Endothelial cells direct human mesenchymal stem cells for osteo- and chondro-lineage differentiation through endothelin-1 and AKT signaling.
Human mesenchymal stem cells (hMSCs) reside in a perivascular niche of the body, suggesting that they interact closely with vascular endothelial cells (ECs) through cell-cell interaction or paracrine signaling to maintain cell functions. Endothelin-1 (ET1) is a paracrine factor mainly secreted by ECs. We thus hypothesize that ECs can regulate cellular activities of hMSCs and direct their stem cell fate. We investigated whether co-cultured human aortic endothelial cells (HAECs) were able to regulate expression of potency- and lineage-related markers in bone marrow-derived hMSCs. We further explored the regulatory effects of ET1 on cell proliferation, expression of surface antigens and pluripotency-related markers, and multilineage differentiation in hMSCs. Activation of the AKT signaling pathway in hMSCs was also analyzed to identify its mechanistic role in the ET1-induced regulation. Co-cultured HAECs enhanced expression of mesenchymal lineage-related markers in hMSCs. Treatment of ET receptor antagonist downregulated the increased expression of CBFA1 in hMSCs cultured with HAEC-conditioned medium. hMSCs treated with ET1 showed cell proliferation and expression of surface antigens, CD73, CD90, and CD105, comparable with those without ET1 treatment. ET1-treated hMSCs also expressed upregulated mRNA transcript levels of OCT3/4, NANOG, CBFA1 and SOX9. When induced for lineage-specific differentiation, hMSCs pre-treated with ET1 showed enhanced osteogenesis and chondrogenesis. However, adipogenic differentiation of hMSCs was not affected by ET1 pretreatment. We further showed that the ET1-induced regulation was mediated by activation of AKT signaling. Our results demonstrate that ET1 secreted by HAECs can direct bone marrow-derived hMSCs for osteo- and chondro-lineage differentiation through activation of the AKT signaling pathway, suggesting that ET1 plays a crucial role in regulation of hMSC activity. Our findings may help understand how hMSCs interact with ECs in a perivascular niche.


Exploiting antidiabetic activity of silver nanoparticles synthesized using Punica granatum leaves and anticancer potential against human liver cancer cells (HepG2).
This study first time reports the novel synthesis of silver nanoparticles (AgNPs) using a Punica granatum leaf extract (PGE). The synthesized AgNPs were characterized by various analytical techniques including UV-Vis, Fourier transform infrared (FTIR), X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS), field emission scanning electron microscopy and energy-dispersive spectra (FESEM-EDS) and high-resolution transmission electron microscopy (HRTEM). FTIR analysis revealed that the involvement of biological macromolecules of P. granatum leaf extract were distributed and involved in the synthesis and stabilization of AgNPs. A surface-sensitive technique of XPS was used to analyse the composition and oxidation state of synthesized AgNPs. The analytical results confirmed that the AgNPs were crystalline in nature with spherical shape. The zeta potential study revealed that the surface charge of synthesized AgNPs was highly negative (-26.6 mV) and particle size distribution was ranging from ∼35 to 60 nm and the average particle size was about 48 nm determined by dynamic light scattering (DLS). The PGE-AgNPs antidiabetic potential exhibited effective inhibition against α-amylase and α-glucosidase (IC50; 65.2 and 53.8 μg/mL, respectively). The PGE-AgNPs showed a dose-dependent response against human liver cancer cells (HepG2) (IC50; 70 μg/mL) indicating its greater efficacy in killing cancer cells. They also possessed in vitro free radical-scavenging activity in terms of ABTS (IC50; 52.2 μg/mL) and DPPH (IC50; 67.1 μg/mL) antioxidant activity. PGE-AgNPs displayed strong antibacterial activity and potent synergy with standard antibiotics against pathogenic bacteria. Thus, synthesized PGE-AgNPs show potential biomedical and industrial applications.


Defect solitons in parity-time periodic potentials.
In this article, properties of solitons in a parity-time periodical lattices with a single-sited defect are investigated. Both of the negative and positive defects are considered. Linear stability analyses show that, when the defect is positive, in the semi-infinite gap, the solitons are always stable, while in the first gap, the solitons are unstable in most of their existence region except for those near the edge of the second band; when the defect is negative, in the semi-infinite gap, other than those near the edge of the first band, most solitons are stable, but in the first gap, all solitons are unstable. Such stability analyses are corroborated by numerical simulations.


The 2014 International Pressure Ulcer Guideline: methods and development.
A discussion of the methodology used to develop the Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline. (2014). International experts representing National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance developed the second edition of this clinical guideline. Discussion paper - methodology. A comprehensive search for papers published up to July 2013 was conducted in 11 databases and identified 4286 studies. After critical appraisal, 356 studies were included and assigned a level of evidence. Guideline recommendations provide guidance on best practice in pressure ulcer prevention and treatment. Understanding the development process of a guideline increases the meaningfulness of recommendations to clinicians. Five hundred and seventy five recommendations arose from the research and its interpretation. The body of evidence supporting each recommendation was assigned a strength of evidence. A strength of recommendation was assigned to recommendation statements using the GRADE system. Recommendations are primarily supported by a body of evidence rated as C (87% of recommendations), representing low quality and/or indirect evidence (30%) and expert opinion (57%). Two hundred and forty seven recommendations (43%) received a strong recommendation ('Do it'). Recommendations were developed with consideration to research of the highest methodological quality evidence and studies that add to clinical insight and provide guidance for areas of care where minimal research has been conducted. Recommendations in the guideline reflect best practice and should be implemented with consideration to local context and resources and the individual's preferences and needs.


Surgical management of an optic nerve glioma with perineural arachnoidal gliomatosis growth pattern.
We describe a vision sparing surgical approach for optic nerve glioma. A 7-year-old girl experienced declining academic performance and social withdrawal attributed to progressive disfiguring proptosis. Three years earlier, she had undergone a limited biopsy, a course of chemotherapy, and orbital radiation therapy for a right optic nerve glioma with perineural arachnoidal gliomatosis (PAG). Because of marked proptosis, another surgery was performed via a lateral orbitotomy. After cutting a window in the thickened dura of the optic nerve, rouge colored spongy tissue was suctioned from the subarachnoid space. Small, more solidified areas were excised with unipolar cautery. Care was taken to avoid identifiable blood vessels and the optic nerve, and approximately 60%-70% of the tumor was removed. The dural window was approximated with interrupted sutures. Postoperatively, there was 9 mm reduction in right proptosis and visual acuity improved to from 20/70 to 20/60. This case illustrates the possibility of debulking optic nerve gliomas without sacrificing vision. It should be stressed that this technique is only applicable to gliomas with PAG and the durability of the surgical benefit is unknown.


Effect of a Single Injection of Benidipine-Impregnated Biodegradable Microcarriers on Bone and Gingival Healing at the Tooth Extraction Socket.
Objective: A dihydropyridine-type calcium channel blocker, benidipine (BD), is extensively used in hypertension therapy. In vitro study reported BD promoting bone metabolism. We evaluated the effect of sustained release of BD-loaded poly(lactic-co-glycolic acid) (PLGA) microcarriers on the promotion of bone and gingival healing at an extraction socket in vivo. In addition, the effect of BD on osteoblasts, osteocytes, fibroblasts, and epithelial cells was evaluated in vitro. Approach: The maxillary first molar of rats was extracted. Next, PLGA microcarriers containing BD were directly injected into the gingivobuccal fold as a single dose. After injection, bone and soft-tissue healing was histologically evaluated. Effect of BD on proliferation, migration, and gene expression of gingival and bone cell was also examined in vitro. Results: After tooth extraction, BD significantly augmented bone volume and density, and also epithelial wound healing. During in vitro studies, BD promoted significant proliferation and migration of fibroblasts and epithelial cells. Real-time RT-PCR revealed that BD upregulated messenger RNA expression of Ahsg (alpha 2-HS glycoprotein) and Csf2 (colony-stimulating factor 2) in osteoblasts. Innovation: The prevention of bone and soft-tissue reduction associated with tooth extraction has been eagerly anticipated in the field of dentistry. This study first reported the effect of BD on extraction socket healing. Conclusion: A single dose of topically administered BD-loaded PLGA microcarriers promoted bone and soft-tissue healing at the extraction site of tooth.


Designing multiplane computer-generated holograms with consideration of the pixel shape and the illumination wave.
The majority of image-generating computer-generated holograms (CGHs) are calculated on a discrete numerical grid, whose spacing is defined by the desired pixel size. For single-plane CGHs the influence of the pixel shape and the illumination wave on the actual output distribution is minor and can be treated separately from the numerical calculation. We show that in the case of multiplane CGHs this influence is much more severe. We introduce a new method that takes the pixel shape into account during the design and derive conditions to retain an illumination-wave-independent behavior.


ERPs recorded during early second language exposure predict syntactic learning.
Millions of adults worldwide are faced with the task of learning a second language (L2). Understanding the neural mechanisms that support this learning process is an important area of scientific inquiry. However, most previous studies on the neural mechanisms underlying L2 acquisition have focused on characterizing the results of learning, relying upon end-state outcome measures in which learning is assessed after it has occurred, rather than on the learning process itself. In this study, we adopted a novel and more direct approach to investigate neural mechanisms engaged during L2 learning, in which we recorded ERPs from beginning adult learners as they were exposed to an unfamiliar L2 for the first time. Learners' proficiency in the L2 was then assessed behaviorally using a grammaticality judgment task, and ERP data acquired during initial L2 exposure were sorted as a function of performance on this task. High-proficiency learners showed a larger N100 effect to open-class content words compared with closed-class function words, whereas low-proficiency learners did not show a significant N100 difference between open- and closed-class words. In contrast, amplitude of the N400 word category effect correlated with learners' L2 comprehension, rather than predicting syntactic learning. Taken together, these results indicate that learners who spontaneously direct greater attention to open- rather than closed-class words when processing L2 input show better syntactic learning, suggesting a link between selective attention to open-class content words and acquisition of basic morphosyntactic rules. These findings highlight the importance of selective attention mechanisms for L2 acquisition.


Valuing and understanding fish populations in the Anthropocene: key questions to address.
Research on the values of fish populations and fisheries has primarily focused on bio-economic aspects; a more nuanced and multidimensional perspective is mostly neglected. Although a range of social aspects is increasingly being considered in fisheries research, there is still no clear understanding as to how to include these additional values within management policies nor is there a cogent appreciation of the major knowledge gaps that should be tackled by future research. This paper results from a workshop held during the 50th anniversary symposium of the Fisheries Society of the British Isles at the University of Exeter, UK, in July 2017. Here, we aim to highlight the current knowledge gaps on the values of fish populations and fisheries thus directing future research. To this end, we present eight questions that are deeply relevant to understanding the values of fish populations and fisheries. These can be applied to all habitats and fisheries, including freshwater, estuarine and marine.


Global profiling of protein lipidation using chemical proteomic technologies.
Protein lipidation is unique amongst post-translational modifications (PTMs) in enabling direct interaction with cell membranes, and is found in every form of life. Lipidation is important in normal function and in disease, but its intricate interplay with disease context presents a challenging for drug development. Global whole-proteome profiling of protein lipidation lies beyond the range of standard methods, but is well-suited to metabolic tagging with small 'clickable' chemical reporters that do not disrupt metabolism and function; chemoselective reactions are then used to add multifunctional labels exclusively to tagged-lipidated proteins. This chemical proteomic technology has opened up the first quantitative whole-proteome studies of the known major classes of protein lipidation, and the first insights into their full scope in vivo.


Clinical significance of phosphatidyl inositol synthase overexpression in oral cancer.
We reported increased levels of phosphatidyl inositol synthase (PI synthase), (enzyme that catalyses phosphatidyl inositol (PI) synthesis-implicated in intracellular signaling and regulation of cell growth) in smokeless tobacco (ST) exposed oral cell cultures by differential display. This study determined the clinical significance of PI synthase overexpression in oral squamous cell carcinoma (OSCC) and premalignant lesions (leukoplakia), and identified the downstream signaling proteins in PI synthase pathway that are perturbed by smokeless tobacco (ST) exposure. Tissue microarray (TMA) Immunohistochemistry, Western blotting, Confocal laser scan microscopy, RT-PCR were performed to define the expression of PI synthase in clinical samples and in oral cell culture systems. Significant increase in PI synthase immunoreactivity was observed in premalignant lesions and OSCCs as compared to oral normal tissues (p = 0.000). Further, PI synthase expression was significantly associated with de-differentiation of OSCCs, (p = 0.005) and tobacco consumption (p = 0.03, OR = 9.0). Exposure of oral cell systems to smokeless tobacco (ST) in vitro confirmed increase in PI synthase, Phosphatidylinositol 3-kinase (PI3K) and cyclin D1 levels. Collectively, increased PI synthase expression was found to be an early event in oral cancer and a target for smokeless tobacco.


Regulation of influenza A virus mRNA splicing by CLK1.
Influenza A virus carries eight negative single-stranded RNAs and uses spliced mRNAs to increase the number of proteins produced from them. Several genome-wide screens for essential host factors for influenza A virus replication revealed a necessity for splicing and splicing-related factors, including Cdc-like kinase 1 (CLK1). This CLK family kinase plays a role in alternative splicing regulation through phosphorylation of serine-arginine rich (SR) proteins. To examine the influence that modulation of splicing regulation has on influenza infection, we analyzed the effect of CLK1 knockdown and inhibition. CLK1 knockdown in A549 cells reduced influenza A/WSN/33 virus replication and increased the level of splicing of segment 7, which encodes the viral M1 and M2 proteins. CLK1-/- mice infected with influenza A/England/195/2009 (H1N1pdm09) virus supported lower levels of virus replication than wild-type mice. Screening of newly developed CLK inhibitors revealed several compounds that have an effect on the level of splicing of influenza A gene segment M in different models and decrease influenza A/WSN/33 virus replication in A549 cells. The promising inhibitor KH-CB19, an indole-based enaminonitrile with unique binding mode for CLK1, and its even more selective analogue NIH39 showed high specificity towards CLK1 and had a similar effect on influenza mRNA splicing regulation. Taken together, our findings indicate that targeting host factors that regulate splicing of influenza mRNAs may represent a novel therapeutic approach.


Identifying evidence-practice gaps and strategies for improvement in Aboriginal and Torres Strait Islander maternal health care.
Adverse pregnancy outcomes are more common among Aboriginal and Torres Strait Islander populations than non-Indigenous populations in Australia. Later in life, most of the difference in life expectancy between Aboriginal and Torres Strait Islander women and non-Indigenous women is due to non-communicable diseases (NCDs). Most Aboriginal and Torres Strait Islander women attend health services regularly during pregnancy. Providing high-quality care within these appointments has an important role to play in improving the current and future health of women and babies. This study engaged stakeholders in a theory-informed process to use aggregated continuous quality improvement (CQI) data to identify 1) priority evidence-practice gaps in Aboriginal and Torres Strait Islander maternal health care, 2) barriers and enablers to high-quality care, and 3) strategies to address identified priorities. Three phases of reporting and feedback were implemented using de-identified CQI data from 91 health services between 2007 and 2014 (4,402 client records). Stakeholders (n = 172) from a range of professions and organisations participated. Stakeholders identified four priority areas relating to NCDs: smoking, alcohol, psychosocial wellbeing and nutrition. Barriers or enablers to high-quality care included workforce support, professional development, teamwork, woman-centred care, decision support, equipment and community engagement. Strategies to address the priorities included upskilling staff to provide best practice care in priority areas, advocating for availability of healthy food, housing and local referral options, partnering with communities on health promotion projects, systems to facilitate continuity of care and clear referral pathways. This novel use of large-scale aggregate CQI data facilitated stakeholder input on priority evidence-practice gaps in maternal health care in Australia. Evidence-practice gaps relating to NCD risk factors and social determinants of health were prioritised, and stakeholders suggested both healthcare-focussed initiatives and approaches involving the community and the wider health sector. The findings can inform health service planning, advocacy, inter-agency strategies, and future research.


Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.
We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential.


Localization of the xeroderma pigmentosum group B-correcting gene ERCC3 to human chromosome 2q21.
The human excision-repair gene ERCC3 was cloned after DNA-mediated gene transfer to the uv-sensitive Chinese hamster ovary mutant cell line 27-1, a member of complementation group 3 of the excision-defective rodent cell lines. The ERCC3 gene specifically corrects the DNA repair defect of xeroderma pigmentosum (XP) complementation group B, which displays the clinical symptoms of XP as well as of another rare excision-repair disorder, Cockayne syndrome. The gene encodes a presumed DNA and chromatin binding helicase, involved in early steps of the excision-repair pathway. ERCC3 was previously assigned to human chromosome 2 (L.H. Thompson, A.V. Carrano, K. Sato, E.P. Salazar, B.F. White, S.A. Stewart, J.L. Minkler, and M.J. Siciliano (1987) Somat. Cell Genet. 13: 539-551). Here we report its subchromosomal localization in the q21 region of chromosome 2 via somatic cell hybrids containing a translocated chromosome 2 and in situ hybridization with fluorescently labeled ERCC3 probes.


Coordinate control of muscle cell survival by distinct insulin-like growth factor activated signaling pathways.
Peptide growth factors control diverse cellular functions by regulating distinct signal transduction pathways. In cultured myoblasts, insulin-like growth factors (IGFs) stimulate differentiation and promote hypertrophy. IGFs also maintain muscle cell viability. We previously described C2 skeletal muscle lines lacking expression of IGF-II. These cells did not differentiate, but underwent progressive apoptotic death when incubated in differentiation medium. Viability could be sustained and differentiation enabled by IGF analogues that activated the IGF-I receptor; survival was dependent on stimulation of phosphatidylinositol 3-kinase (PI3-kinase). We now find that IGF action promotes myoblast survival through two distinguishable PI3-kinase-regulated pathways that culminate in expression of the cyclin-dependent kinase inhibitor, p21. Incubation with IGF-I or transfection with active PI3-kinase led to rapid induction of MyoD and p21, and forced expression of either protein maintained viability in the absence of growth factors. Ectopic expression of MyoD induced p21, and inhibition of p21 blocked MyoD-mediated survival, thus defining one PI3-kinase-dependent pathway as leading first to MyoD, and then to p21 and survival. Unexpectedly, loss of MyoD expression did not impede IGF-mediated survival, revealing a second pathway involving activation by PI3-kinase of Akt, and subsequent induction of p21. Since inhibition of p21 caused death even in the presence of IGF-I, these results establish a central role for p21 as a survival factor for muscle cells. Our observations also define a MyoD-independent pathway for regulating p21 in muscle, and demonstrate that distinct mechanisms help ensure appropriate expression of this key protein during differentiation.


Challenges and barriers to improving care of the musculoskeletal patient of the future - a debate article and global perspective.
With greater technological developments in the care of musculoskeletal patients, we are entering an era of rapid change in our understanding of the pathophysiology of traumatic injury; assessment and treatment of polytrauma and related disorders; and treatment outcomes. In developed countries, it is very likely that we will have algorithms for the approach to many musculoskeletal disorders as we strive for the best approach with which to evaluate treatment success. This debate article is founded on predictions of future health care needs that are solely based on the subjective inputs and opinions of the world's leading orthopedic surgeons.Hence, it functions more as a forum-based rather than a scientific-based presentation. This exposé was designed to stimulate debate about the emerging patients' needs in the future predicted by leading orthopedic surgeons that provide some hint as to the right direction for orthopedic care and outlines the important topics in this area. The authors aim to provide a general overview of orthopedic care in a typical developed country setting. However, the regional diversity of the United States and every other industrialized nation should be considered as a cofactor that may vary to some extent from our vision of improved orthopedic and trauma care of the musculoskeletal patient on an interregional level.In this forum, we will define the current and future barriers in developed countries related to musculoskeletal trauma, total joint arthroplasty, patient safety and injuries related to military conflicts, all problems that will only increase as populations age, become more mobile, and deal with political crisis. It is very likely that the future will bring a more biological approach to fracture care with less invasive surgical procedures, flexible implants, and more rapid rehabilitation methods. This international consortium challenges the trauma and implants community to develop outcome registries that are managed through health care offices and to prepare effectively for the many future challenges that lie in store for those who treat musculoskeletal conditions.


The effect of the extracellular matrix on the detachment of human endothelial cells.
Human umbilical vein endothelial cells can be serially passaged by supplementing medium with a partially purified growth factor. Cell-substratum detachment of early and late passage endothelial cells was examined using trypsin, collagenase, or homocysteine. Late-passage cells detached more rapidly than early passage cells under all conditions tested. The rate of detachment was dependent upon the specific agent used. Protease-mediated detachment was most rapid, occurring over minutes, in contrast to homocysteine-induced detachment, which occurred over hours. When detached cells were collected and replated in the absence of the detaching agent, these cells reattached, spread, and continued to proliferate. No significant difference was observed in the rate of adhesion of either early or late passage cells to a gelatin matrix. When early or late-passage endothelial cells were plated and grown to confluence on a matrix synthesized by the opposite cell type, the rate of protease-mediated cell detachment resembled the cell type from which the matrix was derived. The ease of endothelial cell detachment was determined by the origin of the extracellular matrix. Examination of the extracellular matrices from early and late passage cells revealed significant differences in the amounts of glycosaminoglycans and sulfated proteins present. These studies demonstrate the importance of the endothelial cell extracellular matrix in protease-mediated cell detachment. The rate of cell detachment was controlled by the extracellular matrices are not altered by the endothelial cells.


Public trust in genomic risk assessment for type 2 diabetes mellitus.
Patient trust in personal medical information is critical to increasing adherence to physician recommendations and medications. One of the anticipated benefits of learning of one's genomic risk for common diseases is the increased adoption of screening, preventive care and lifestyle changes. However, the equivocal results thus far reported of the positive impact of knowledge of genomic risk on behavior change may be due to lack of patients' trust in the results. As part of a clinical study to compare two methods of communication of genomic risk results for Type 2 diabetes mellitus (T2DM), we assessed patients' trust and preferred methods of delivery of genomic risk information. A total of 300 participants recruited from the general public in Durham, NC were randomized to receive their genomic risk for T2DM in-person from a genetic counselor or online through the testing company's web-site. Participants completed a baseline survey and three follow-up surveys after receiving results. Overall, participants reported high levels of trust in the test results. Participants who received their results in-person from the genetic counselor were significantly more likely to trust their results than those who reviewed their results on-line (p = 0.005). There was not a statistically significant difference in levels of trust among participants with increased genetic risk, as compared to other those with decreased or same as population risk (p = 0.1154). In the event they undergo genomic risk testing again, 55 % of participants overall indicated they would prefer to receive their results online compared to 28 % that would prefer to receive future results in-person. Of those participants preferring to receive results online, 77 % indicated they would prefer to have the option to speak to someone if they had questions with the online results (compared to accessing results online without the option of professional consultation). This is the first study to assess satisfaction with genomic risk testing by the method of delivery of the test result. The higher rate of trust in results delivered in-person suggests that online access reports may not result in serious consideration of results and lack of adoption of recommended preventive recommendations.


Calcium and vitamin D intake and risk of incident premenstrual syndrome.
Premenstrual syndrome (PMS) is one of the most common disorders of premenopausal women. Studies suggest that blood calcium and vitamin D levels are lower in women with PMS and that calcium supplementation may reduce symptom severity, but it is unknown whether these nutrients may prevent the initial development of PMS. We conducted a case-control study nested within the prospective Nurses' Health Study II cohort. Participants were a subset of women aged 27 to 44 years and free from PMS at baseline in 1991, including 1057 women who developed PMS over 10 years of follow-up and 1968 women reporting no diagnosis of PMS and no or minimal menstrual symptoms. Intake of calcium and vitamin D was measured in 1991, 1995, and 1999 by a food frequency questionnaire. After adjustment for age, parity, smoking status, and other risk factors, women in the highest quintile of total vitamin D intake (median, 706 IU/d) had a relative risk of 0.59 (95% confidence interval, 0.40-0.86) compared with those in the lowest quintile (median, 112 IU/d) (P = .01 for trend). The intake of calcium from food sources was also inversely related to PMS; compared with women with a low intake (median, 529 mg/d), participants with the highest intake (median, 1283 mg/d) had a relative risk of 0.70 (95% confidence interval, 0.50-0.97) (P = .02 for trend). The intake of skim or low-fat milk was also associated with a lower risk (P<.001). A high intake of calcium and vitamin D may reduce the risk of PMS. Large-scale clinical trials addressing this issue are warranted. Given that calcium and vitamin D may also reduce the risk of osteoporosis and some cancers, clinicians may consider recommending these nutrients even for younger women.


Is a controlled trial of long-term oral anticoagulants in patients with stroke and non-rheumatic atrial fibrillation worthwhile?
A controlled randomised trial large enough to assess the value of anticoagulating stroke patients in atrial fibrillation would be difficult to conduct in the UK and the results would be applicable to only a small proportion of stroke patients. It would be more worthwhile to organise a trial that also assessed the value of other treatments that are simpler and applicable to all stroke patients. A trial that assessed the value of aspirin and beta-blockers against control in all stroke patients would not cost much more than one restricted to comparing anticoagulants against control in patients with stroke and atrial fibrillation but would provide information of more relevance to the management of patients with stroke in the UK.


Recurrent and recent selective sweeps in the piRNA pathway.
Uncontrolled transposable element (TE) insertions and excisions can cause chromosome breaks and mutations with dramatic deleterious effects. The PIWI interacting RNA (piRNA) pathway functions as an adaptive TE silencing system during germline development. Several essential piRNA pathway proteins appear to be rapidly evolving, suggesting that TEs and the silencing machinery may be engaged in a classical "evolutionary arms race." Using a variety of molecular evolutionary and population genetic approaches, we find that the piRNA pathway genes rhino, krimper, and aubergine show patterns suggestive of extensive recurrent positive selection across Drosophila species. We speculate that selection on these proteins reflects crucial roles in silencing unfamiliar elements during vertical and horizontal transmission of TEs into naïve populations and species, respectively.


Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic.
Owing to a dramatic increase in average life expectancy and the Family Planning program of the 1970s - 1990s, China is rapidly becoming an aging society. Therefore, the investigation of healthspan-extending drugs becomes more urgent. Astragalus membranaceus (Huangqi) is a major medicinal herb that has been commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders, or marketed as life-prolonging extracts for human use in China, for more than 2000 years. The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has antioxidant, anti-inflammatory, immunoregulatory, anticancer, hypolipidemic, antihyperglycemic, hepatoprotective, expectorant, and diuretic effects. A proprietary extract of the dried root of Astragalus membranaceus, called TA-65, was associated with a significant age-reversal effect in the immune system. Our review focuses on the function and the underlying mechanisms of Astragalus membranaceus in lifespan extension, anti-vascular aging, anti-brain aging, and anti-cancer effects, based on experimental and clinical studies.


Use of ropivacaine and lidocaine for axillary plexus blockade.
The use of certain peripheral nerve blocks in paediatric patients is gaining increasing popularity, although distinctive characteristics of the juvenile anatomy, psychological barriers, time constraints on block placement, and risks of neurotoxic and cardio toxic side effects are still mentioned. However, newer agents like Ropivacaine and Levobupivacaine seem to offer excellent alternatives to Bupivacaine and Lidocaine, especially for use in paediatric patients. We evaluated Ropivacaine 0.5% and Lidocaine 1.0% using axillary plexus blockade as a single-shot technique in 50 children in the age group of 2 to 10 years and undergoing short upper limb surgery. The primary objectives were to compare onset time, duration and quality of block and the incidence of breakthrough pain. Onset time was longer in the Ropivacaine group (15.4 minutes) than in the Lidocaine group (8.2 minutes). The duration of the effect was greater in patients in the Ropivacaine group (337 minutes) than in the Lidocaine group (137 minutes). Duration appeared to vary with patient's age but this effect was not statistically significant. Axillary plexus anaesthesia provides satisfactory perioperative pain relief in infants undergoing short-trauma surgery. Apart from its safety, these results underline that Ropivacaine 0.5% can be recommended for axillary brachial plexus block in children.


Purinergic signaling and energy homeostasis in psychiatric disorders.
Purinergic signaling regulates numerous vital biological processes in the central nervous system (CNS). The two principle purines, ATP and adenosine act as excitatory and inhibitory neurotransmitters, respectively. Compared to other classical neurotransmitters, the role of purinergic signaling in psychiatric disorders is not well understood or appreciated. Because ATP exerts its main effect on energy homeostasis, neuronal function of ATP has been underestimated. Similarly, adenosine is primarily appreciated as a precursor of nucleotide synthesis during active cell growth and division. However, recent findings suggest that purinergic signaling may explain how neuronal activity is associated neuronal energy charge and energy homeostasis, especially in mental disorders. In this review, we provide an overview of the synaptic function of mitochondria and purines in neuromodulation, synaptic plasticity, and neuron-glia interactions. We summarize how mitochondrial and purinergic dysfunction contribute to mental illnesses such as schizophrenia, bipolar disorder, autism spectrum disorder (ASD), depression, and addiction. Finally, we discuss future implications regarding the pharmacological targeting of mitochondrial and purinergic function for the treatment of psychiatric disorders.


Alpine Grassland Phenology as Seen in AVHRR, VEGETATION, and MODIS NDVI Time Series - a Comparison with In Situ Measurements.
This study evaluates the ability to track grassland growth phenology in the Swiss Alps with NOAA-16 Advanced Very High Resolution Radiometer (AVHRR) Normalized Difference Vegetation Index (NDVI) time series. Three growth parameters from 15 alpine and subalpine grassland sites were investigated between 2001 and 2005: Melt-Out (MO), Start Of Growth (SOG), and End Of Growth (EOG).We tried to estimate these phenological dates from yearly NDVI time series by identifying dates, where certain fractions (thresholds) of the maximum annual NDVI amplitude were crossed for the first time. For this purpose, the NDVI time series were smoothed using two commonly used approaches (Fourier adjustment or alternatively Savitzky-Golay filtering). Moreover, AVHRR NDVI time series were compared against data from the newer generation sensors SPOT VEGETATION and TERRA MODIS. All remote sensing NDVI time series were highly correlated with single point ground measurements and therefore accurately represented growth dynamics of alpine grassland. The newer generation sensors VGT and MODIS performed better than AVHRR, however, differences were minor. Thresholds for the determination of MO, SOG, and EOG were similar across sensors and smoothing methods, which demonstrated the robustness of the results. For our purpose, the Fourier adjustment algorithm created better NDVI time series than the Savitzky-Golay filter, since latter appeared to be more sensitive to noisy NDVI time series. Findings show that the application of various thresholds to NDVI time series allows the observation of the temporal progression of vegetation growth at the selected sites with high consistency. Hence, we believe that our study helps to better understand largescale vegetation growth dynamics above the tree line in the European Alps.


A ten-year retrospective evaluation of acute flaccid myelitis at 5 pediatric centers in the United States, 2005-2014.
Acute flaccid myelitis (AFM) is a severe illness similar to paralytic poliomyelitis. It is unclear how frequently AFM occurred in U.S. children after poliovirus elimination. In 2014, an AFM cluster was identified in Colorado, prompting passive US surveillance that yielded 120 AFM cases of unconfirmed etiology. Subsequently, increased reports were received in 2016 and 2018. To help inform investigations on causality of the recent AFM outbreaks, our objective was to determine how frequently AFM had occurred before 2014, and if 2014 cases had different characteristics. We conducted a retrospective study covering 2005-2014 at 5 pediatric centers in 3 U.S. regions. Possible AFM cases aged ≤18 years were identified by searching discharge ICD-9 codes and spinal cord MRI reports (>37,000). Neuroradiologists assessed MR images, and medical charts were reviewed; possible cases were classified as AFM, not AFM, or indeterminate. At 5 sites combined, 26 AFM cases were identified from 2005-2013 (average annual number, 3 [2.4 cases/100,000 pediatric hospitalizations]) and 18 from 2014 (12.6 cases/100,000 hospitalizations; Poisson exact p<0.0001). A cluster of 13 cases was identified in September-October 2014 (temporal scan p = 0.0001). No other temporal or seasonal trend was observed. Compared with cases from January 2005-July 2014 (n = 29), cases from August-December 2014 (n = 15) were younger (p = 0.002), more frequently had a preceding respiratory/febrile illness (p = 0.03), had only upper extremities involved (p = 0.008), and had upper extremity monoplegia (p = 0.03). The cases had higher WBC counts in cerebrospinal fluid (p = 0.013). Our data support emergence of AFM in 2014 in the United States, and those cases demonstrated distinctive features compared with preceding sporadic cases.


Schedule to inject in vitro matured oocytes may increase pregnancy after intracytoplasmic sperm injection.
To ascertain the value of using immature oocytes in an intracytoplasmic sperm injection (ICSI) program, the authors designed a schedule, at 5 p.m. on day 1 (the day of oocyte retrieval) and at 8 a.m. and 2 p.m. on day 2, to recognize and inject the in vitro matured (IVM) oocytes. For the 1,166 oocytes retrieved in 107 ICSI cycles, 128 (11.0%) were at the stage of metaphase I (MI) and 113 (9.7%) at germinal vesicle. Routine ICSI for metaphase 11 oocytes was performed at 2 p.m. on day 1 (initial ICSI). In culture medium of human tubal fluid with 15% maternal serum, 85.1% (205/241) immature oocytes progressed to maturation in which 16.4% (21/128) of MI oocytes matured at 5 p.m. of day 1. The rate of normal fertilization for IVM oocytes (58.5%) was not significantly different from that of initial ICSI (64.0%). One patient received a transfer of two fertilized IVM oocytes alone that were injected at 5 p.m. of day 1, maturing from the MI stage, and achieved a normal pregnancy. The fertilized IVM oocytes were replaced along with the embryos from initial ICSI for 40 cycles that led to 14 (35%) clinical pregnancies. In 43 fertilized IVM oocytes donated for research, we observed that cleavage (95.3%) to the 2- to 4-cell stage was not distinct from that of initial ICSI (94.6%); however, the percentage of embryos of grade I and II morphology was significantly smaller (24.4% vs. 62.5%). Only five (11.6%) developed to blastocysts in vitro. Twenty-one fertilized IVM oocytes were frozen for future transfer. A schedule to inject IVM oocytes in ICSI cycles may generate more accessible embryos for fresh transfer or cryopreservation to increase the chance of pregnancy, although the embryo quality was relatively poor.


Delay differential analysis of electroencephalographic data.
We propose a time-domain approach to detect frequencies, frequency couplings, and phases using nonlinear correlation functions. For frequency analysis, this approach is a multivariate extension of discrete Fourier transform, and for higher-order spectra, it is a linear and multivariate alternative to multidimensional fast Fourier transform of multidimensional correlations. This method can be applied to short and sparse time series and can be extended to cross-trial and cross-channel spectra (CTS) for electroencephalography data where multiple short data segments from multiple trials of the same experiment are available. There are two versions of CTS. The first one assumes some phase coherency across the trials, while the second one is independent of phase coherency. We demonstrate that the phase-dependent version is more consistent with event-related spectral perturbation analysis and traditional Morlet wavelet analysis. We show that CTS can be applied to short data windows and yields higher temporal resolution than traditional Morlet wavelet analysis. Furthermore, the CTS can be used to reconstruct the event-related potential using all linear components of the CTS.


Association of common variants in the human eyes shut ortholog (EYS) with statin-induced myopathy: evidence for additional functions of EYS.
Of the nearly 38 million people in the USA who receive statin therapy, 0.1-0.5% experience severe or life-threatening myopathic side effects. We performed a genome-wide association study (GWAS) in a group of patients with severe statin myopathy versus a statin-tolerant group to identify genetic susceptibility loci. Replication studies in independent groups of severe statin myopathy (n = 190) and statin-tolerant controls (n = 130) resulted in the identification of three single-nucleotide polymorphisms (SNPs), rs9342288, rs1337512, and rs3857532, in the eyes shut homolog (EYS) on chromosome 6 suggestive of an association with risk for severe statin myopathy (P = 0.0003-0.0008). Analysis of EYS cDNA demonstrated that EYS gene products are complex and expressed with relative abundance in the spinal cord as well as in the retina. Structural similarities of these EYS gene products to members of the Notch signaling pathway and to agrin suggest a possible functional role in the maintenance and regeneration of the structural integrity of skeletal muscle.


Supplementation of a Lactobacillus acidophilus fermentation product can attenuate the acute phase response following a lipopolysaccharide challenge in weaned pigs.
Lactobacillus acidophilus fermentation products have been used to improve the performance of nursery pigs. However, research on the influence of this supplement on health is lacking. This study was designed to determine if feeding a Lactobacillus acidophilus fermentation product to weaned pigs would reduce stress and acute phase responses (APR) following a lipopolysaccharide (LPS) challenge. Pigs (n=30; 6.4±0.1 kg) were individually housed in stainless steel pens with ad libitum access to feed and water. Pigs were weighed upon arrival, assigned to one of three groups (n=10/treatment), and fed for 18 days: (1) Control, fed a non-medicated starter diet; (2) Control diet with the inclusion of a Lactobacillus acidophilus fermentation product at 1 kg/metric ton (SGX1) and (3) Control diet with the inclusion of a Lactobacillus acidophilus fermentation product at 2 kg/metric ton (SGX2). On day 7 pigs were anesthetized for insertion of an i.p. temperature device, and similarly on day 14 for insertion of a jugular catheter. Pigs were challenged i.v. with LPS (25 µg/kg BW) on day 15. Blood samples were collected at 0.5 h (serum) and 1 h (complete blood cell counts) intervals from -2 to 8 h and at 24 h relative to LPS administration at 0 h. Pigs and feeders were weighed on days 7, 14 and 18. The supplemented pigs had increased BW and average daily gain before the challenge. In response to LPS, there was a greater increase in i.p. temperature in Control pigs compared with supplemented pigs. In addition, cortisol was reduced in SGX2 pigs while cortisol was elevated in SGX1 pigs at several time points post-challenge. White blood cells, neutrophils and lymphocytes were decreased in SGX1 and SGX2 compared with Control pigs. Furthermore, the pro-inflammatory cytokine response varied by treatment and dose of treatment. Specifically, serum TNF-α was greatest in SGX2, intermediate in Control, and least in SGX1 pigs, while the magnitude and temporal pattern of IFN-γ in SGX2 pigs was delayed and reduced. In contrast, IL-6 concentrations were reduced in both SGX treatment groups compared with Control pigs. These data demonstrate that different supplementation feed inclusion rates produced differential responses, and that feeding SynGenX to weaned pigs attenuated the APR to an LPS challenge.


Gene expression analysis of children with acute hematogenous osteomyelitis caused by Methicillin-resistant Staphylococcus aureus: correlation with clinical severity of illness.
Children with acute hematogenous osteomyelitis (AHO) demonstrate a broad spectrum of clinical manifestations, ranging from mild to severe. Several advances have been achieved in the study of host immune response to acute invasive Staphylococcus aureus infections through gene expression analysis. However, previous research has neither attempted to evaluate the response of children with AHO specific to Methicillin-resistant Staphylococcus aureus (MRSA) nor to correlate gene expression with clinical phenotype. Study objective was to correlate gene expression of children with AHO due to MRSA with clinical severity of illness. Whole blood samples were obtained in Tempus tubes from 12 children with osteomyelitis once cultures obtained directly from the site of infection confirmed to be positive for MRSA. Using an Illumina platform and a systems-wide modular analysis, microarray findings from ten of these children were compared to that of nine healthy (age, ethnicity and gender) matched controls and correlated with clinical severity of illness. Children with AHO from MRSA demonstrated over-expression of innate immunity with respect to neutrophil activity, coagulation, inflammatory response, and erythrocyte development. Concurrently, these children demonstrated under-expression of adaptive immunity with respect to lymphocyte activation and activity of T-cell, cytotoxic or NK cell, and B-cell lines. Three over-expressed genes, P2RX1, SORT1, and RETN, and two under-expressed genes, LOC641788 and STAT 4, were significantly correlated with severity of illness. STAT 4 showed the strongest correlation (R2 = -0.83). STAT4 downregulation could potentially explain under-expression of genes related to adaptive immunity in this cohort of patients with AHO. This study identified specific genes which correspond to disease severity during the early hospitalization of children with AHO from MRSA. Pattern recognition of this combination of genes could help to identify in the future severe clinical phenotypes before the disease is fully manifest and direct appropriate attention and resources to those children.


Whole Exome Sequencing of Highly Aggregated Lung Cancer Families Reveals Linked Loci for Increased Cancer Risk on Chromosomes 12q, 7p, and 4q.
Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer. Parametric genetic linkage analysis was performed on these samples using two distinct analyses-the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected. The AAC analysis yielded a genome-wide significant result at rs61943670 in POLR3B at 12q23.3. POLR3B has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near SSPO at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in DSPP at 4q22.1 and PTPN13 at 4q21.3. Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. POLR3B, SSPO, DSPP, and PTPN13 are currently the best candidate genes. Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.


Asymptomatic cryptococcemia in resource-limited settings.
Despite increasing availability of anti-retroviral therapy, invasive cryptococcal disease continues to be a leading cause of death among HIV-infected individuals in resource-limited settings. Screening asymptomatic HIV-infected individuals with advanced immunosuppression for serum cryptococcal antigen clearly identifies a population at high risk of cryptococcal meningitis and death. However, screening with serum cryptococcal antigen alone identifies a heterogeneous clinical population, many of whom have mild clinical symptoms, sub-clinical meningeal infection, or fungemia. Currently, there is wide variation in practice and little evidence to guide the use of anti-fungal and anti-retroviral treatment for asymptomatic cryptococcal antigenemia (ACA). Furthermore, implementing a targeted screening and treatment intervention for ACA presents numerous operational challenges for already overburdened health care systems in resource-limited settings. While such an intervention shows promise, there are critical gaps in our understanding of ACA and its implications in the outpatient setting and an urgent need for additional research in this area.


Revision anterior cruciate ligament reconstruction using a 2-stage technique with bone grafting of the tibial tunnel.
Revision anterior cruciate ligament surgery is often considered a salvage procedure with limited goals. However, this limitation need not be the case. Similar to primary reconstruction, the goal should be to choose an appropriate graft and place it in an anatomical position in a good quality bone. The issue of good quality bone seems to have been ignored. A 2-stage anterior cruciate ligament revision reconstruction with bone grafting of the tibial tunnel and the use of a different femoral tunnel will produce measured knee laxity and International Knee Documentation Committee scores similar to a primary anterior cruciate ligament reconstruction. Case control study; Level of evidence, 3. This prospective study involved 49 consecutive 2-stage anterior cruciate ligament revisions (group R) performed by a single surgeon from 1993 to 2000. Two-stage revision surgery was performed if the tibial tunnel from a previous reconstruction surgery would overlap (either partially or fully) the correctly placed revision tunnel. The first stage consisted of removal of the old graft and interfering metalwork, together with bone grafting of the tibial tunnel. After ensuring adequate bone graft incorporation using computed tomography scan, the second stage revision was undertaken. This stage comprised harvesting the autograft, its anatomical placement, and its adequate fixation. The results were compared with the results of a matched group of patients with primary anterior cruciate ligament reconstruction (group P). In group R, as meniscal and chondral lesions were more common, the International Knee Documentation Committee scores were lower than those of group P (61.2 for group R and 72.8 for group P; P = .006). Objective laxity measurement was similar in both groups (1.36 mm for group R and 1.2 mm for group P; P = .25). This study establishes that the laxity measurements achieved with a 2-stage revision anterior cruciate ligament reconstruction can be similar to those achieved after primary anterior cruciate ligament reconstruction, although the International Knee Documentation Committee rating is lower.


Chronic recurrent multifocal osteomyelitis: the prevalence of lower-limb and foot involvement.
Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory condition. The lesions are reported to present most frequently in the long bones. This study aimed to review the presenting features of CRMO in a cohort of children diagnosed as having CRMO and to compare the level of agreement between the clinical and published diagnostic criteria. A case notes review was undertaken of patients with a clinical diagnosis of CRMO. Patients were younger than 16 years at the time of diagnosis. Features were identified in each patient that agreed or disagreed with the published diagnostic criteria. The location of bone lesions in the lower limb at onset and disease progression was recorded. A total of 37 patients were included. There was a high prevalence in white individuals. Agreement with the diagnostic criteria of Jansson et al and El-Shanti and Ferguson was poor, with levels of agreement of 40.5% and 43%, respectively, and low kappa scores (κ = 0.07 and 0.09, respectively). The lower limb was affected in 49% of patients at onset and in 72% overall. This study presents one of the largest published cohorts of pediatric patients with CRMO and also presents racial/ethnic group data that have not previously been reported in other studies. Despite being a condition considered to affect the metaphysis of long bones, the ankle area and foot bones were also frequently affected. The agreement between the clinical diagnosis and the published diagnostic criteria was weak.


Eye-movements and visual imagery: a working memory approach to the treatment of post-traumatic stress disorder.
It has been claimed that the symptoms of post-traumatic stress disorder (PTSD) can be ameliorated by eye-movement desensitization-reprocessing therapy (EMD-R), a procedure that involves the individual making saccadic eye-movements while imagining the traumatic event. We hypothesized that these eye-movements reduce the vividness of distressing images by disrupting the function of the visuospatial sketchpad (VSSP) of working memory, and that by doing so they reduce the intensity of the emotion associated with the image. This hypothesis was tested by asking non-PTSD participants to form images of neutral and negative pictures under dual task conditions. Their images were less vivid with concurrent eye-movements and with a concurrent spatial tapping task that did not involve eye-movements. In the first three experiments, these secondary tasks did not consistently affect participants' emotional responses to the images. However, Expt 4 used personal recollections as stimuli for the imagery task, and demonstrated a significant reduction in emotional response under the same dual task conditions. These results suggest that, if EMD-R works, it does so by reducing the vividness and emotiveness of traumatic images via the VSSP of working memory. Other visuospatial tasks may also be of therapeutic value.


Invasive implantation and intimate placental associations in a placentotrophic African lizard, Trachylepis ivensi (scincidae).
In the viviparous lizard Trachylepis ivensi (Scincidae) of central Africa, reproducing females ovulate tiny ∼1 mm eggs and supply the nutrients for development by placental means. Histological study shows that this species has evolved an extraordinary placental pattern long thought to be confined to mammals, in which fetal tissues invade the uterine lining to contact maternal blood vessels. The vestigial shell membrane disappears very early in development, allowing the egg to absorb uterine secretions. The yolk is enveloped precocially by the trilaminar yolk sac and no isolated yolk mass or yolk cleft develops. Early placentas are formed from the chorion and choriovitelline membranes during the neurula through pharyngula stages. During implantation, cells of the chorionic ectoderm penetrate between uterine epithelial cells. The penetrating tissue undergoes hypertrophy and hyperplasia, giving rise to sheets of epithelial tissue that invade beneath the uterine epithelium, stripping it away. As a result, fetal epithelium entirely replaces the uterine epithelium, and lies in direct contact with maternal capillaries and connective tissue. Placentation is endotheliochorial and fundamentally different from that of all other viviparous reptiles known. Further, the pattern of fetal membrane development (with successive loss and re-establishment of an extensive choriovitelline membrane) is unique among vertebrates. T. ivensi represents a new extreme in placental specializations of reptiles, and is the most striking case of convergence on the developmental features of viviparous mammals known.


The effect of body position, sedation, and thoracic bandaging on functional residual capacity in healthy deep-chested dogs.
The objective of this study was to determine the effect of body position, chest wrap, and sedation on functional residual capacity (FRC) in 6 healthy dogs. Functional residual capacity was determined by helium dilution (re-breathing) whilst in different clinically relevant conditions. These conditions included the standing (sternal) and lateral positions in unsedated dogs and then again both standing and lateral following chest bandaging, and sedation with acepromazine, IV and butorphanol, IV. The mean FRC at each measurement point was determined, as was the change in FRC (delta FRC) from one measurement point to another. Analysis of variance (ANOVA) with repeated measures with Fisher's LSD post hoc test was used to evaluate the effect of interventions. The differences in delta FRC were evaluated using a t-test or Wilcoxon rank-sum test. P < 0.05 was considered significant. The mean FRC at baseline, defined as standing, unsedated and unwrapped, was 75.3 +/- 23.8 mL/kg. Body position or sedation had the most profound effect on FRC with right lateral recumbency lowering FRC by a median of 20.4 mL/kg and sedation lowering FRC by a median of 19.8 mL/kg. Common clinical procedures and positioning result in lowered FRC in healthy deep-chested dogs. In critically ill or injured dogs, the iatrogenic loss of FRC through chest bandaging, sedation, or body position may be clinically relevant.


Assessing the specificity of autobiographical memory in individuals at a trait-based vulnerability to bipolar disorder using a sentence completion task.
Overgeneral autobiographical memory recall has been associated with the diagnosis of bipolar disorder, but the role of overgenerality in the vulnerability to bipolar disorder remains under-researched. While a previous study suggested that high-risk individuals for bipolar disorder recall emotionally negative memories in specific detail, this is in contrast to memory recall patterns noted in bipolar samples. The Autobiographical Memory Test (AMT) used in previous non-clinical studies has also been criticised for not being sensitive to overgenerality due to its repetition of specificity instructions and practice trials. The traditional AMT format may allow some individuals to override their trait-based tendencies to be overgeneral. The current study used a sentence completion task to assess memory specificity in groups of students at a low and high trait-based vulnerability for bipolar disorder. In contrast to previous research, high-risk individuals recalled fewer specific positive memories and greater numbers of overgeneral negative memories than low-risk individuals. These results support the notion that the vulnerability for bipolar disorder might be associated with similar recall biases as demonstrated in bipolar samples, and that the AMT might not be sufficiently sensitive to detect overgenerality in non-clinical groups. The implications of these findings and directions for future research are discussed.


Risk stratification and dental management of the patient with cardiovascular diseases. Part I: Etiology, epidemiology, and principles of medical management.
The heart pumps blood through a system of blood vessels under the control of an electric conduction system to deliver oxygen to all cells of the body. When the blood volume becomes greater than the limited volume capacity of the vascular system, the patient develops hypertension. When the myocardium does not get enough oxygen because of coronary artery disease, the patient will experience angina pectoris. If oxygen deprivation to the myocardium persists, the patient may develop myocardial infarction. When the conduction system malfunctions, arrhythmias occur and the heart is unable to pump blood through the vascular system at a regular rate and rhythm. When the heart is no longer able to pump enough blood to meet the metabolic demands of the body for oxygen, the patient is said to have developed heart failure. In addition, many of the above conditions can lead to thromboembolic complications. These cardiovascular diseases are the leading cause of death in the United States and most other Western countries. In the United States alone, more than 1 million annual deaths and as many as three times that number of serious consequences can be attributed to these conditions. To provide care to patients with cardiovascular disease, oral health care providers must understand the disease, its treatment, and its impact on the patient's ability to undergo and respond to dental care.


Hydrogeological characterisation of groundwater over Brazil using remotely sensed and model products.
For Brazil, a country frequented by droughts and whose rural inhabitants largely depend on groundwater, reliance on isotope for its monitoring, though accurate, is expensive and limited in spatial coverage. We exploit total water storage (TWS) derived from Gravity Recovery and Climate Experiment (GRACE) satellites to analyse spatial-temporal groundwater changes in relation to geological characteristics. Large-scale groundwater changes are estimated using GRACE-derived TWS and altimetry observations in addition to GLDAS and WGHM model outputs. Additionally, TRMM precipitation data are used to infer impacts of climate variability on groundwater fluctuations. The results indicate that climate variability mainly controls groundwater change trends while geological properties control change rates, spatial distribution, and storage capacity. Granular rocks in the Amazon and Guarani aquifers are found to influence larger storage capability, higher permeability (>10-4 m/s) and faster response to rainfall (1 to 3months' lag) compared to fractured rocks (permeability <10-7 m/s and lags > 3months) found only in Bambui aquifer. Groundwater in the Amazon region is found to rely not only on precipitation but also on inflow from other regions. Areas beyond the northern and southern Amazon basin depict a 'dam-like' pattern, with high inflow and slow outflow rates (recharge slope > 0.75, discharge slope < 0.45). This is due to two impermeable rock layer-like 'walls' (permeability <10-8 m/s) along the northern and southern Alter do Chão aquifer that help retain groundwater. The largest groundwater storage capacity in Brazil is the Amazon aquifer (with annual amplitudes of > 30cm). Amazon's groundwater declined between 2002 and 2008 due to below normal precipitation (wet seasons lasted for about 36 to 47% of the time). The Guarani aquifer and adjacent coastline areas rank second in terms of storage capacity, while the northeast and southeast coastal regions indicate the smallest storage capacity due to lack of rainfall (annual average is rainfall <10cm).


Epistemic and ontological cognition of entering and postdidactic occupational therapy students.
Beliefs about knowledge and knowing, also called epistemic and ontological cognition (EOC), are associated with many aspects of learning and achievement; no published studies have described the EOC of occupational therapy students. This study compares and contrasts occupational therapy students' EOC at entry and on completion of didactic coursework. Twenty-one incoming and 33 postdidactic students completed the Epistemic Beliefs Inventory and the modified Four-Quadrant Scale and provided explanations for their self-ratings. Results indicate that the postdidactic students held more sophisticated stances toward occupational therapy-specific knowledge. The entering students demonstrated dogmatist and skeptic perspectives, with minimal evidence of a rationalist view of knowledge, whereas the postdidactic students showed evidence of primarily skeptic stances, with the emergence of rationalist views. Implications for occupational therapy theory, education, and research are discussed.


Self-managed, computerised speech and language therapy for patients with chronic aphasia post-stroke compared with usual care or attention control (Big CACTUS): a multicentre, single-blinded, randomised controlled trial.
Post-stroke aphasia might improve over many years with speech and language therapy; however speech and language therapy is often less readily available beyond a few months after stroke. We assessed self-managed computerised speech and language therapy (CSLT) as a means of providing more therapy than patients can access through usual care alone. In this pragmatic, superiority, three-arm, individually randomised, single-blind, parallel group trial, patients were recruited from 21 speech and language therapy departments in the UK. Participants were aged 18 years or older and had been diagnosed with aphasia post-stroke at least 4 months before randomisation; they were excluded if they had another premorbid speech and language disorder caused by a neurological deficit other than stroke, required treatment in a language other than English, or if they were currently using computer-based word-finding speech therapy. Participants were randomly assigned (1:1:1) to either 6 months of usual care (usual care group), daily self-managed CSLT plus usual care (CSLT group), or attention control plus usual care (attention control group) with the use of computer-generated stratified blocked randomisation (randomly ordered blocks of sizes three and six, stratified by site and severity of word finding at baseline based on CAT Naming Objects test scores). Only the outcome assessors and trial statistician were masked to the treatment allocation. The speech and language therapists who were doing the outcome assessments were different from those informing participants about which group they were assigned to and from those delivering all interventions. The statistician responsible for generating the randomisation schedule was separate from those doing the analysis. Co-primary outcomes were the change in ability to retrieve personally relevant words in a picture naming test (with 10% mean difference in change considered a priori as clinically meaningful) and the change in functional communication ability measured by masked ratings of video-recorded conversations, with the use of Therapy Outcome Measures (TOMs), between baseline and 6 months after randomisation (with a standardised mean difference in change of 0·45 considered a priori as clinically meaningful). Primary analysis was based on the modified intention-to-treat (mITT) population, which included randomly assigned patients who gave informed consent and excluded those without 6-month outcome measures. Safety analysis included all participants. This trial has been completed and was registered with the ISRCTN, number ISRCTN68798818. From Oct 20, 2014, to Aug 18, 2016, 818 patients were assessed for eligibility, of which 278 (34%) participants were randomly assigned (101 [36%] to the usual care group; 97 [35%] to the CSLT group; 80 [29%] to the attention control group). 86 patients in the usual care group, 83 in the CSLT group, and 71 in the attention control group contributed to the mITT. Mean word finding improvements were 1·1% (SD 11·2) in the usual care group, 16·4% (15·3) in the CSLT group, and 2·4% (8·8) in the attention control group. Word finding improvement was 16·2% (95% CI 12·7 to 19·6; p<0·0001) higher in the CSLT group than in the usual care group and was 14·4% (10·8 to 18·1) higher than in the attention control group. Mean changes in TOMs were 0·05 (SD 0·59) in the usual care group (n=84), 0·04 (0·58) in the CSLT group (n=81), and 0·10 (0·61) in the attention control group (n=68); the mean difference in change between the CSLT and usual care groups was -0·03 (-0·21 to 0·14; p=0·709) and between the CSLT and attention control groups was -0·01 (-0·20 to 0·18). The incidence of serious adverse events per year were rare with 0·23 events in the usual care group, 0·11 in the CSLT group, and 0·16 in the attention control group. 40 (89%) of 45 serious adverse events were unrelated to trial activity and the remaining five (11%) of 45 serious adverse events were classified as unlikely to be related to trial activity. CSLT plus usual care resulted in a clinically significant improvement in personally relevant word finding but did not result in an improvement in conversation. Future studies should explore ways to generalise new vocabulary to conversation for patients with chronic aphasia post-stroke. National Institute for Health Research, Tavistock Trust for Aphasia.


Percutaneous ablation therapies of inoperable pancreatic cancer: a systematic review.
Initial studies about ablation therapies of the pancreas were associated with significant morbidity and mortality, which limited widespread adoption. Development of techniques with high quality imaging used as guidance improve outcomes reducing complications. Moreover, only few experiences of percutaneous pancreatic ablations are reported. They are performed by very skilled operators in highly specialized centers. This review presents the current status of percutaneous local ablative therapies in the treatment of advanced pancreatic cancer.


Variation among populations in the immune protein composition of mother's milk reflects subsistence pattern.
Adaptive immune proteins in mothers' milk are more variable than innate immune proteins across populations and subsistence strategies. These results suggest that the immune defenses in milk are shaped by a mother's environment throughout her life. Mother's milk contains immune proteins that play critical roles in protecting the infant from infection and priming the infant's developing immune system during early life. The composition of these molecules in milk, particularly the acquired immune proteins, is thought to reflect a mother's immunological exposures throughout her life. In this study, we examine the composition of innate and acquired immune proteins in milk across seven populations with diverse disease and cultural ecologies. Milk samples (n = 164) were collected in Argentina, Bolivia, Nepal, Namibia, Philippines, Poland and the USA. Populations were classified as having one of four subsistence patterns: urban-industrialism, rural-shop, horticulturalist-forager or agro-pastoralism. Milk innate (lactalbumin, lactoferrin and lysozyme) and acquired (Secretory IgA, IgG and IgM) protein concentrations were determined using triple-quadrupole mass spectrometry. Both innate and acquired immune protein composition in milk varied among populations, though the acquired immune protein composition of milk differed more among populations. Populations living in closer geographic proximity or having similar subsistence strategies (e.g. agro-pastoralists from Nepal and Namibia) had more similar milk immune protein compositions. Agro-pastoralists had different milk innate immune protein composition from horticulturalist-foragers and urban-industrialists. Acquired immune protein composition differed among all subsistence strategies except horticulturist-foragers and rural-shop. Our results reveal fundamental variation in milk composition that has not been previously explored in human milk research. Further study is needed to understand what specific aspects of the local environment influence milk composition and the effects this variation may have on infant health outcomes.


Comparison of microglia and infiltrating CD11c⁺ cells as antigen presenting cells for T cell proliferation and cytokine response.
Tissue-resident antigen-presenting cells (APC) exert a major influence on the local immune environment. Microglia are resident myeloid cells in the central nervous system (CNS), deriving from early post-embryonic precursors, distinct from adult hematopoietic lineages. Dendritic cells (DC) and macrophages infiltrate the CNS during experimental autoimmune encephalomyelitis (EAE). Microglia are not considered to be as effective APC as DC or macrophages. In this work we compared the antigen presenting capacity of CD11c⁺ and CD11c⁻ microglia subsets with infiltrating CD11c⁺ APC, which include DC. The microglial subpopulations (CD11c⁻ CD45dim CD11b⁺ and CD11c⁺ CD45dim CD11b⁺) as well as infiltrating CD11c⁺ CD45high cells were sorted from CNS of C57BL/6 mice with EAE. Sorted cells were characterised by flow cytometry for surface phenotype and by quantitative real-time PCR for cytokine expression. They were co-cultured with primed T cells to measure induction of T cell proliferation and cytokine response. The number of CD11c⁺ microglia cells increased dramatically in EAE. They expressed equivalent levels of major histocompatibility complex and co-stimulatory ligands CD80 and CD86 as those expressed by CD11c⁺ cells infiltrating from blood. CD11c⁺ microglia differed significantly from blood-derived CD11c⁺ cells in their cytokine profile, expressing no detectable IL-6, IL-12 or IL-23, and low levels of IL-1β. By contrast, CD11c⁻ microglia expressed low but detectable levels of all these cytokines. Transforming growth factor β expression was similar in all three populations. Although CNS-resident and blood-derived CD11c⁺ cells showed equivalent ability to induce proliferation of myelin oligodendrocyte glycoprotein-immunised CD4⁺ T cells, CD11c⁺ microglia induced lower levels of T helper (Th)1 and Th17 cytokines, and did not induce Th2 cytokines. Our findings show distinct subtypes of APC in the inflamed CNS, with a hierarchy of functional competence for induction of CD4⁺ T cell responses.


AP endonuclease and poly(ADP-ribose) polymerase-1 interact with the same base excision repair intermediate.
Base excision repair (BER) is a defense system that protects cells from deleterious effects secondary to modified or missing DNA bases. BER is known to involve apurinic/apyrimidinic endonuclease (APE) and DNA polymerase ss (ss-pol) among other enzymes, and recent studies have suggested that poly(ADP-ribose) polymerase-1 (PARP-1) also plays a role by virtue of its binding to BER intermediates. The main role of APE is cleavage of the DNA backbone at abasic sites, and the enzyme also can catalyze 3'- to 5'-exonuclease activity at the cleaved abasic site. Photocross-linking studies with mouse embryonic fibroblast (MEF) cell extracts described here indicated that APE and PARP-1 interact with the same APE-cleaved abasic site BER intermediate. The model BER intermediate used includes a synthetic abasic site sugar, i.e. tetrahydrofuran (THF), in place of the natural deoxyribose. APE cross-linked efficiently with this intermediate, but not with a molecule lacking the 5'-THF phosphate group, and the same property was demonstrated for PARP-1. The addition of purified APE to the MEF extract reduced the amount of PARP-1 cross-linked to the BER intermediate, suggesting that APE can compete with PARP-1. APE and PARP-1 were antagonists of each other in in vitro BER related reactions on this model BER intermediate. These results suggest that PARP-1 and APE can interact with the same BER intermediate and that competition between these two proteins may influence their respective BER related functions.


Cytoplasmic calcium gradients and calmodulin in the early development of the fucoid alga Pelvetia compressa.
The predicted existence of cytoplasmic Ca2+ gradients during the photopolarization of the zygotes of the brown algae, Pelvetia and Fucus, has proved to be difficult to establish, and the downstream targets of the putative gradients are not known. We have used quantitative microinjection of the long excitation wavelength Ca2+ indicator, Calcium Crimson, and of antibodies against calmodulin to investigate these matters in the zygotes and early embryos of Pelvetia. We found that there is a window of cytoplasmic Calcium Crimson concentration that gives an adequate signal above autofluorescence yet allows normal development of the zygotes. As Calcium Crimson is not a ratiometric indicator, we injected other zygotes with a Ca2+-insensitive dye, rhodamine B, and imaged the cells at the same time that Calcium Crimson-injected cells were imaged. Ratios were calculated by dividing the averaged pixel values of Calcium Crimson images by the averaged pixel values of corresponding rhodamine B images. By this method, we observed the formation of a cytoplasmic Ca2+ gradient within one hour of the exposure of the cells to unilateral blue light during the photosensitive period. The region of high Ca2+ was localized to and predictive of the site of future rhizoid formation. We validated this somewhat indirect method by applying it to the growing rhizoid, where the existence of a tip-localized Ca2+ gradient is well established. The method clearly revealed the known gradient. The injection of ungerminated zygotes with antibodies made against Dictyostelium calmodulin inhibited germination, and this inhibition was abolished if the calmodulin antibodies were coinjected with an excess of purified maize calmodulin. Likewise, the growth of the rhizoids was inhibited by calmodulin antibody injections. The fungus-derived calmodulin antagonist, ophiobolin A, which has previously been shown to be a potent inhibitor of germination, also inhibited rhizoidal growth. Our results provide evidence that a cytoplasmic Ca2+ gradient is present during photopolarization and that calmodulin acts as a mediator of Ca2+ gradients throughout the early developmental processes of germination and rhizoidal growth in Pelvetia compressa.


Evaluation and Predictive Modeling of Removal Condition for Bioadsorption of Indigo Blue Dye by Spirulina platensis.
Among the different chemical and physical treatments used to remove the color of the textile effluents, bioremediation offers many benefits to the environment. In this study, we determined the potential of Spirulina platensis (S. platensis) for decolorizing indigo blue dye under different incubation conditions. The microalgae were incubated at different pH (from 4 to 10) to calibrate for the optimal discoloration condition; a pH of 4 was found to be optimal. The biomass concentration in all experiments was 1 g/L, which was able to decolorize the indigo blue dye by day 3. These results showed that S. platensis is capable of removing indigo blue dye at low biomass. However, this was dependent on the treatment conditions, where temperature played the most crucial role. Two theoretical adsorption models, namely (1) a first-order model equation and (2) a second-order rate equation, were compared with observed adsorption vs. time curves for different initial concentrations (from 25 to 100 mg/L). The comparison between models showed similar accuracy and agreement with the experimental values. The observed adsorption isotherms for three temperatures (30, 40, and 50 °C) were plotted, showing fairly linear behavior in the measured range. The adsorption equilibrium isotherms were estimated, providing an initial description of the dye removal capacity of S. platensis.


Trap Height Affects Catches of Bark and Woodboring Beetles (Coleoptera: Curculionidae, Cerambycidae) in Baited Multiple-Funnel Traps in Southeastern United States.
In north-central Georgia, trap height affected catches of some species of bark and woodboring beetles (Coleoptera) in traps baited with lures used in surveillance programs to detect non-native forest insects. Traps were placed within the canopy and understory of mature oak trees (Quercus spp.) with collection cups placed 18-23 m above ground level (AGL), and 0.3-0.5 m AGL, respectively. Traps were baited with ethanol to target ambrosia beetles (Curculionidae: Scolytinae) in one experiment, ethanol + syn-2,3-hexanediol + racemic 3-hydroxyhexan-2-one + racemic 3-hydroxyoctan-2-one to target hardwood woodborers (Cerambycidae) in a second experiment, and α-pinene + racemic ipsenol + racemic ipsdienol to target pine bark beetles (Curculionidae) and woodborers (Cerambycidae) in a third experiment. Canopy traps were more effective than understory traps for detecting Cnestus mutilatus (Blandford) (Curculionidae), Neoclytus scutellaris (Olivier), and Monochamus titillator (F.) (Cerambycidae). The reverse was true for Xylosandrus crassiusculus (Motschulsky), Dendroctonus terebrans (Olivier) (Curculionidae), and Neoclytus acuminatus (F.) (Cerambycidae). Catches of a third group which included Hylobius pales (Herbst), Ips grandicollis (Eichhoff) (Curculionidae), Neoclytus mucronatus (F.), and Anelaphus pumilus (Newman) (Cerambycidae) were largely unaffected by trap height. Similar patterns were noted for species of Cleridae, Scarabaeidae, Trogossitidae, and Zopheridae but not Histeridae or Tenebrionidae (Coleoptera). Catches of the bee assassin Apiomerus crassipes (F.) (Hemiptera: Reduviidae) in traps baited with the hardwood borer blend were greater in canopy traps than in understory traps.


The shear response of copper bicrystals with Σ11 symmetric and asymmetric tilt grain boundaries by molecular dynamics simulation.
Grain boundaries (GBs) are important microstructure features and can significantly affect the properties of nanocrystalline materials. Molecular dynamics simulation was carried out in this study to investigate the shear response and deformation mechanisms of symmetric and asymmetric Σ11<1 1 0> tilt GBs in copper bicrystals. Different deformation mechanisms were reported, depending on GB inclination angles and equilibrium GB structures, including GB migration coupled to shear deformation, GB sliding caused by local atomic shuffling, and dislocation nucleation from GB. The simulation showed that migrating Σ11(1 1 3) GB under shear can be regarded as sliding of GB dislocations and their combination along the boundary plane. A non-planar structure with dissociated intrinsic stacking faults was prevalent in Σ11 asymmetric GBs of Cu. This type of structure can significantly increase the ductility of bicrystal models under shear deformation. A grain boundary can be a source of dislocation and migrate itself at different stress levels. The intrinsic free volume involved in the grain boundary area was correlated with dislocation nucleation and GB sliding, while the dislocation nucleation mechanism can be different for a grain boundary due to its different equilibrium structures.


Tunicamycin enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human prostate cancer cells.
Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L). In this study, we showed that tunicamycin, a naturally occurring antibiotic, is a potent enhancer of TRAIL-induced apoptosis through up-regulation of DR5 expression. Tunicamycin significantly sensitized PC-3, androgen-independent human prostate cancer cells, to TRAIL-induced apoptosis. The tunicamycin-mediated enhancement of TRAIL-induced apoptosis was markedly blocked by a recombinant human DR5/Fc chimeric protein. Tunicamycin and TRAIL cooperatively activated caspase-8, -10, -9, and -3 and Bid cleavage and this activation was also blocked in the presence of the DR5/Fc chimera. Tunicamycin up-regulated DR5 expression at the mRNA and protein levels in a dose-dependent manner. Furthermore, the tunicamycin-mediated sensitization to TRAIL was efficiently reduced by DR5 small interfering RNA, suggesting that the sensitization was mediated through induction of DR5 expression. Tunicamycin increased DR5 promoter activity and this enhanced activity was diminished by mutation of a CHOP-binding site. In addition, suppression of CHOP expression by small interfering RNA reduced the tunicamycin-mediated induction of DR5. Of note, tunicamycin-mediated induction of CHOP and DR5 protein expression was not observed in normal human peripheral blood mononuclear cells. Moreover, tunicamycin did not sensitize the cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may be a promising candidate for prostate cancer therapy.


Simultaneous or staged installation with guided bone augmentation of transmucosal titanium implants. A 3-year prospective cohort study.
A prospective cohort study of 45 nonsmoking consecutively admitted patients was studied for the treatment outcomes following jaw bone augmentation in conjunction with installment of oral implants. Twenty-eight patients were treated for both bone augmentation and implant treatment simultaneously, while 17 patients were treated with a staged approach with the bone augmentation being performed 6-8 months prior to implant installation. Three months following this, prosthetic reconstructions were incorporated. One year thereafter, baseline data and 3 years after reconstruction, follow-up data were obtained. Moderately low mean scores for the bleeding on probing percentage were found at baseline (24%) and after 3 years of function (17%), while the corresponding values at the implant sites were 40.6% and 52.4%, respectively. However, the modified gingival index (mGI) = 2 was found in only 4.8%, and 6.9% at the baseline and 3-year examinations. Peri-implant Probing depth (PPD) and level of attachment mean values did not vary between baseline and follow-up examinations. Only a small proportion of 1.8% yielded PPD = 6.0 mm after 3 years of function. Radiographic bone level measurements showed that 18.2% of the implants lost 0.5 mm during the observation period. Seventy percent of the sites were considered completely stable. It was concluded that predictable treatment outcomes resulted for oral implant installation combined with or staged after jawbone augmentation. Only 6.5% of the sites had lost 1.5% crestal bone with the staged approach while 14% of the sites had lost 1.5 mm, when the implants were placed simultaneously. This suggests that the staged approach may have a lower risk for greater amounts of crestal bone loss as the simultaneous approach. In general, crestal bone loss encountered in the present study corresponded very well with that reported following placement of the same implant system into nonaugmented bone.


Rationale of Hemoadsorption during Extracorporeal Membrane Oxygenation Support.
Extracorporeal membrane oxygenation (ECMO) and extracorporeal life support are increasingly used for treating various forms of shock, lung failure, protected interventions and life support including resuscitation. Most patients on ECMO are affected by a systemic inflammatory response caused by the underlying disease as well as the ECMO support itself, which contributes to vasoplegia, multi-organ failure, deterioration and death. Unfortunately, effective strategies for control of inflammation and related organ failure and shock on ECMO are lacking. Recently, a new polystyrene-based device for hemoadsorption, which aims to reduce excessive levels of inflammatory molecules such as interleukins, cytokines as well as damage- and pathogen-associated molecular patterns, has become available. Here we summarize the rationale, available data and technical aspects of polystyrene-based hemoadsorption during ECMO support, and give recommendations based on existing experience.


Localized desensitization of Limulus photoreceptors produced by light or intracellular calcium ion injection.
Spots of light were used to measure the light sensitivity of spatially separated regions of single Limulus photoreceptors. The desensitization caused by irradiating part of the cell was largest in the irradiated region. The desensitization caused by intracellular calcium ion injection was largest near the infection site. The spread of desensitization away from the injection site suggests that calcium ion can diffuse over neuronal dimensions, but that the effective rate of diffusion is not so high as to abolish calcium gradients. The results are compatible with the previously proposed hypothesis that a rise in the intracellular calcium ion concentration mediates light adaptation.


From Cohort to Cohort: A Similar Mixture Approach (SMACH) to Evaluate Exposures to a Mixture Leading to Thyroid-Mediated Neurodevelopmental Effects Using NHANES Data.
Prenatal exposure to a mixture (MIX N) of eight endocrine-disrupting chemicals has been associated with language delay in children in a Swedish pregnancy cohort. A novel approach was proposed linking this epidemiological association with experimental evidence, where the effect of MIX N on thyroid hormone signaling was assessed using the Xenopus eleuthero-embryonic thyroid assay (XETA OECD TG248). From this experimental data, a point of departure (PoD) was derived based on OECD guidance. Our aim in the current study was to use updated toxicokinetic models to compare exposures of women of reproductive age in the US population to MIX N using a Similar Mixture Approach (SMACH). Based on our findings, 66% of women of reproductive age in the US (roughly 38 million women) had exposures sufficiently similar to MIX N. For this subset, a Similar Mixture Risk Index (SMRIHI) was calculated comparing their exposures to the PoD. Women with SMRIHI > 1 represent 1.1 million women of reproductive age. Older women, Mexican American and other/multi race women were less likely to have high SMRIHI values compared to Non-Hispanic White women. These findings indicate that a reference mixture of chemicals identified in a Swedish cohort-and tested in an experimental model for establishment of (PoDs)-is also of health relevance in a US population.


Preoperative C-Peptide Predicts Weight Gain After Pancreas Transplantation.
Transplant recipients are susceptible to cardiovascular complications, obesity, and increased insulin resistance after transplant. Here we assess weight gain in diabetic recipients after pancreas transplantation. This is a single-center study of 32 simultaneous pancreas and kidney and 5 pancreas after kidney transplant recipients from 2014 to 2018. Starting C-peptide levels ≤ 0.1 ng/mL were used to denote insulin nondetectability (n = 25) and C-peptide levels > 0.1 ng/mL as insulin detectability (n = 12). Hemoglobin A1c, body mass index (BMI), and weight following transplantation were assessed. Hemoglobin A1c at 1 year was 5.9% in the insulin nondetectable recipients and 5.6% in the insulin detectable group (P = .56). Average BMI after transplant was higher in the insulin detectable group 28.6 versus 24.4 kg/m2 (P = .03) despite no difference in starting BMIs (24.9 versus 24.0 kg/m2, P = .42). The insulin detectable group also had a larger percentage weight change from their starting weight 13.1% versus 0.9 % at 1 year (P = .02). Linear regression demonstrated that starting C-peptide was a significant predictor of weight gain posttransplant. Patients with elevated C-peptides at time of transplant are susceptible to rapid weight gain postoperatively. These patients may benefit from aggressive nutritional management.


COST-EFFECTIVENESS OF EARLY NUTRITIONAL THERAPY IN MALNOURISHED ADULT PATIENTS IN A HIGH COMPLEXITY HOSPITAL.
hospital malnutrition is a frequent worldwide problem and its potential issues related include increased complications, length of stay, mortality, and healthcare costs. the aim of this study was to establish the cost-effectiveness of early nutritional therapy for malnourished patients in a high complexity hospital. this analytical study with economic assessment included 227 adult hospitalised and malnourished according to the Subjective Global Assessment. The cohort prospective received Early Nutrition Therapy (ENT), whereas the cohort retrospective received Delayed Nutrition Therapy (DNT). The measures of cost-effectiveness included costs by: length of stay, complications and discharge condition. the cohorts were similar in demographic and clinical characteristics, except that the median age, for the ENT was 61 years (interquartile range [IQR]: 48-71) and for the DNT was 55 years (IQR: 44-67) (p = 0.024). The median length of stay was lower in the ENT (11 days, IQR: 7-17) than in the DNT (18 days, IQR: 10-28) (p < 0.001). The cost per patient discharged alive was US $ 10,261.55 in the ENT and US $ 15,553.11 in the DNT (p=0.043); the cost per patient with complications was US $ 13,663.90 in the ENT and US $ 17,860.32 in the DNT (p= 0.058). ENT increased the likelihood of being discharged alive, RR adjusted=0.31; 95% confidence interval (CI): 0.1; 0.6; (p<0.001) and decreased the likelihood of complications RR crude=0.8; 95% CI: 0.6; 0.9; (p=0.006). early nutritional therapy for malnourished adult patients appears to be cost-effective because it can reduce the length of stay, complications, mortality and associated costs.


Motor cortex inhibition induced by acoustic stimulation.
The influence of the brainstem motor system on cerebral motor areas may play an important role in motor control in health and disease. A new approach to investigate this interaction in man is combining acoustic stimulation activating the startle system with transcranial magnetic stimulation (TMS) over the motor cortex. However, it is unclear whether the inhibition of TMS responses following acoustic stimulation occurs at the level of the motor cortex through reticulo-cortical projections or subcortically, perhaps through reticulo-spinal projections. We compared the influence of acoustic stimulation on motor effects elicited by TMS over motor cortical areas to those evoked with subcortical electrical stimulation (SES) through depth electrodes in five patients treated with deep brain stimulation for Parkinson's disease. SES bypasses the motor cortex, demonstrating any interaction with acoustic stimuli at the subcortical level. EMG was recorded from the contralateral biceps brachii muscle. Acoustic stimulation was delivered binaurally through headphones and used as a conditioning stimulus at an interstimulus interval of 50 ms. When TMS was used as the test stimulus, the area and amplitude of the conditioned motor response was significantly inhibited (area: 57.5+/-12.9%, amplitude: 47.9+/-7.4%, as percentage of unconditioned response) whereas facilitation occurred with SES (area: 110.1+/-4.3%, amplitude: 116.9+/-6.9%). We conclude that a startle-evoked activation of reticulo-cortical projections transiently inhibits the motor cortex.