diminution of its fluorescence intensity. Dual conformation changes in structure-switching OTABA synergistically amplified the fluorescence signal and improved the sensitivity of the aptasensor, especially for that with OTABA3. The detection limits of the OTABA4-ThT and OTABA3-ThT systems for OTA were 0.28 and 0.059 ng ml-1 , with a 1.4-fold and 6.7-fold higher sensitivity than that of the original OTABA-ThT system, respectively. They performed well in corn and peanut samples and met the requirements of the food safety inspections.


Benign paroxysmal positional vertigo and clinical test of sensory interaction and balance in ankylosing spondylitis.
To assess the frequency and characteristics of benign paroxysmal positional vertigo (BPPV) and clinical test of sensory interaction and balance (CTSIB) abnormalities in patients with ankylosing spondylitis (AS). A series of consecutive patients that fulfilled the modified New York diagnostic criteria for AS and matched controls were studied. The study was performed at the Otolaryngology Division of a tertiary reference center. Fifty-nine patients with AS (47 men [79.6%]) attending hospital outpatient rheumatology clinics between March and October 2008, and 46 controls (34 men [73.9%]) were studied. Dix-Hallpike and cephalic rotational tests and CTSIB were performed in AS patients and age-, sex-, and ethnically frequency-matched controls. Type and frequency of BPPV and CTSIB conditions were assessed. BPPV was diagnosed in 6 patients (10.1%) with AS and in 2 (4.3%) of the controls (p = 0.24). Abnormal caloric test was more commonly observed in patients with AS (n = 15 [25.4%]) than the controls (n = 0) (p < 0.001). Increased frequency of abnormal CTSIB also was observed in patients (19/59 [32%]) compared with the controls (3 [6.5%]) (odds ratio, 6.81 [95% confidence interval, 1.77-38.0]; p = 0.001). Among the abnormal CTSIB patterns, the vestibular loss was the most commonly observed in patients with AS (15/59 [25.4%]). The present study shows an increased frequency of abnormal postural control in CTSIB test of vestibular origin in patients with AS.


Overview of dietary flavonoids: nomenclature, occurrence and intake.
Flavonoids and their polymers constitute a large class of food constituents, many of which alter metabolic processes and have a positive impact on health. Flavonoids are a subclass of polyphenols. They generally consist of two aromatic rings, each containing at least one hydroxyl, which are connected through a three-carbon "bridge" and become part of a six-member heterocyclic ring. The flavonoids are further divided into subclasses based on the connection of an aromatic ring to the heterocyclic ring, as well as the oxidation state and functional groups of the heterocyclic ring. Within each subclass, individual compounds are characterized by specific hydroxylation and conjugation patterns. Many flavonoids in foods also occur as large molecules (tannins). These include condensed tannins (proanthocyanidins), derived tannins and hydrolysable tannins. For proanthocyanidins, three subclasses (15 characterized) have been identified in foods. Monomers are connected through specific carbon-carbon and ether linkages to form polymers. Derived tannins are formed during food handling and processing, and found primarily in black and oolong teas. Flavonoids are widely distributed in nature, albeit not uniformly. As a result, specific groups of foods are often rich sources of one or more subclasses of these polyphenols. The polyphenolic structure of flavonoids and tannins renders them quite sensitive to oxidative enzymes and cooking conditions. Scientists in several countries have estimated intakes of a few subclasses of flavonoids from limited food composition databases. These observations suggest large differences in consumption, due in part to cultural and food preferences among populations of each country.


Regulation of Arabidopsis thaliana Em genes: role of ABI5.
In order to identify new factors involved in Em (a class I Late Embryogenesis Abundant protein) gene expression, Arabidopsis mutants with an altered expression of an Em promoter GUS fusion construct and a modified accumulation of Em transcripts and proteins were isolated. Germination tests on ABA showed that the most affected mutant had a weak abi phenotype. Complementation tests further revealed this mutant to be a new abi5 allele, consequently named abi5-5. In addition to reducing the final level of Em transcripts in the dry seed, the abi5-5 mutation causes a delay in the accumulation of AtEm1 during seed development. An additional characteristic of the abi5-5 mutant, is the ability of its seeds to germinate at high concentrations of salt and mannitol. The abi5-5 mutation was characterized at the molecular level and was shown to result from a two base pair deletion in the coding sequence of the ABI 5 gene. The wild type and mutant recombinant proteins were produced in E. coli and were assayed for DNA-binding activity on their target promoters by electrophoretic mobility shift assay (EMSA). The ABI5 recombinant protein binds the ABRE sequence in the AtEm6 promoter as shown by Dnase footprinting. Among the ABRE-type sequences selected on both Em promoters, the G-box type AGACACGTGGCATGT element of the AtEm6 promoter shows the strongest binding by EMSA quantification.


At the heart of COVID-19.
Coronavirus disease (COVID-19) first presented in Wuhan, Hubei province, China in December 2019. Since then, it has rapidly spread across the world, and is now formally considered a pandemic. The disease does not discriminate but increasing age and the presence of comorbidities are associated with severe form of the disease and poor outcomes. Although the prevalence of COVID-19 in patients with cardiovascular disease is under-reported, there is evidence that pre-existing cardiac disease can render individuals vulnerable. It is thought that COVID-19 may have both a direct and indirect effect on the cardiovascular system; however, the primary mechanism of underlying cardiovascular involvement is still uncertain. Of particular interest is the role of angiotensin-converting enzyme 2, which is well known for its cardiovascular effects and is also considered to be important in the pathogenesis of COVID-19. With a range of different drug candidates being suggested, effective anti-virals and vaccines are an area of on-going research. While our knowledge of COVID-19 continues to rapidly expand, this review highlights recent advances in our understanding of the interaction between COVID-19 and the cardiovascular system.


Awareness of LGBTQ+ health disparities: A survey study of complementary integrative health providers.
The purpose of this study was to survey awareness of lesbian, gay, bisexual, transgender, queer/questioning, plus health disparities among complementary integrative health providers; chiropractors, naturopaths, acupuncturists, and massage therapists and secondly, examine how providers' sexual and gender identity correlated with that awareness. An electronic survey was designed, which included demographic questions as well as closed-ended and Likert response items to measure provider awareness of LGBTQ+ patients and the health disparities they experience. Kruskal-Wallis H tests with pairwise comparisons were used to evaluate the differences between defined groups and their awareness of health disparities of LGBTQ+ adults and youth. The survey showed that most complementary integrative health care providers agreed that LGBTQ+ individuals experience discrimination and health disparities. However, providers are unaware of the specific disparities experienced in this population, including increased risk of substance abuse and mental health issues. Pairwise comparison tests demonstrated that providers that identify as a part of the LGBTQ+ community are often more aware of disparities than their heterosexual cisgender counterparts. Complementary integrative health care providers demonstrated some general awareness of LGBTQ+ health disparities yet most providers lacked awareness of specific disparities that pose major health risks for this community. Cultural competency training specific to LGBTQ+ individuals is lacking and may explain some of the findings in this study. This suggests that education is needed, both in professional educational programs and in the health care community by way of conferences, webinars, and other opportunities.


Molecular species of prostaglandins involved in modulating luteinising hormone pulses of female rats under infectious stress conditions.
Mammalian reproductive function is controlled by the hypothalamic-pituitary-gonadal (HPG) axis, which is suppressed under infectious stress conditions. By analysing the pulsatility of luteinising hormone (LH), we have previously demonstrated that prostaglandins (PGs) in the central nervous system mediate infectious stress to suppress the activity of the HPG axis. The present study aimed to characterise the types of PGs responsible for suppression of the HPG axis. We focused on three major types of PGs: PGE2 , PGD2 and PGF2α . We used female rats overiectomised bilaterally 1 week before the experiments. Lipopolysaccharide (100 μg kg-1 ) suppressed LH pulses at the same time as enhancing the concentration of all three PGs in the cerebrospinal fluid, which was restored by indomethacin (10 mg kg-1 ). Subsequently, we observed LH pulsatility after a single injection of each PG and after co-injection of PGE2 with PGF2α into the third cerebral ventricle. A single injection of PGE2 dose-dependently induced a transient increase in mean LH concentration and LH pulse amplitude, and PGD2 significantly increased the amplitude of LH pulses, wereas PGF2α did not affect LH pulsatility. On the other hand, co-injection of PGE2 and PGF2α induced a significant suppression of both the frequency and amplitude of LH pulses. These results suggest that PGE2 and PGF2α can represent two of the mediators that suppress the HPG axis in situations of infectious stress. Moreover, the results imply that there are two contradictory effects of PGE2 on LH pulsatility: (i) enhancive when working alone and (ii) suppressive when working together with PGF2α .


Association Analysis of FOXO3 Longevity Variants With Blood Pressure and Essential Hypertension.
The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)- rs2802292 , rs2253310 , and rs2802288 -are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). In a primary study involving Americans of Japanese ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set. Replication of rs2802292 with EHT was attempted in Japanese SONIC study subjects and of each SNP in a meta-analysis of genome-wide association studies of BP in individuals of European ancestry. In Americans of Japanese ancestry, women homozygous for the longevity-associated (minor) allele of each FOXO3 SNP had 6mm Hg lower systolic BP and 3mm Hg lower diastolic BP compared with major allele homozygotes (Bonferroni corrected P < 0.05 and >0.05, respectively). Frequencies of minor allele homozygotes were 3.3-3.9% in women with EHT compared with 9.5-9.6% in normotensive women ( P = 0.03-0.04; haplotype analysis P = 0.0002). No association with BP or EHT was evident in males. An association with EHT was seen for the minor allele of rs2802292 in the Japanese SONIC cohort ( P = 0.03), while in European subjects the minor allele of each SNP was associated with higher systolic and diastolic BP. Longevity-associated FOXO3 variants may be associated with lower BP and EHT in Japanese women.


Discovery of benzimidazole derivatives as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity.
Aldehyde dehydrogenase 1A1 (ALDH1A1) plays vital physiological and toxicological functions in many areas, such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of ALDH1A1 has been disclosed to play an important role in obesity, diabetes and other diseases, indicating the potential need for the identification and development of small molecule ALDH1A1 inhibitors. Herein, a series of benzimidazole derivatives was designed, synthesized and evaluated. Among them, compounds 21, 27, 29, 61 and 65 exhibited excellent inhibitory activity against ALDH1A1 with IC50 values in the low micromolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Moreover, an in vitro study demonstrated that all five compounds effectively improved glucose consumption in HepG2 cells, of which, 61 and 65 at 10 µM produced nearly equal glucose consumption with positive control Metformin (Met) at 1 mM. Furthermore, 61 and 65 showed desirable metabolic stability in human liver microsomes. All these results suggest that 61 and 65 are suitable for further studies.


Reduced mRNA expression of PTGDS in peripheral blood mononuclear cells of rapid-cycling bipolar disorder patients compared with healthy control subjects.
Disturbances related to the arachidonic acid cascade and prostaglandin metabolism may be involved in the pathophysiology of bipolar disorder, as supported by a recent genome-wide association study meta-analysis; however, evidence from clinical studies on a transcriptional level is lacking. Two enzymes in the arachidonic acid cascade are the prostaglandin D synthase (PTGDS), which catalyzes the conversion of prostaglandin H2 to prostaglandin D2 (PGD2), and the aldo-keto reductase family 1 member C3 (AKR1C3), which catalyzes the reduction of PGD2. We aimed to test the hypothesis that mRNA expression of PTGDS and AKR1C3 is deregulated in rapid-cycling disorder patients in a euthymic or current affective state compared with healthy control subjects, and that expression alters with affective states. PTGDS and AKR1C3 mRNA expression in peripheral blood mononuclear cells was measured in 37 rapid-cycling bipolar disorder patients and 40 age- and gender-matched healthy control subjects using reverse transcription quantitative real-time polymerase chain reaction. Repeated measurements of PTGDS and AKR1C3 mRNA expression were obtained in various affective states during 6-12 months and compared with repeated measurements in healthy control subjects. Adjusted for age and gender, PTGDS mRNA expression was down-regulated in rapid-cycling bipolar disorder patients in a euthymic, depressive, and manic/hypomanic state compared with healthy control subjects. No difference in PTGDS mRNA expression was observed between affective states. AKR1C3 mRNA expression did not differ between bipolar disorder patients in any affective state or in comparison with healthy control subjects. The results suggest a role for aberrantly-regulated PTGDS mRNA expression in rapid-cycling bipolar disorder. The sample size was limited; replication of the findings in larger, independent samples is warranted to further explore the role of the arachidonic acid cascade and prostaglandin metabolism as a potential therapeutic target in bipolar disorder.


Prognosis of patients with esophageal squamous cell carcinoma after esophagectomy using the log odds of positive lymph nodes.
To compare the log odds of positive lymph nodes (LODDS) with the number of positive lymph nodes (pN), lymph node ratio (LNR), removed lymph node (RLN) count, and negative lymph node (NLN) count in determining the prognosis of patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. The records of patients with ESCC who received esophagectomy were retrospectively reviewed. The log-rank test was used to compare curves for overall survival (OS), and Cox regression analysis was performed to identify prognostic factors. The prognostic performance of the different lymph node staging systems were compared using the linear trend chi-square test, likelihood ratio chi-square test, and Akaike information criterion. A total of 589 patients were enrolled. Univariate Cox analysis showed that pN stage, LNR, RLN count, NLN count, and the LODDS were significantly associated with OS (p < 0.05 for all). Multivariate Cox analysis adjusted for significant factors indicated that LODDS was independent risk factor on overall survival (OS), and a higher LODDS was associated with worse OS (hazard ratio = 3.297, 95% confidence interval: 2.684-4.050, p < 0.001). The modified Tumor-LODDS-Metastasis staging system had better discriminatory ability, monotonicity, and homogeneity, and better optimistic prognostic stratification than the Tumor-Node-Metastasis staging system in determining the prognosis of patients with ESCC. The LODDS staging system was superior to other lymph node classifications in determining the prognosis of patients with ESCC after esophagectomy. LODDS may be incorporated into esophageal staging system if these results are eventually confirmed by other studies.


Evidence from high-altitude acclimatization for an integrated cerebrovascular and ventilatory hypercapnic response but different responses to hypoxia.
Ventilation and cerebral blood flow (CBF) are both sensitive to hypoxia and hypercapnia. To compare chemosensitivity in these two systems, we made simultaneous measurements of ventilatory and cerebrovascular responses to hypoxia and hypercapnia in 35 normal human subjects before and after acclimatization to hypoxia. Ventilation and CBF were measured during stepwise changes in isocapnic hypoxia and iso-oxic hypercapnia. We used MRI to quantify actual cerebral perfusion. Measurements were repeated after 2 days of acclimatization to hypoxia at 3,800 m altitude (partial pressure of inspired O2 = 90 Torr) to compare plasticity in the chemosensitivity of these two systems. Potential effects of hypoxic and hypercapnic responses on acute mountain sickness (AMS) were assessed also. The pattern of CBF and ventilatory responses to hypercapnia were almost identical. CO2 responses were augmented to a similar degree in both systems by concomitant acute hypoxia or acclimatization to sustained hypoxia. Conversely, the pattern of CBF and ventilatory responses to hypoxia were markedly different. Ventilation showed the well-known increase with acute hypoxia and a progressive decline in absolute value over 25 min of sustained hypoxia. With acclimatization to hypoxia for 2 days, the absolute values of ventilation and O2 sensitivity increased. By contrast, O2 sensitivity of CBF or its absolute value did not change during sustained hypoxia for up to 2 days. The results suggest a common or integrated control mechanism for CBF and ventilation by CO2 but different mechanisms of O2 sensitivity and plasticity between the systems. Ventilatory and cerebrovascular responses were the same for all subjects irrespective of AMS symptoms. NEW & NOTEWORTHY Ventilatory and cerebrovascular hypercapnic response patterns show similar plasticity in CO2 sensitivity following hypoxic acclimatization, suggesting an integrated control mechanism. Conversely, ventilatory and cerebrovascular hypoxic responses differ. Ventilation initially increases but adapts with prolonged hypoxia (hypoxic ventilatory decline), and ventilatory sensitivity increases following acclimatization. In contrast, cerebral blood flow hypoxic sensitivity remains constant over a range of hypoxic stimuli, with no cerebrovascular acclimatization to sustained hypoxia, suggesting different mechanisms for O2 sensitivity in the two systems.


Determination of thermal diffusion coefficient in equimolar n-alkane mixtures: Empirical correlations.
In this article we determined the thermal diffusion coefficient (D(T)) in equimolar mixtures of n-alkanes nC(i)-nC(12) (i=5,6,7,8,9,17,18), nC(i)-nC(10) (i=5,6,7,15,16,17,18), and nC(i)-nC(6) (i=10,12,14,16,18) at 25 degrees C and at atmospheric pressure using the thermogravitational technique. The results obtained from this study together with the previously published ones in the series of nC(i)-nC(18) (i=5,6,7,8,9,10,11,12,13) show that the main parameter that determines D(T) in each series is in association with the molecular weights of the mixture's components. However, an empirical quantitative correlation has been obtained between D(T), the molecular weights of the components, the viscosity, and the thermal expansion coefficient of the mixtures. This is the first report of a closely accurate correlation for D(T) in liquid mixtures.


The Y-specific pDP31 rearrangement polymorphism in southern African populations.
The pDP31 rearrangement polymorphism was studied in 353 individuals encompassing the southern African Khoisan, Negroid and Caucasoid populations. The three alleles representing the ancestral (unrearranged) DNA configuration, the duplication, and the triplication were detected in most of the populations studied. The duplication occurred at higher frequencies in Caucasoid groups than in African populations, whilst the triplication was most common in Negroids. Populations of mixed ancestry exhibited allele frequencies closer to Caucasoids than to Negroids, in accordance with their historical origins.


Markers of Bone Metabolism in Patients With Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma.
There are no studies comparing some of the most important markers, such as vitamin D, parathormone, osteocalcin, bone alkaline phosphatase, and calcium, in patients with chronic benign and malignant pancreatic diseases. Our objective was to comparatively evaluate serum markers of bone metabolism in patients with chronic pancreatitis and in those with ductal pancreatic adenocarcinoma. Sixty-three consecutive subjects were studied: 30 patients with a firm diagnosis of chronic pancreatitis and 33 having histologically confirmed pancreatic adenocarcinoma. Serum 25-hydroxyvitamin D, bone alkaline phosphatase, osteocalcin, parathormone, and calcium were determined using commercially available kits. Taking into consideration the clinical variables of all 63 patients studied, 25-hydroxyvitamin D was inversely correlated with only the body mass index (P = 0.007), whereas it was not correlated with age (P = 0.583) or fecal elastase-1 concentrations (P = 0.556). Regarding the other substances studied, parathormone was positively correlated with only the age of the patients (P = 0.015). Of the 5 substances studied, only bone alkaline phosphates were significantly different (P < 0.001) between patients with chronic pancreatitis and those with pancreatic ductal adenocarcinoma. Within the 2 groups of patients, the 23 patients with chronic pancreatitis without diabetes mellitus had serum concentrations of 25-hydroxyvitamin D significantly lower (P = 0.045) than those with chronic pancreatitis having diabetes mellitus, whereas smokers with pancreatic ductal adenocarcinoma had serum concentrations of calcium significantly higher (P < 0.001) as compared to nonsmokers. Altered bone metabolism seems to be associated with chronic diseases of the pancreas; however, the mechanism should be better elucidated.


Prognosis of high-grade endometrial cancer: a comparison of serous-type and clear cell type to grade 3 endometrioid-type.
To evaluate prognosis of high-grade endometrial cancers, comparing serous (SC) and clear cell (CCC) types to grade 3 endometrioid carcinoma (ECG3). Among patients with endometrial cancer treated in two decades, medical records of patients with high-grade endometrial cancer were retrospectively investigated. Of 447 endometrial cancers, 107 (24%) high-grade endometrial cancers were identified, with the increasing incidence in the last decade (28% vs 19%; p = 0.026). There were 24 SC, 14 CCC and 69 ECG3. Median age was 62, 68, and 61 years, respectively, with the CCC type showing an elder age than the ECG3 type (p = 0.012). The rates of patients with Stage IIIc-IV, lymph node assessment or complete resection at primary surgery, and post-operative chemotherapy were not significantly different; however, response rate to first-line chemotherapy in patients with measurable disease was lower in SC than ECG3 (3 / 11, 27% vs 14 / 19, 74%; p = 0.037), regardless of regimens. Five-year overall survival (OS) was 40%, 71%, and 71% respectively, and five-year progression-free survival (PFS) was 25%, 71%, and 61%, respectively, showing SC with worse prognosis than ECG3 on both OS (p = 0.026) and PFS (p = 0.0028). According to the multivariate analysis, age > or = 70, Stage IIIc-IV and incomplete resection were independent prognostic factors on poor OS, whereas SC, Stage IIIc-IV and incomplete resection were on poor PFS. The increasing trend of high-grade endometrial cancer and different outcomes according to histological subtypes, especially poor PFS and chemotherapeutic response in SC, were suggested.


Fine needle aspiration cytology of pilomatrixoma (calcifying epithelioma of Malherbe). Report of a case.
A case of a facial pilomatrixoma (calcifying epithelioma of Malherbe) in a child initially diagnosed following fine needle aspiration is presented. On cytologic examination, basaloid cells, multinucleated giant cells and deposits of calcium were identified. Adjacent to the basaloid cells were acellular masses suggestive of, but not diagnostic of, ghost cells. The diagnosis was confirmed by histology.


Compliance, counseling and satisfaction with oral contraceptives: a prospective evaluation.
Oral contraceptive users' risk of accidental pregnancy may be higher than it should be, because of inconsistent pill-taking. However, few reliable data are available on pill users' everyday experiences with their method, especially characteristics that may affect consistency of use. Two months after initiating or resuming oral contraceptive use, a nationwide sample of 943 women completed questionnaires examining their compliance with instructions for proper use, the quality of their interactions with their provider, their satisfaction with the method, and the frequency and costs of visits or calls to their providers because of pill-related side effects. Regression analyses were used to determine the factors associated with compliance difficulties and method dissatisfaction. In all, 47% of users missed one or more pills per cycle, and 22% missed two or more. Women who lacked an established pill-taking routine, who did not read and understand all of the informational material accompanying the pill package, or who experienced spotting or heavy bleeding had increased odds of missing two or more pills per cycle. Method satisfaction was most likely among women who were aware of the pill's noncontraceptive benefits, were satisfied with their relationship with their provider, had used the pill in the past and experienced few side effects. Some 22% of users called their provider at least once about pill-related side effects, and 9% made at least one visit for this reason; these women spent $25 and $62, respectively, to treat side effects. Improving pill use is a shared responsibility of the provider, the patient and, to a lesser degree, pill manufacturers. Awareness of potential difficulties such as inadequate counseling is a key step in helping women use oral contraceptives effectively.


Lugol staining and histological evaluation of esophageal mucosa in achalasia.
Esophageal cancer in achalasia is often diagnosed in the advanced stage, which makes for a poor prognosis. Therefore, the aim of this study was to evaluate the macroscopic and histological features of the esophageal mucosa in order to improve the early detection of cancer. We studied the macroscopic features of esophageal mucosa using Lugol's solution and compared them with histological analysis of the entire mucosa in 20 esophagectomy specimens resected for achalasia. Intraepithelial neoplasia, when detected, was selected for DNA ploidy analysis through static cytometry. Macroscopically, the mucosa showed opacification and/or diffuse irregularities in 19 specimens. Advanced squamous cell carcinoma was diagnosed in 2 cases. Using Lugol, the esophageal mucosa acquired irregular brownish color. Clear unstained areas were circumscribed in 5 esophagi. They were macroscopically defined as ulcer, neoplasia (2 cases) and mucosal irregularities (2 cases). The histological analysis showed ulcer, squamous cell carcinoma (2 cases), Barrett's esophagus and esophagitis, respectively. The histological study of the stained mucosa revealed minute foci of DNA aneuploid intraepithelial neoplasia in 4 cases. Macroscopic examination using Lugol failed to identify minute foci of early carcinoma. The stained mucosa does not exclude the esophageal cancer risk in achalasia.


Native Mass Spectrometry in Fragment-Based Drug Discovery.
The advent of native mass spectrometry (MS) in 1990 led to the development of new mass spectrometry instrumentation and methodologies for the analysis of noncovalent protein-ligand complexes. Native MS has matured to become a fast, simple, highly sensitive and automatable technique with well-established utility for fragment-based drug discovery (FBDD). Native MS has the capability to directly detect weak ligand binding to proteins, to determine stoichiometry, relative or absolute binding affinities and specificities. Native MS can be used to delineate ligand-binding sites, to elucidate mechanisms of cooperativity and to study the thermodynamics of binding. This review highlights key attributes of native MS for FBDD campaigns.


Optimum use of biologics and role of maintenance therapy in colon cancer.
The current standard of care for the treatment of metastatic colorectal cancer involves at least six different regimens, and with the advent of new therapies, including biologic therapies, patients are projected to live beyond an average of 2 years. Data suggest a synergy between the biologics, which are in their infancy in terms of utilization, and they are being tested in the adjuvant setting in stage II and stage III disease. Ongoing and future trials will determine how best to incorporate these medicines into combination chemotherapy and determine if these medicines (or others) will have a role in maintenance chemotherapy for patients with metastatic colon cancer. However, the concept of incorporating maintenance therapy for colon cancer is clearly not established. Maintenance therapy has a requirement for less toxicity than current front-line therapies, and over the coming years, new agents will become available that maintain response and improve quality of life. Clinical trials involving novel agents as maintenance therapy are needed.


The Obsessive-Compulsive Cocaine Scale (OCCS): a pilot study of a new questionnaire for assessing cocaine craving.
This study aimed to develop a scale (Obsessive-Compulsive Cocaine Scale [OCCS]) for measuring cocaine craving based on the Obsessive Compulsive Drinking Scale (OCDS). We tested the scale on 116 French-speaking cocaine users. The scale was reliable (Cronbach's α= 0.93). It was significantly correlated with a visual analogue scale of craving (r = 0.641, p < .001) and discriminated between cocaine-dependant subjects (score 36 ± 11) and abusers (score 17 ± 9, p < .001). Prospective tests on a sample of 20 subjects showed that the OCCS score changed over 3 weeks of treatment and was significantly correlated with the visual analogue scale of craving (r = 0.492, p = .038). Principal component analysis identified three factors: resistance, intensity, and interference. The OCCS questionnaire could be used to repeatedly assess cocaine craving in prospective studies in cocaine addicts. (Am J Addict 2012;00:1-7).


[Experience with Health Quality of Life Questionnaire for the epileptic child (CAVE)].
The practical application of a questionnaire designed to evaluate the quality of life of an epileptic child, known as the CAVE test, is described. This is the first scale of its kind. The test consists of 8 parameters: conduct, attendance at school, learning, independence, social relationships, frequency of crises, intensity of crises and parental opinion. Each aspect is given a score, from a minimum of 1 point to a maximum of 5 points. A total of 203 tests were carried out. 179 of these were considered to be useful. Nine Spanish neuropediatric departments took part in this study. The age limits were from 0 to 14 years old. The best results showed a direct relationship to the children's age, idiopathic etiology and monotherapy as treatment. The quality of life worsened from those with partial simple crises to those with typical absences and generalized tonic-clonic crises. The lowest scores were found in children with infantile spasms and in those with Lennox-Gastaut syndrome. There was a clear statistical relationship between the highest score obtained and the best clinical condition, with regard to the frequency and intensity of crises. Parental opinion was in keeping with the clinical evaluation of the disorder to a certain extent. The study is still in progress, so as to interview 1000 children altogether. Then any modifications considered advisable will be made by the multicentre group of the Sociedad Española de Neurología Pediátrica, and may be validated internationally.


Screening of exogenous enzymes for ruminant diets: relationship between biochemical characteristics and in vitro ruminal degradation.
With the objective of developing a rational approach for the selection of feed enzymes for ruminants, 22 commercial enzyme products were examined in terms of protein concentration, enzymic activities on model substrates, and hydrolytic capacity, the latter determined from the release of reducing sugars from alfalfa hay and corn silage. An in vitro ruminal degradation assessment was carried out using the same substrates, untreated or treated with the 22 enzyme products at 1.5 microL/g forage DM. Stepwise regressions were then performed to establish relationships between these factors. Protein concentration and enzymic activities explained at least 84% (P < 0.01) of the variation in the release of reducing sugars from alfalfa and corn silage. Alfalfa DM degradation after incubation with ruminal fluid for 18 h was positively related to xylanase activity (R2 = 0.29, P < 0.01), but the same activity was negatively related to DM degradation of corn silage (R2 = 0.19, P < 0.05). Protease activity explained a further 10% of the alfalfa DM degradation (P < 0.10). Following sequential steps involving the determination of rate and extent of DM and fiber degradation, the best candidates for alfalfa and corn silage were selected. Enzyme products effective with alfalfa hay seemed to exert part of their effect during the pretreatment period, whereas enzymes effective with corn silage worked exclusively after ruminal fluid was added. This finding suggests that different modes of action of exogenous enzymes are attacking different substrates and may partly explain enzyme-feed specificity. In alfalfa, it seems that effective enzymes work by removing structural barriers that retard the microbial colonization of digestible fractions, increasing the rate of degradation. In corn silage, effective enzymes seem to interact with ruminal enzymes to degrade the forage more rapidly, which is consistent with previous findings of synergism between exogenous and ruminal enzymes.


Magnetic iron oxide nanoparticles for tumor-targeted therapy.
Magnetic nanoparticles have been intensively investigated due to their magnetic characteristics, quantum dot effects, as well as their potential applications in the area of bioscience and medicine. Very promising nanoparticles are magnetic iron oxide nanoparticles with appropriate surface modification which have been widely used experimentally for masses of in vivo applications such as magnetic resonance imaging contrast enhancement, drug delivery, and hyperthermia, etc.. All these biomedical applications require that these nanoparticles have effective magnetic values and suitable sizes. On the other hand, these applications need special surface modification of these particles, which not only have to be non-toxic and biocompatible, but also allow a targetable drug delivery in a specific area. This review summarizes the current research situation and development of magnetic iron oxide nanoparticles, and the biomedical applications ranging from drug delivery to hyperthermia for tumor-targeted therapy.


Mortality in spinal cord injuries. Follow-up report.
The principal cause among 137 deaths in a series of 1,613 patients with traumatic spinal cord lesions treated at Veterans Administration Hospital, Long Beach, was renal disease attributable to the paralysis of the bladder and bladder sphincter and resultant genito-urinary tract infections. The second ranking cause was pulmonary disease. Before 1960 no deaths from cancer had occurred in this series, but between 1960 and 1962 three patients died of carcinoma of the bladder. It can be expected that as these patients reach higher age groups the incidence of neoplasms will increase.


Some (mostly Scottish) local anaesthetic heroes.
In 1884 a young Viennese doctor, Carl Koller, was the first to recognise the significance of the topical effects of the alkaloid cocaine and thus introduced drug-induced local anaesthesia to clinical practice. Most subsequent development took place in Europe and the United States, with British interest not becoming apparent for over twenty years. This is surprising because a number of doctors working in Scotland, or with Scottish connections, had made important contributions to the earlier evolution of local anaesthetic techniques. This paper reviews the relevant work of James Young Simpson, Alexander Wood, James Arnott, Benjamin Ward Richardson and Alexander Hughes Bennett and the role of John William Struthers in the later promotion of the techniques.


Primary bladder amyloidosis.
Primary localised bladder amyloidosis is a very rare entity, with only 200 cases reported worldwide. Our case illustrates the classical presentation of isolated bladder amyloidosis with frank painless haematuria and irritative voiding symptoms.


New evidence of shared dinosaur across Upper Jurassic Proto-North Atlantic: Stegosaurus from Portugal.
More than one century after its original description by Marsh in 1877, we report in this paper the first uncontroversial evidence of a member of the genus Stegosaurus out of North America. The specimen consists of a partial skeleton from the Upper Jurassic of Portugal, herein considered as Stegosaurus cf. ungulatus. The presence of this plated dinosaur in the upper Kimmeridgian-lower Tithonian Portuguese record and synchronic levels of the Morrison Formation of North America reinforces previous hypothesis of a close relationship between these two areas during the Late Jurassic. This relationship is also supported by geotectonic evidences indicating high probability of an episodic corridor between the Newfoundland and Iberian landmasses. Together, Portuguese Stegosaurus discovery and geotectonic inferences could provide a scenario with episodical faunal contact among North Atlantic landmasses during the uppermost Kimmeridgian-lowermost Tithonian (ca. 148-153 Ma ago).


Multiscale Fuzzy C-Means Image Classification for Multiple Weighted MR Images for the Assessment of Photodynamic Therapy in Mice.
We are investigating in vivo small animal imaging and analysis methods for the assessment of photodynamic therapy (PDT), an emerging therapeutic modality for cancer treatment. Multiple weighted MR images were acquired from tumor-bearing mice pre- and post-PDT and 24-hour after PDT. We developed an automatic image classification method to differentiate live, necrotic and intermediate tissues within the treated tumor on the MR images. We used a multiscale diffusion filter to process the MR images before classification. A multiscale fuzzy C-means (FCM) classification method was applied along the scales. The object function of the standard FCM was modified to allow multiscale classification processing where the result from a coarse scale is used to supervise the classification in the next scale. The multiscale fuzzy C-means (MFCM) method takes noise levels and partial volume effects into the classification processing. The method was validated by simulated MR images with various noise levels. For simulated data, the classification method achieved 96.0 ± 1.1% overlap ratio. For real mouse MR images, the classification results of the treated tumors were validated by histologic images. The overlap ratios were 85.6 ± 5.1%, 82.4 ± 7.8% and 80.5 ± 10.2% for the live, necrotic, and intermediate tissues, respectively. The MR imaging and the MFCM classification methods may provide a useful tool for the assessment of the tumor response to photodynamic therapy in vivo.


Complementarity in marine biodiversity manipulations: reconciling divergent evidence from field and mesocosm experiments.
Mounting concern over the loss of marine biodiversity has increased the urgency of understanding its consequences. This urgency spurred the publication of many short-term studies, which often report weak effects of diversity (species richness) driven by the presence of key species (the sampling effect). Longer-term field experiments are slowly accumulating, and they more often report strong diversity effects driven by species complementarity, calling into question the generality of earlier findings. However, differences among study systems in which short- and long-term studies are conducted currently limit our ability to assess whether these differences are simply due to biological or environmental differences among systems. In this paper, we compared the effect of intertidal seaweed species richness on biomass accumulation in mesocosms and field experiments using the same pool of species. We found that seaweed species richness increased biomass accumulation in field experiments in both short (2-month) and long (3-year) experiments, although effects were stronger in the long-term experiment. In contrast, richness had no effect in mesocosm experiments, where biomass accumulation was completely a function of species identity. We argue that the short-term experiments, like many published experiments on the topic, detect only a subset of possible mechanisms that operate in the field over the longer term because they lack sufficient environmental heterogeneity to allow expression of niche differences, and they are of insufficient length to capture population-level responses, such as recruitment. Many published experiments, therefore, likely underestimate the strength of diversity on ecosystem processes in natural ecosystems.


Anomalies of the wolffian duct derivatives encountered at radical prostatectomy.
Abnormalities of wolffian duct derivatives are usually encountered in young subjects. We identified 4 instances of embryologic malformations of these structures in patients who underwent radical prostatectomy (RP). The first patient had unilateral renal agenesis and a seminal vesicle cyst identified preoperatively by computed tomography. The seminal vesicle cyst was removed during RP. The second patient had renal agenesis and an ectopic ureter entering the right seminal vesicle. These were treated with ureterectomy during RP. The third patient had unilateral duplication of the vas deferens of no clinical consequence. Finally, the fourth patient had left-sided absence of both the vas deferens and seminal vesicle. The anatomy of the lower pelvis is most accurately shown on magnetic resonance imaging. Lower urinary tract malformations are an uncommon occurrence in males. Surgeons who perform numerous RPs will, however, find additional urologic pathologies during RP that may require consideration and tailored management.


Cytokine regulation by platelet-activating factor in a human B cell line.
TNF-alpha is an inflammatory cytokine produced by B cells that also impacts B cell differentiation and Ig secretion. We have investigated the regulation of the TNF-alpha gene in a human B cell line in response to platelet-activating factor (PAF), a potent phospholipid often produced in inflammatory reactions. We report here that PAF increases the RNA levels for the TNF-alpha gene in the human B cell line Ramos. This is mediated by an increase in the transcription rate and a longer half-life of the TNF-alpha transcripts. Induction of the TNF-alpha gene is rapid in these cells and independent of new protein synthesis. Despite increasing RNA for the TNF-alpha gene, PAF increases TNF-alpha protein levels only in the presence of a costimulus, such as PMA. We hypothesize that PAF acts at the transcriptional level to increase TNF-alpha RNA, but a post-transcriptional block acts to regulate protein production. We also report that PAF enhances PMA-induced TNF-alpha production from human peripheral B cells. This increase is maximal at 0.1 microM PAF and is blocked by PAF receptor antagonists. The ability of PAF to modulate cytokine production from human B cells provides further evidence that PAF has a role in B cell biology and suggests it may be important in conditions involving B cell-derived cytokines.


Seeking Safety Pilot Outcome Study at Walter Reed National Military Medical Center.
Post-traumatic stress disorder (PTSD) and substance use disorder are two of the most prominent psychiatric disorders among military service members. Seeking Safety (SS) is an evidence-based behavioral therapy model for this comorbidity. This article reports results of a study of SS conducted in a military setting. Our pilot trial addressed outcomes, feasibility, and satisfaction. SS was conducted as is to evaluate its impact without adaptation for military culture. The sample was 24 outpatient service members (from the Army, Navy, Air Force, and Marines) with 33% minority representation. Inclusion criteria were current PTSD and/or SUD. Ten clinicians participated in this study after receiving SS training. Results showed significant improvements on most outcomes, including substance use on the Brief Addiction Monitor; PTSD symptoms on the PTSD Checklist-Military Version (total and criterion D); and the Trauma Symptom Checklist-40 (sexual abuse trauma index and anxiety subscale); functioning on the Sheehan Disability Scale (total and family subscale); psychopathology on the Zung Depression Scale total; the Behavior and Symptom Identification Scale (BASIS)-24 (total and subscales depression functioning, emotional liability, and psychosis); and the Brief Symptom Inventory-18 (total and anxiety subscale); and coping on the Coping Self-Efficacy Scale (total). Satisfaction was strong. Discussion includes methodology limitations and next steps.