Unmet Health Care Need in US Adolescents and Adult Health Outcomes.
Adolescence is a formative period when health care services have a unique opportunity to influence later health outcomes. Unmet health care need in adolescence is known to be associated with poor contemporaneous health outcomes; it is unknown whether it predicts poor adult health outcomes. We used nationally representative data from 14 800 subjects who participated in Wave I (mean age: 15.9 years [1994/1995]) and Wave IV (mean age: 29.6 years [2008]) of the National Longitudinal Study of Adolescent to Adult Health. Logistic regression models were used to estimate the association between unmet health care need in adolescence and 5 self-reported measures of adult health (fair/poor general health, functional impairment, time off work/school, depressive symptoms, and suicidal ideation). Models were adjusted for baseline health, insurance category, age, gender, race/ethnicity, household income, and parental education. Unmet health care need was reported by 19.2% of adolescents and predicted worse adult health: fair/poor general health (adjusted odds ratio [aOR]: 1.27 [95% confidence interval (CI): 1.00-1.60]); functional impairment (aOR: 1.52 [95% CI: 1.23-1.87]); depressive symptoms (aOR: 1.36 [95% CI: 1.13-1.64]); and suicidal ideation (aOR: 1.30 [95% CI: 1.03-1.68]). There was no significant association between unmet health care need and time off work/school (aOR: 1.13 [95% CI: 0.93-1.36]). Cost barriers accounted for only 14.8% of unmet health care need. The reason for unmet need was not significantly related to the likelihood of poor adult health outcomes. Reported unmet health care need in adolescence is common and is an independent predictor of poor adult health. Strategies to reduce unmet adolescent need should address health engagement and care quality, as well as cost barriers to accessing services.


α11β1 Integrin is Induced in a Subset of Cancer-Associated Fibroblasts in Desmoplastic Tumor Stroma and Mediates In Vitro Cell Migration.
Integrin α11β1 is a collagen receptor that has been reported to be overexpressed in the stroma of non-small cell lung cancer (NSCLC) and of head and neck squamous cell carcinoma (HNSCC). In the current study, we further analyzed integrin α11 expression in 14 tumor types by screening a tumor tissue array while using mAb 203E3, a newly developed monoclonal antibody to human α11. Different degrees of expression of integrin α11 were observed in the stroma of breast, ovary, skin, lung, uterus, stomach, and pancreatic ductal adenocarcinoma (PDAC) tumors. Co-expression queries with the myofibroblastic cancer-associated fibroblast (myCAF) marker, alpha smooth muscle actin (αSMA), demonstrated a moderate level of α11+ in myCAFs associated with PDAC and HNSCC tumors, and a lack of α11 expression in additional stromal cells (i.e., cells positive for fibroblast-specific protein 1 (FSP1) and NG2). The new function-blocking α11 antibody, mAb 203E1, inhibited cell adhesion to collagen I, partially hindered fibroblast-mediated collagen remodeling and obstructed the three-dimensional (3D) migration rates of PDAC myCAFs. Our data demonstrate that integrin α11 is expressed in a subset of non-pericyte-derived CAFs in a range of cancers and suggest that α11β1 constitutes an important receptor for collagen remodeling and CAF migration in the tumor microenvironment (TME).


Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X.
Cytochrome P450c17 (P450c17) is a bifunctional enzyme necessary for the production of glucocorticoids (17-hydroxylase activity) and sex steroids (17,20-lyase activity). Isolated 17,20-lyase deficiency is a rare condition characterized by a deficient production of androgens resulting in 46,XY disorders of sex development (DSD) while the production of glucocorticoids is intact. Several missense mutations in the CYP17A1 gene are known to cause this condition. Cytochrome b(5) (CytB5) is an important factor in 17,20-lyase activity, probably by acting as an allosteric factor. The aim of this study was to investigate the role of CytB5 in a patient with defective 17,20-lyase activity. We conducted the study in a pediatric outpatient clinic of a University Hospital. We studied a 46,XY DSD patient with 17,20-lyase deficiency without missense mutation in the CYP17A1 gene and his parents. We sequenced the CYB5 gene and measured steroid hormone levels. Analysis of the CYB5 gene in our patient revealed a homozygous W27X mutation, leading to the formation of a premature stop codon; his parents were both heterozygous carriers of this mutation. This mutation results in the absence of residues E48 and E49 of CytB5, which are necessary for an intact 17,20-lyase activity. We demonstrated 17,20-lyase deficiency due to an aberrant CytB5. Our findings thus provide evidence for an alternative etiology for this disorder.


Improving the use of research evidence in guideline development: 9. Grading evidence and recommendations.
The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the ninth of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. We reviewed the literature on grading evidence and recommendations in guidelines. We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct a full systematic review ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. Should WHO grade the quality of evidence and the strength of recommendations? Users of recommendations need to know how much confidence they can place in the underlying evidence and the recommendations. The degree of confidence depends on a number of factors and requires complex judgments. These judgments should be made explicitly in WHO recommendations. A systematic and explicit approach to making judgments about the quality of evidence and the strength of recommendations can help to prevent errors, facilitate critical appraisal of these judgments, and can help to improve communication of this information. What criteria should be used to grade evidence and recommendations? Both the quality of evidence and the strength of recommendations should be graded. The criteria used to grade the strength of recommendations should include the quality of the underlying evidence, but should not be limited to that. The approach to grading should be one that has wide international support and is suitable for a wide range of different types of recommendations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which is currently suggested in the Guidelines for WHO Guidelines, is being used by an increasing number of other organizations internationally. It should be used more consistently by WHO. Further developments of this approach should ensure its wide applicability. Should WHO use the same grading system for all of its recommendations? Although there are arguments for and against using the same grading system across a wide range of different types of recommendations, WHO should use a uniform grading system to prevent confusion for developers and users of recommendations.


Treatment response after relapse in a placebo-controlled maintenance trial in schizophrenia.
While placebo-controlled studies continue to be required by regulatory authorities for the licensing of new drugs for schizophrenia to demonstrate maintenance of effect, the long-term risks to participants are largely unknown. We compared the response to treatment with paliperidone palmitate before and after relapse in such a study. This was a post-hoc analysis of 97 patients with schizophrenia who relapsed while receiving placebo in a multinational relapse prevention clinical trial. Patients underwent an initial open-label treatment phase of 33 weeks (comprising a 9-week transition phase to switch patients to paliperidone palmitate, a 12-week flexible-dose phase and a 12-week fixed-dose phase); a double-blind phase of variable duration during which stabilized patients were randomized 1:1 to either continue paliperidone palmitate or receive placebo; and an optional 52-week open-label flexible-dose extension phase. There was a small but significant increase in PANSS total scores after eight months of treatment following relapse (56.7[12.68]) compared with prerelapse endpoint (54.5[11.74]) (p=0.026). Fourteen of 97 (14.4%) patients who had initially responded favorably to treatment met predefined nonresponse criteria in the postrelapse treatment phase, suggesting that treatment refractoriness may evolve in a subset of patients after relapse. However, relapses occurred in 18% of patients randomized to ongoing treatment in the double-blind phase, raising the possibility that treatment failure may also evolve in patients receiving continuous treatment. These findings may help inform decisions regarding the future of placebo-controlled trials in schizophrenia.


Focused bedside echocardiography in the surgical intensive care unit: comparison of 3 methods to estimate cardiac index.
We sought to determine which of 3 methods used to evaluate cardiac index (CI) is the most accurate using focused bedside echocardiography (ECHO). We hypothesized that the fractional shortening (FS) method would provide a more accurate estimate of CI than the left ventricular outflow tract/velocity-time integral (LVOT/VTI) or Simpson's methods. This was a prospective observational cohort study conducted in the surgical ICU of an urban level 1 trauma center utilizing all patients with a pulmonary artery catheter (PAC) in place. Three surgical intensive care unit (SICU) faculty and 3 fellows underwent focused cardiac ultrasound training. Focused ECHO exams-bedside echocardiographic assessment in trauma/critical care (BEAT)- were performed using the Sonosite portable ultrasound device (Bothall, Washington). Stroke volume (SV) measurements were prospectively obtained on all trauma/SICU patients, with a PAC in place, using FS, LVOT/VTI, and Simpson's methods. The investigators were blinded to the PAC data. From each measurement, CI was calculated and categorized as low, normal, or high, based on a normal range of 2.4 to 4.0 L/min per m(2). Each CI obtained from the PAC was similarly categorized. The association between the BEAT and PAC estimates of CI was evaluated for each method using chi-square goodness of fit. Eighty five BEAT exams were performed on consecutive SICU patients, 56% were on trauma and 44% on emergency general surgery patients. There was a statistically significant association between the CI estimate using the FS method (P = .012), but not the LVOT/VTI (P = .33) or Simpson's method (P = .74). Our data showed a significant association between the PAC estimate of CI and our estimate using the FS method. The other methods were difficult to obtain, subjective, and inaccurate. Fractional shortening was the method of choice to estimate CI for the BEAT exam performed by intensivists in SICU patients.


Strategies for overcoming inherent and acquired resistance to EGFR inhibitors by targeting downstream effectors in the RAS/PI3K pathway.
Mutations in K-Ras are observed in approximately 40% of colon tumours. This has significant implications for predicting likelihood of response to the antibody-based EGFR inhibitors, cetuximab and panitumumab, with K-Ras mutant patients now clearly shown to be inherently resistant to these agents. Alternative treatment strategies for K-Ras mutant patients are therefore urgently needed. Farnesyltransferase inhibitors, developed to inhibit K-Ras, have to-date been largely unsuccessful. However, a number of agents which target signaling components in the MAPK and PI3K pathways downstream of mutant K-Ras are currently being evaluated in clinical trials and will be discussed. A further clinical concern is that K-Ras wild type patients who initially respond to EGFR inhibitors eventually develop acquired resistance to these agents and experience tumour progression. Studies from the use of related agents in other disease settings as well as pre-clinical studies provide important insights into mechanisms by which this may occur. While no evidence presently exists for somatic mutations as a basis for acquired resistance to EGFR inhibitors in colon cancer, several studies implicate upregulation and signaling via other Her family members, c-Met, IGFR and Src. Upregulation of the pro-angiogenic factor, VEGF, is also a possible mechanism of acquired resistance. This review discusses drugs currently in clinical trials that may potentially achieve more efficient and prolonged targeting of the EGFR pathway by overcoming these mechanisms of resistance.


Plasmodium vivax Pv12 B-cell epitopes and HLA-DRβ1*-dependent T-cell epitopes in vitro antigenicity.
Malaria is an infectious disease caused by parasites from the genus Plasmodium (P. falciparum and P. vivax are responsible for 90% of all clinical cases); it is widely distributed throughout the world's tropical and subtropical regions. The P. vivax Pv12 protein is involved in invasion, is expressed on merozoite surface and has been recognised by antibodies from individuals exposed to the disease. In this study, B- and T-cell epitopes from Pv12 were predicted and characterised to advance in the design of a peptide-based vaccine against malaria. For evaluating the humoral response of individuals exposed to natural P. vivax infection from two endemic areas in Colombia, BepiPred-1.0 software was used for selecting B-cell epitopes. B-cell epitope 39038 displayed the greatest recognition by naturally-acquired antibodies and induced an IgG2/IgG4 response. NetMHCIIpan-3.1 prediction software was used for selecting peptides having high affinity binding for HLA-DRβ1* allele lineages and this was confirmed by in-vitro binding assays. T-epitopes 39113 and 39117 triggered a memory T-cell response (Stimulation Index≥2) and significant cytokine production. Combining in-silico, in-vitro and functional assays, two Pv12 protein regions (containing peptides 39038, 39040, 39113 and 39117) have thus been characterised as promising vaccine candidates against P. vivax malaria.


Focal attention in the frog: behavioral and physiological correlates.
The prey-catching response of frogs toward small moving objects can be facilitated by small movements of the same stimulus a few seconds earlier, even though initial movements seldom trigger the feeding response. This focal attention phenomenon may be related to the observation that one class of tectal unit continues to discharge for a few seconds following a brief stimulus motion. Together with anatomical data of other investigators, results of the present study suggest that self-exciting neural loops within the tectum mediate this type of selective attention.


Endothelial progenitor cells restore renal function in chronic experimental renovascular disease.
Endothelial progenitor cells (EPCs) promote neovascularization and endothelial repair. Renal artery stenosis (RAS) may impair renal function by inducing intrarenal microvascular injury and remodeling. We investigated whether replenishment with EPCs would protect the renal microcirculation in chronic experimental renovascular disease. Single-kidney hemodynamics and function were assessed with the use of multidetector computed tomography in vivo in pigs with RAS, pigs with RAS 4 weeks after intrarenal infusion of autologous EPCs, and controls. Renal microvascular remodeling and angiogenic pathways were investigated ex vivo with the use of micro-computed tomography, histology, and Western blotting. EPCs increased renal expression of angiogenic factors, stimulated proliferation and maturation of new vessels, and attenuated renal microvascular remodeling and fibrosis in RAS. Furthermore, EPCs normalized the blunted renal microvascular and filtration function. The present study shows that a single intrarenal infusion of autologous EPCs preserved microvascular architecture and function and decreased microvascular remodeling in experimental chronic RAS. It is likely that restoration of the angiogenic cascade by autologous EPCs involved not only generation of new vessels but also acceleration of their maturation and stabilization. This contributed to preserving the blood supply, hemodynamics, and function of the RAS kidney, supporting EPCs as a promising therapeutic intervention for preserving the kidney in renovascular disease.


From parallel to intersecting narratives in cases of sexual assault.
Restorative justice alternatives to criminal justice are designed to balance the needs of victims, offenders, families, friends, and the community at large to achieve social justice, repair of victims, and deterrence of crime. In the model we evaluated from RESTORE (Responsibility and Equity for Sexual Transgressions Offering a Restorative Experience), each offender and victim received individual services and met in guided conferencing to mutually determine reparative actions for the offender. At the exit meeting, the offender, as the responsible person, read a written apology to the survivor/victim. In this article, we analyze the expression of empathy in the apology, in which the initial mitigation of responsibility in early documents was replaced by acknowledgment of harm to the survivor/victim and acceptance of responsibility for the assault. Those accused of felony rape and those targeting a visible person in cases of misdemeanor indecent exposure expressed greater regret and remorse than offenders of indecent exposure with an indeterminate victim.


Risk Factors of Pediatric Arterial Ischemic Stroke; A Regional Survey.
Considering that better understanding of the underlying mechanisms and risk factors of arterial ischemic stroke (AIS) would be helpful for better management of stroke and its outcome in children as well as preventing or reducing the occurrence of its related potential disabilities, the aim of this study was to investigate the most common risk factors and causes of AIS in patients referred to the referral hospitals in Tehran and Isfahan cities of Iran. In this study, medical files of all pediatric patients admitted to the Mofid and Imam Hossein children's hospitals with the diagnosis of AIS from 2001 to 2011 and 2011 to 2016, respectively, were evaluated. Identified risk factors of AIS were categorized as arteriopathies, cardiac disorders (CDs), infection, acute head-and-neck disorders, acute systemic conditions, chronic systemic conditions, prothrombotic states, chronic head-and-neck disorders, atherosclerosis-related RFs, and others. In this study, 61 patients were evaluated. Mean (standard deviation) age of the patients was 5.1 (3.9) years. About 62.3% of the patients were boys while 37.7% were girls (P < 0.01). A total of 36 patients (59%) had at least one risk factor for AIS. About 40.9% of patients had undetermined risk factors. CDs (21.31%) and vascular disease (21.31%) were the most common risk factors of AIS in the studied children. Nearly 11.5% of the patients had moyamoya vascular disease (MMD). The findings of our study indicated that the most common risk factors for AIS in the two studied regions are congenital heart and vascular diseases. The results of the current study could be used for planning more preventive strategies in patients suffering from the mentioned diseases. In addition, the obtained data could be used for conducting targeted education and management of high-risk patients.


Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response.
Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late-phase response to formalin injection in 275 male and female Diversity Outbred mice genotyped for over 70,000 single nucleotide polymorphisms. One quantitative trait locus reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity quantitative trait locus 4; MGI: 5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of Diversity Outbred founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the 7 other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, TRPA1-TRPV1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.


Novel functions of the phosphatase SHP2 in the DNA replication and damage checkpoints.
Replication stress- and DNA damage-induced cell cycle checkpoints are critical for maintaining genome stability. To identify protein phosphatases involved in the activation and maintenance of the checkpoints, we have carried out RNA interference-based screens with a human phosphatome shRNA library. Several phosphatases, including SHP2 (also called PTPN11) were found to be required for cell survival upon hydroxyurea-induced replicative stress in HeLa cells. More detailed studies revealed that SHP2 was also important for the maintenance of the checkpoint after DNA damage induced by cisplatin or ionizing radiation in HeLa cells. Furthermore, SHP2 was activated after replicative stress and DNA damage. Although depletion of SHP2 resulted in a delay in cyclin E accumulation and an extension of G(1) phase, these cell cycle impairments were not responsible for the increase in apoptosis after DNA damage. Depletion of SHP2 impaired CHK1 activation, checkpoint-mediated cell cycle arrest, and DNA repair. These effects could be rescued with a shRNA-resistant SHP2. These results underscore the importance of protein phosphatases in checkpoint control and revealed a novel link between SHP2 and cell cycle checkpoints.


Stereoselective glucuronidation of ofloxacin in rat liver microsomes.
The stereoselective glucuronidation of ofloxacin [(+/-)-OFLX], a new quinolone antibacterial agent, was studied in vitro using rat liver microsomes. OFLX glucuronidation exhibited Michaelis-Menten kinetics in rat liver microsomes. Stereoselective glucuronidation of the optical enantiomers occurred. S-(-)-OFLX glucuronide was produced 7-fold more than R-(+)-OFLX glucuronide with little or no difference in the values of KM of the enantiomers. The value of Vmax/KM for the glucuronide conjugate of S-(-)-OFLX was 8-fold greater than for the conjugate of R-(+)-OFLX. These results demonstrate that OFLX undergoes stereoselective glucuronidation in vitro. Moreover, we studied the in vivo interaction between enantiomers of OFLX in rats to clarify the effects of R-(+)-OFLX on the metabolism and disposition of S-(-)-OFLX. When the racemate [(+/-)-OFLX (20 mg/kg)] or single enantiomer [S-(-)-OFLX (10 mg/kg)] is administered iv to the rat, the serum concentrations of S-(-)-OFLX were higher after racemate administration than those after enantiomer administration, although the dose of S-(-)-OFLX was identical in both cases. These results indicate that R-(+)-OFLX may compete with S-(-)-OFLX in the in vivo glucuronidation. Furthermore, the results of the enantiomeric inhibition study showed that R-(+)-OFLX competitively inhibited S-(-)-OFLX glucuronidation in vitro with a Ki value of 2.92 mM.


Assessing HIV resistance in developing countries: Brazil as a case study.
Increased transmission of resistant HIV has been raised as a potential consequence of expanded access to antiretroviral therapy. We review how limitations in resources and health care infrastructure may impact the transmission of resistant HIV, and we examine data from Brazil as a case study. We introduce a biological and clinical framework to identify the major determinants of transmitted resistance and to discuss how these determinants may be affected by a lack of infrastructure. We then use our framework to examine HIV resistance data from Brazil. This country was chosen as a case study due to its extensive experience delivering antiretroviral drugs and because of the availability of data on the prevalence of resistant HIV there. The data from Brazil show that antiretroviral therapy can be delivered in a resource-limited setting without resulting in widespread transmission of resistant virus. While the Brazilian experience does not necessarily generalize to countries with less health care infrastructure, neither theory nor data support a foregone conclusion that resistance will necessarily dominate HIV epidemics in the developing world to a greater extent than it does in the developed world.


Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine.
Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase(AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.


Decreased contractility of the ductus arteriosus in experimental pulmonic stenosis.
Delayed closure of the ductus arteriosus after birth has been observed in newborn infants with critical pulmonic stenosis and in newborn lambs with experimental pulmonic stenosis. This delayed ductal closure may be caused by a decreased ability of the muscle to contract when exposed to oxygen or to an increased production of or sensitivity to prostaglandin (PG) E2, the endogenous ductus arteriosus vasodilator. To determine whether the abnormal hemodynamic pattern during fetal life associated with pulmonic stenosis alters the responsiveness of the ductus arteriosus, we operated on 10 fetal lambs of gestational ages 70 to 77 days (term is 148 days) and placed a band around the pulmonary artery. Catheterization at 137 to 142 days showed severe pulmonic stenosis. We then studied isolated rings of ductus arteriosus from these lambs. The oxygen-induced increase in tension in rings of ductus arteriosus from lambs with pulmonic stenosis was significantly decreased (2.55 +/- 0.38; n = 10) compared with rings from control lambs (4.03 +/- 0.51; n = 6, p less than .03). There was no difference between the two groups in either the amount of PGE2 released by the rings or in the sensitivity (expressed as median effective dose) of the rings to PGE2. There was also no difference in the increase in tension when endogenous PGE2 was inhibited by indomethacin. We conclude that delayed closure of the ductus arteriosus in lambs with experimental pulmonic stenosis is not caused by increased sensitivity to or production of PGE2 in the ductus arteriosus (as it is in premature lambs) but rather is the result of a diminished ability of the ductus arteriosus to contract when exposed to oxygen.


Multitechnique investigation of the pH dependence of phosphate induced transformations of ZnO nanoparticles.
In order to properly evaluate the ecological and human health risks of ZnO manufactured nanomaterials (MNMs) released to the environment, it is critical to understand the likely transformation products in various environments, such as soils, surface and ground waters, and wastewater treatment processes. To address this knowledge gap, we examined the transformation of 30 nm ZnO MNMs in the presence of different concentrations of phosphate as a function of time and pH using a variety of orthogonal analytical techniques. The data reveal that ZnO MNMs react with phosphate at various concentrations and transform into two distinct morphological/structural phases: a micrometer scale crystalline zinc phosphate phase (hopeite-like) and a nanoscale phase that likely consists of a ZnO core with an amorphous Zn3(PO4)2 shell. The P species composition was also pH dependent, with 82% occurring as hopeite-like P at pH 6 while only 15% occurred as hopeite-like P at pH 8. These results highlight how reactions of ZnO MNMs with phosphate are influenced by environmental variables, including pH, and may ultimately result in structurally and morphologically heterogeneous end products.


Therapeutic Efficacy of Home-Use Photobiomodulation Devices: A Systematic Literature Review.
Perform systematic literature review on photobiomodulation (PBM) devices used at home for nonesthetic applications. Home-use PBM devices have been marketed for cosmetic and therapeutic purposes. This is the first systematic literature review for nonesthetic applications. A systematic literature search was conducted for PBM devices self-applied at home at least thrice a week. Two independent reviewers screened the articles and extracted the data. Treatment dosage appropriateness was compared to the World Association for Laser Therapy (WALT) recommendations. The efficacy was evaluated according to the relevant primary end-point for the specific indication. Eleven studies were suitable. Devices were applied for a range of indications, including pain, cognitive dysfunction, wound healing, diabetic macular edema, and postprocedural side effects, and were mostly based on near-infrared, pulsed light-emitting diodes with dosages within WALT recommendations. Regarding efficacy, studies reported mostly positive results. Home-use PBM devices appear to mediate effective, safe treatments in a variety of conditions that require frequent applications. Conclusive evaluation of their efficacy requires additional, randomized controlled studies.


Linear free energy relationships for transition metal chemistry: case study of CH activation with copper-oxygen complexes.
We propose a computational framework for developing Taft-like linear free energy relationships to characterize steric effects on the catalytic activity of transition metal complexes. This framework uses the activation strain model and energy decomposition analysis to isolate electronic and geometric effects, and identifies structural descriptors to construct linear relationships. We demonstrate proof-of-principle for CH activation with enzyme-inspired [Cu2O2]2+ complexes coordinated to bidentate diamine N-donors. Electronic effects are largely similar across chosen systems and geometric effects - quantified by strain energies - are accurately captured by a linear combination of two structural descriptors. A powerful linear free energy relationship emerges that is transferable to asymmetrically substituted complexes. We outline steps for expanding this approach to create a generalizable Taft framework for inorganic catalyst design.


Pneumocystis carinii pneumonia presenting as asthma: increased bronchial hyperresponsiveness in Pneumocystis carinii pneumonia.
Two male patients presented with clinical and laboratory findings consistent with typical bronchial asthma and subsequently developed Pneumocystis carinii pneumonia (PCP). Only on subsequent questioning did both admit to homosexuality and behavior associated with a high risk of HIV-infection. In order to determine how frequently reversible airway obstruction is seen in patients with PCP, we measured peak expiratory flow rates (PEFR) before and after bronchodilator administration in 37 of these patients. Initial PEFR measurements revealed a significant decrease in PEFR (< 80% predicted) in 84%, with 54% of these exhibiting a significant bronchodilator response (> or = 15% increase). For comparison, peak flow measurements were made in a control group of 31 HIV-infected patients without acute PCP, divided between those with asymptomatic HIV-infection, AIDS-related complex (ARC), and AIDS, (including patients with previous PCP). Only 23% of these individuals had low PEFR, and only 3% exhibited bronchodilator responses. In order to confirm the existence of bronchial hyperreactivity in patients with PCP, another 16 patients with PCP were tested by methacholine bronchial challenge and 50% were found to have positive responses. These findings suggest that both reversible airway obstruction and airway hyperreactivity are found in association with acute PCP and that as a result some patients with PCP may present with symptoms of asthma. It is important for physicians to have a high degree of suspicion to avoid missing a diagnosis of PCP in a patient presenting with apparent asthma.


Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.


Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract NK cells.
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell-based immunotherapy. We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype. We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell-mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor-derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell-mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2. ATC cell lines are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell-based immunotherapy.


Suicidal Behavior During Lithium and Valproate Treatment: A Within-Individual 8-Year Prospective Study of 50,000 Patients With Bipolar Disorder.
Conclusions regarding lithium's antisuicidal effect for bipolar disorder have been limited due to nonrepresentative subjects and potential confounding factors, including varying severity of illness. Findings regarding the effect of valproate, the most common alternative to lithium, are inconsistent for suicidal behavior. This study investigated the associations of these two drugs with the risk of suicide-related events, and possible differences between drugs, by using within-individual designs in a register-based longitudinal cohort. Through linkage of multiple Swedish national registers, 51,535 individuals with bipolar disorder were followed from 2005 to 2013 for treatment with lithium and valproate. Stratified Cox regression was used to estimate the hazard ratios of suicide-related events during treated periods compared with untreated periods. For significant associations between medication and suicide-related events, the population attributable fraction was estimated to assess the public health impact for patients with bipolar disorder. During follow-up, 10,648 suicide-related events occurred. The incidence rate was significantly decreased by 14% during lithium treatment (hazard ratio 0.86, 95% confidence interval [CI] 0.78-0.95) but not during valproate treatment (hazard ratio 1.02, 95% CI 0.89-1.15). The difference in hazard ratios of suicide-related events between lithium and valproate was statistically significant. Estimates of the population attributable fraction suggested that 12% (95% CI 4%-20%) of suicide-related events could have been avoided if patients had taken lithium during the entire follow-up. The results suggest that lithium should be considered for patients with bipolar disorder with suspected suicidal intentions, although risk for suicide is only one of the considerations when providing clinical care.


Patients with Van Buchem disease, an osteosclerotic genetic disease, have elevated bone formation markers, higher bone density, and greater derived polar moment of inertia than normal.
Van Buchem disease is an autosomal recessive disease characterized by overgrowth of the skeleton. In a group of Dutch patients the disease is thought to be due to a 52-kb deletion that results in decreased expression of the SOST gene. To further characterize the disease, the morphology of the metacarpals of six adult subjects and two juveniles with Van Buchem disease were measured on hand x-rays along with nine normal adults and nine adult carriers of the disease. Serum bone formation markers, alkaline phosphatase, type I procollagen peptide, and osteocalcin, and the urinary bone resorption marker, cross-linked N-telopeptide, were determined. Van Buchem patients had increased metacarpal outer diameter, inner diameter, cortical thickness, and bone mineral density. Calculated bone volume and derived polar moment of inertia were markedly elevated (elevations of 158 +/- 33% and 497 +/- 95%, respectively) consistent with increased bone strength. Serum procollagen peptide and osteocalcin were significantly higher in Van Buchem patients. Urinary cross-linked N-telopeptide was significantly elevated in Van Buchem patients. None of these changes was found in Van Buchem carriers. These observations indicate that decreased expression of the SOST gene can lead to increased bone formation and to stronger bones.


Getting the 'blues': the existence, diffusion and influence of pornography on young peoples' sexual health in Sierra Leone.
While substantial research has examined the effects of pornography on young people in developed societies, existing studies fall short in addressing how sexually-explicit material affects young people in developing countries. The importance of such knowledge increases as the globalising effects of technology expand young peoples' access and exposure to pornography. During the summer of 2012, a study was undertaken in Sierra Leone examining factors affecting young peoples' sexual and reproductive health. The research assessed the influence of HIV knowledge, communication about sex, civil war and contraception myths on sexual behaviours, while remaining open to unanticipated factors. During data collection, respondents identified pornography, also called blues, as an influential factor, detailing its newfound accessibility driven by improved access to information and communication technologies in the country. Respondents also addressed several presumed ways in which pornography impacts young peoples' decisions about sexual health. The following study examines perceived effects of young peoples' exposure to pornography based on existing literature. It then outlines the findings of research conducted in Sierra Leone, drawing on primary data from the respondents and relevant published literature and concludes with proposals for addressing its negative effects.


Antiresonant decoupling of parallel dielectric waveguides.
Two open waveguides with finite spacing can be decoupled, if the index between them is a suitable function of the transverse coordinates. An analytical proof is provided that makes use of vector properties of electromagnetic waves. On the contrary, decoupling is shown to be impossible for scalar waves and thus incompatible with the weakly guiding assumption. Decoupling can be interpreted as a distributed antiresonance in the region between the waveguides.


High resolution imaging and wavefront aberration correction in plenoptic systems.
Plenoptic imaging systems are becoming more common since they provide capabilities unattainable in conventional imaging systems, but one of their main limitations is the poor bidimensional resolution. Combining the wavefront phase measurement and the plenoptic image deconvolution, we propose a system capable of improving the resolution when a wavefront aberration is present and the image is blurred. In this work, a plenoptic system is simulated using Fourier optics, and the results show that an improved resolution is achieved, even in the presence of strong wavefront aberrations.


Effective treatment of female androgenic alopecia with dutasteride.
Dihydrotestosterone is the main molecule responsible for androgenic alopecia. Finasteride, which reduces transformation of testosterone into dihydrotestosterone and decreases dihydrotestosterone activity, is approved for treatment of androgenic alopecia in men. We describe the case of a 46-year-old woman with androgenic alopecia, non-responsive to minoxidil, who initially benefited from finasteride. Due to only limited improvement after finasteride and persisting profound psychological distress resulting from androgenic alopecia, another 5-reductase inhibitor, dutasteride, was introduced. Clinical evaluation and trichogram were applied for assessment of dutasteride efficacy in this patient. Additionally, mean hair diameter was monitored by means of computer dermoscopy. After 6 months of therapy, significant improvement was observed and after 9 months the clinical diagnosis of androgenic alopecia could no longer be made in this patient. No side effects were observed. In conclusion, theoretical data and our experience in this case show that dutasteride might develop into a true alternative in treatment of androgenic alopecia.


A rapid review of the impact of COVID-19 on the mental health of healthcare workers: implications for supporting psychological well-being.
Health and social care workers (HSCWs) have carried a heavy burden during the COVID-19 crisis and, in the challenge to control the virus, have directly faced its consequences. Supporting their psychological wellbeing continues, therefore, to be a priority. This rapid review was carried out to establish whether there are any identifiable risk factors for adverse mental health outcomes amongst HSCWs during the COVID-19 crisis. We undertook a rapid review of the literature following guidelines by the WHO and the Cochrane Collaboration's recommendations. We searched across 14 databases, executing the search at two different time points. We included published, observational and experimental studies that reported the psychological effects on HSCWs during the COVID-19 pandemic. The 24 studies included in this review reported data predominantly from China (18 out of 24 included studies) and most sampled urban hospital staff. Our study indicates that COVID-19 has a considerable impact on the psychological wellbeing of front-line hospital staff. Results suggest that nurses may be at higher risk of adverse mental health outcomes during this pandemic, but no studies compare this group with the primary care workforce. Furthermore, no studies investigated the psychological impact of the COVID-19 pandemic on social care staff. Other risk factors identified were underlying organic illness, gender (female), concern about family, fear of infection, lack of personal protective equipment (PPE) and close contact with COVID-19. Systemic support, adequate knowledge and resilience were identified as factors protecting against adverse mental health outcomes. The evidence to date suggests that female nurses with close contact with COVID-19 patients may have the most to gain from efforts aimed at supporting psychological well-being. However, inconsistencies in findings and a lack of data collected outside of hospital settings, suggest that we should not exclude any groups when addressing psychological well-being in health and social care workers. Whilst psychological interventions aimed at enhancing resilience in the individual may be of benefit, it is evident that to build a resilient workforce, occupational and environmental factors must be addressed. Further research including social care workers and analysis of wider societal structural factors is recommended.


Impact of JNK and Its Substrates on Dendritic Spine Morphology.
The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory proteins. JNK1 also phosphorylates dendritic spine proteins, and Jnk1-/- mice display a long-term depression deficit. Whether JNK1 or other JNKs regulate spine morphology is thus of interest. Here, we characterize dendritic spine morphology in hippocampus of mice lacking Jnk1-/- using Lucifer yellow labelling. We find that mushroom spines decrease and thin spines increase in apical dendrites of CA3 pyramidal neurons with no spine changes in basal dendrites or in CA1. Consistent with this spine deficit, Jnk1-/- mice display impaired acquisition learning in the Morris water maze. In hippocampal cultures, we show that cytosolic but not nuclear JNK, regulates spine morphology and expression of phosphomimicry variants of JNK substrates doublecortin (DCX) or myristoylated alanine-rich C kinase substrate-like protein-1 (MARCKSL1), rescue mushroom, thin, and stubby spines differentially. These data suggest that physiologically active JNK controls the equilibrium between mushroom, thin, and stubby spines via phosphorylation of distinct substrates.


Screening level assessment of risks due to dioxin emissions from burning oil from the BP Deepwater Horizon Gulf of Mexico spill.
Between April 28 and July 19 of 2010, the U.S. Coast Guard conducted in situ oil burns as one approach used for the management of oil spilled after the explosion and subsequent sinking of the BP Deepwater Horizon platform in the Gulf of Mexico. The purpose of this paper is to describe a screening level assessment of the exposures and risks posed by the dioxin emissions from these fires. Using upper estimates for the oil burn emission factor, modeled air and fish concentrations, and conservative exposure assumptions, the potential cancer risk was estimated for three scenarios: inhalation exposure to workers, inhalation exposure to residents on the mainland, and fish ingestion exposures to residents. U.S. EPA's AERMOD model was used to estimate air concentrations in the immediate vicinity of the oil burns and NOAA's HYSPLIT model was used to estimate more distant air concentrations and deposition rates. The lifetime incremental cancer risks were estimated as 6 × 10(-8) for inhalation by workers, 6 × 10(-12) for inhalation by onshore residents, and 6 × 10(-8) for fish consumption by residents. For all scenarios, the risk estimates represent upper bounds and actual risks would be expected to be less.


Intermolecular charge fluxes and far-infrared spectral intensities of liquid formamide.
The intensity generation mechanisms of the far-infrared (far-IR) [or terahertz (THz)] spectrum of liquid formamide, particularly with regard to the behavior of electrons induced by modulations of the hydrogen-bonding conditions of the molecules, are examined theoretically. The theoretical analysis is done in the following two steps. First, density functional theory (DFT) calculations are carried out for the dimers and larger clusters of formamide to analyze the change in the dipole derivative (the square of which is proportional to the IR intensity) induced by hydrogen-bond formation. Then, by using the information derived in the first step, molecular dynamics-based spectral simulations are carried out. It is shown that, upon formation of a hydrogen bond, a change in the dipole derivative is induced along the direction of the hydrogen bond, and is reasonably modeled by the intermolecular charge flux mechanism, where a certain amount of electron density is transferred between molecules according to the modulation of the hydrogen-bond length, similarly to the case of liquid water. This model is in a form that is suitable for use in molecular dynamics-based spectral simulations. From these spectral simulations, it is found that the observed spectral features of the far-IR spectrum of liquid formamide are reasonably reproduced, and that the inclusion of the effect of intermolecular charge flux is essential for it. Contrary to the case of liquid water, the molecular libration band (rather than the molecular translation band) is significantly enhanced by the intermolecular charge flux. It is discussed that this difference is related to the geometrical relation between the hydrogen bonds and the atomic displacements in the molecular translations and librations (rotations). It is considered that, in general, in hydrogen-bonding liquids, modulations of hydrogen-bond lengths occurring upon dynamics of molecules give rise to intermolecular charge fluxes, significantly affecting the dipole derivatives, and hence, the IR intensity distributions in the spectra.


Roles of meditation on alleviation of oxidative stress and improvement of antioxidant system.
According to MEDLINE/Pubmed search to December 2009, the modulation effects of meditation on oxidative stress have been increasingly investigated for acute, short and long-term effects. Both invasive and noninvasive measurements have been utilized. Long-term transcendental and Zen meditators have been showed to diminish oxidative stress seen by a reduction of lipid peroxidation and biophoton emission. Glutathione level and activity of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase) have been facilitated in Yoga and Sudarshan Kriya practitioners. One year of Tai Chi training has been reported to promote superoxide dismutase activity and lessen lipid peroxidation. Performing diaphragmatic breathing after exhaustive exercise has attenuated oxidative stress faster than control. These data suggest possible roles of meditation and meditation-based techniques on the decrease of oxidative stress which may assist to prevent and/or alleviate deterioration of related diseases. However, further research needs to elucidate the cellular and molecular mechanisms which remain challenge to accomplish.


The importance of nonlinear tissue modelling in finite element simulations of infant head impacts.
Despite recent efforts on the development of finite element (FE) head models of infants, a model capable of capturing head responses under various impact scenarios has not been reported. This is hypothesized partially attributed to the use of simplified linear elastic models for soft tissues of suture, scalp and dura. Orthotropic elastic constants are yet to be determined to incorporate the direction-specific material properties of infant cranial bone due to grain fibres radiating from the ossification centres. We report here on our efforts in advancing the above-mentioned aspects in material modelling in infant head and further incorporate them into subject-specific FE head models of a newborn, 5- and 9-month-old infant. Each model is subjected to five impact tests (forehead, occiput, vertex, right and left parietal impacts) and two compression tests. The predicted global head impact responses of the acceleration-time impact curves and the force-deflection compression curves for different age groups agree well with the experimental data reported in the literature. In particular, the newly developed Ogden hyperelastic model for suture, together with the nonlinear modelling of scalp and dura mater, enables the models to achieve more realistic impact performance compared with linear elastic models. The proposed approach for obtaining age-dependent skull bone orthotropic material constants counts both an increase in stiffness and decrease in anisotropy in the skull bone-two essential biological growth parameters during early infancy. The profound deformation of infant head causes a large stretch at the interfaces between the skull bones and the suture, suggesting that infant skull fractures are likely to initiate from the interfaces; the impact angle has a profound influence on global head impact responses and the skull injury metrics for certain impact locations, especially true for a parietal impact.


Effect of subchronic feeding of genetically modified corn (CBH351) on immune system in BN rats and B10A mice.
Subchronic animal feeding studies to examine the effect on the immune system of genetically modified corn CBH351, which contains the Cry9C protein derived from Bacillus thuringiensis subspecies tolworthi, were conducted in female BN rats and B10A mice. The studies were designed to compare the effect of a line of genetically modified corn CBH351 (GM corn) with that of isoline corn (non-GM corn). Heat-treated corn meal was incorporated into the diets of the rats and mice at a concentration of 50%. The study duration was 13 weeks. Growth, food intake, and organ weights of the thymus, spleen, and liver were compared between animals fed the non-GM and GM lines. The histological findings in thymus, spleen, mesenteric lymph nodes, Peyer's patches, small intestines, liver, kidney, and bone marrow, and the presence of Cry9C-specific IgE, IgG, IgG1 and IgA antibodies in serum were also compared. The results showed no significant differences in growth, feeding value, or the histological findings in immunity-related organs between the animals fed the GM and non-GM lines. Production of Cry9 C-specific IgE and IgA was not detected in the serum of either group. Production of Cry9C-specific IgG and IgG1 was slightly increased in the 50% GM groups of BN rats. No Cry9C-specific IgG or IgG1 was detected in the serum of BN rats fed the diet containing 5% GM-corn In conclusion, no immunotoxic activity was detected in the GM-corn-fed rats and mice in this subchronic dietary study.


Complementary and alternative therapy use by patients with myofascial temporomandibular disorders.
To examine the prevalence and predictors of complementary and alternative medicine (CAM) use among patients with temporomandibular disorders (TMD), prior to their first treatment with an intraoral splint. Sixty-three women with a diagnosis of myofascial TMD, and who had never been prescribed an intraoral appliance, reported on their use of CAM and other treatments for their facial pain. In addition to providing a comprehensive symptom history, participants completed a 2-week daily diary in which they described the nature of daily efforts to reduce their facial pain. Although more than half of all participants had not sought any prior treatment for their facial pain, 22.2% had received CAM treatment. The only single type of treatment more commonly used than CAM treatment was medication (28.6%). The most common type of CAM treatment was relaxation therapy (12.7%), followed by chiropractic treatment (9.5%). Although pain duration, pain severity, or mood did not predict CAM use, users were significantly more likely to report work or social disability associated with their facial pain and were more likely to report onset associated with an accident. CAM users were more likely than non-users to employ multiple pain reduction strategies over the 2-week daily diary report, including prescription medication use. A sizeable minority of women with myofascial TMD report CAM treatment for their pain, even prior to an initial treatment with an intraoral splint. Since empirical reports have not adequately demonstrated their safety or efficacy, there is a need for controlled clinical trials evaluating the utility of CAM treatments for TMD.


Ultra performance liquid chromatography tandem mass spectrometry method for the measurement of anandamide in human plasma.
Anandamide (N-arachidonoylethanolamine, AEA) is an endocannabinoid present in human plasma that is associated with several physiological functions and disease states. Significant variability in AEA plasma concentrations has been reported between studies, because quantification of AEA is fraught with methodological difficulties. A rapid, highly sensitive, robust, specific, and highly reproducible ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method is described here for the analysis of AEA in human plasma. This fully validated method using octa-deuterated AEA (AEA-d8) as an internal standard represents an improvement over previous analyses in terms of run time (4 min), limit of detection (0.055 fmol on column, 18.75 fmol/ml plasma), precision (relative standard deviations of 3.7, 3.9, and 4.8% for 1.66, 6.65, and 133 fmol on column), and accuracy (97.5-104.5%). AEA analysis was linear over the range 0.23 to 19 nM (1.66 to 133 fmol on column). To demonstrate the usefulness of this method for the measurement of AEA levels in clinical samples, plasma samples obtained from female volunteers at different stages of the menstrual cycle and pregnant women were assayed. Plasma AEA concentrations were significantly (P=0.0078) lower in the luteal phase of the menstrual cycle compared to the follicular phase. In pregnancy, the concentrations were lowest in the first and second trimesters with levels comparable to those observed in the luteal phase of the menstrual cycle and modestly increased in the third trimester. The highest plasma AEA levels were observed in women in active labour, and these were significantly (P=0.0147) higher than those observed in women at term but not in active labour. Postmenopausal women had AEA concentrations comparable to levels observed during the luteal phase of premenopausal women and were significantly (P=0.0389) lower than AEA plasma concentrations obtained during the follicular phase. The sensitivity and precision of the validated method described here suggests that this method is suitable for the analysis of AEA in clinical samples and may be utilised for the investigation of biomatrices containing limited amounts of AEA.


Relation of hyperacusis in sensorineural tinnitus patients with normal audiological assessment.
Hyperacusis is mainly a consequence of the noise level in the twenty-first century, owing to dramatic changes in people's lifestyles. Of every 100 people with otological complaints (e.g., tinnitus and hyperacusis), 20 are affected by hyperacusis. Because of its high incidence, this symptom has long been the subject of investigation. Nine patients (eight female, one male) with sensorineural tinnitus voluntarily participated in this study. Among the evaluated patients, three were between 25 and 40 years of age and six were between 41 and 60 years. The patients did not report a history of acoustic trauma, use of drugs, or otological diseases. The duration of complaints at the time the study began varied from 3 months to 8 years. The patients answered a questionnaire, submitted to an ear, nose, and throat examination, and were evaluated by pure-tone and speech audiometry and otoacoustic emissions and laboratory tests. In all patients, ear, nose, and throat assessments and audiological tests were within the normal ranges. Of the nine subjects in our study, 100% had tinnitus, and 89% (n = 8) had hyperacusis as an associated symptom. Six subjects (67%) had severe tinnitus; among them, four had moderate hyperacusis, one had severe hyperacusis, and one was not affected by hyperacusis. In two subjects (22%) with moderate tinnitus, one had moderate hyperacusis and the other referred severe symptoms. Another patient (11%) reported mild tinnitus and mild hyperacusis. No patient classified his or her tinnitus as disabling. The findings of the present study led us to conclude that the most affected age range of patients with tinnitus and hyperacusis was 41-60 years and that women are affected significantly more often than men. Tinnitus preceded hyperacusis as a complaint in 78% of the subjects. Hyperacusis was present in eight (89%) of the patients. There was no direct correlation between the severity of tinnitus and of hyperacusis, although we noticed that the discomfort of tinnitus was generally perceived as equal to or worse than that of hyperacusis.


Priming the access to names of famous faces.
There is a continuing controversy in models of face identification concerning the level of access to names relative to semantic information. In order to determine whether names are accessed sequentially after or in parallel to semantic information, we studied participants' speeded decisions about famous faces that were primed by partial semantic or partial name information. Decisions that required the access to the celebrity's name (one or more forename syllables, Expt 1) were significantly primed by partial name primes (initials or name fragments). However, at variance with sequential stage models, no reliable priming was observed by partial semantic primes (information about nationality, occupation, or whether a person was dead or alive). Moreover, there was a clear and consistent priming effect by partial semantic primes if the task was a nationality (British or American) decision that required the access to semantic information (Expt 2), demonstrating the effectiveness of these primes. The effects of partial name primes on nationality decisions were less consistent, with a significant effect for name fragments but not initials. However, effects of name primes were generally greater for syllable decisions than nationality decisions, and effects of semantic primes were generally greater for nationality decisions than syllable decisions. Taken together, these results favour a model of parallel rather than sequential access and suggest some degree of independence in the access to personal semantics and names.


Comparison of Local Injection of Platelet Rich Plasma and Corticosteroids in the Treatment of Lateral Epicondylitis of Humerus.
Lateral epicondylitis or Tennis Elbow is one of the most common causes of upper extremity pain with various treatment options. Platelet-rich plasma (PRP) offers a new option for the treatment of lateral epicondylitis. This study was conducted with an aim to compare the efficacy of PRP versus methyl-prednisolone local injection in patients with lateral epicondylitis. Sixty five patients with lateral epicondylitis were included in the study and randomized into two groups. Group A was treated with single injection of 1ml PRP with absolute platelet count of at least 1 million platelets/ mm(3). Group B was treated with single injection of 1ml (40mg) methyl-prednisolone. Pain, grip strength and functional improvements were assessed using visual analogue scale, dynamometer and quick Disabilities of the Arm, Shoulder and Hand scale respectively at baseline, 15 days, 1 month and 3 months. Sixty patients completed the follow up. All assessment parameters improved significantly in both the Groups at each follow up compared to baseline. At the end of three months group A showed significantly better improvement as compared to Group B. PRP and methyl-prenisolone both are effective in the treatment of lateral epicondylitis. However, PRP is a superior treatment option for longer duration efficacy.


ANGIOTONIN-ACTIVATOR, RENIN- AND ANGIOTONIN-INHIBITOR, AND THE MECHANISM OF ANGIOTONIN TACHYPHYLAXIS IN NORMAL, HYPERTENSIVE, AND NEPHRECTOMIZED ANIMALS.
1. Angiotonin does not exert its vasoconstrictor effect in the absence of a substance contained in red blood cells and serum which we have called "angiotonin-activator." A fraction has been separated from blood in which angiotonin-activator is concentrated. It contains little or no reninactivator. 2. Repeated intravenous injections of angiotonin into animals causes the pressor response gradually to lessen and finally to disappear (the phenomenon of tachyphylaxis), but much more slowly than when renin is injected. When the response to angiotonin is abolished, renin also fails to act. Large doses of renin reduce and finally abolish the responsiveness to angiotonin. Exhaustion of renin-activator in the blood abolishes the response to renin without abolishing the response to angiotonin. 3. Blood from animals made tachyphylactic by infusion of angiotonin contains greatly reduced amounts of angiotonin-activator. An inhibitor also appears in the blood. 4. Bilateral nephrectomy prolongs and greatly enhances the rise of arterial pressure following injection of angiotonin and renin. The enhancement reaches a maximum in from 24 to 30 hours after operation. Blood from these animals exhibits greatly increased ability to activate angiotonin and renin when tested in isolated perfused organs. Large amounts of angiotonin are required to reduce the amount of activator in their blood. Renin-activator is simultaneously but little affected. 5. Tranfusion of blood from an animal made tachyphylactic to angiotonin into a nephrectomized dog reduces the response of the latter to angiotonin. Angiotonin when added to the blood of the recipient of the transfusion and perfused through a rabbit's ear also exhibits greatly reduced vasoconstrictor action. 6. Transfusion of normal blood in large amounts into nephrectomized or hypertensive dogs reduces the recipient's response to renin. If renintachyphylaxis is established in the donor, transfusion abolishes the response to renin in the recipient. The blood from such animals exhibits greatly reduced vasoconstrictor properties when perfused through an isolated organ with renin or angiotonin. 7. Renin-tachyphylactic or normals dog's blood does not reduce arterial pressure elevated by a single injection of renin into nephrectomized dogs. 8. Nephrectomized dogs exhibit the greatest pressor response to infusion of angiotonin and renin, normal animals the least, and hypertensive animals about midway between.


[Research progress of hydrogen-rich saline for eye diseases].
As an antioxidant, hydrogen-rich water has been widely studied in recent years. It is mild enough neither to disturb metabolic redox reactions nor to affect signaling reactive oxygen species. Therefore, there should be no or few adverse effects of H(2). Numerous studies in biology and medicine show that hydrogen-rich water has achieved good results in nervous system, digestive system, respiratory system, heart and kidney diseases. At present, there are few studies on the treatment of eye diseases with hydrogen-rich water. This review summarizes the research progress of hydrogen-rich water for eye diseases in the domestic and foreign literatures. (Chin J Ophthalmol, 2018, 54: 631-635).


Improving recruitment of older people to research through good practice.
There is widespread evidence both of the exclusion of older people from clinical research, and of under-recruitment to clinical trials. This review and opinion piece provides practical advice to assist researchers both to adopt realistic, achievable recruitment rates and to increase the number of older people taking part in research. It analyses 14 consecutive recently published trials, providing the number needed to be screened to recruit one older participant (around 3:1), numbers excluded (up to 49%), drop out rates (5-37%) and whether the planned power was achieved. The value of planning and logistics are outlined, and approaches to optimising recruitment in hospital, primary care and care home settings are discussed, together with the challenges of involving older adults with mental incapacity and those from minority groups in research. The increasingly important task of engaging older members of the public and older patients in research is also discussed. Increasing the participation of older people in research will improve the generalisability of research findings and inform best practice in the clinical management of the growing older population.


Corrugated metallodielectric superlattices via release-rollup assembly.
A 'release-rollup' assembly (RRA) technique is described that yields corrugated metallodielectric superlattices. Bilayers of polymer/Au cast onto diffraction gratings are released and rolled into multilayers with registration of the stacked corrugations across mm-scales. Optical imaging reveals Moiré fringes with reflection spectra that track the bilayer thickness due to mis-stacking. Angular-resolved spectra show spectrally-modulated diffraction opposite to that of the metallic stop-bands, but which agrees with a simple model. This scalable fabrication strategy is thus widely exploitable for laterally patterned metamaterials and optical superlattices.


Disruption of synaesthesia by posthypnotic suggestion: an ERP study.
This study examined whether the behavioral and electrophysiological correlates of synaesthetic response conflict could be disrupted by posthypnotic suggestion. We recorded event-related brain potentials while a highly suggestible face-color synaesthete and matched controls viewed congruently and incongruently colored faces in a color-naming task. The synaesthete, but not the controls, displayed slower response times, and greater P1 and sustained N400 ERP components over frontal-midline electrodes for incongruent than congruent faces. The behavioral and N400 markers of response conflict, but not the P1, were abolished following a posthypnotic suggestion for the termination of the participant's synaesthesia and reinstated following the cancellation of the suggestion. These findings demonstrate that the conscious experience of synaesthesia can be temporarily abolished by cognitive control.


The mechanism of Intralipid®-mediated cardioprotection complex IV inhibition by the active metabolite, palmitoylcarnitine, generates reactive oxygen species and activates reperfusion injury salvage kinases.
Intralipid® administration at reperfusion elicits protection against myocardial ischemia-reperfusion injury. However, the underlying mechanisms are not fully understood. Sprague-Dawley rat hearts were exposed to 15 min of ischemia and 30 min of reperfusion in the absence or presence of Intralipid® 1% administered at the onset of reperfusion. In separate experiments, the reactive oxygen species (ROS) scavenger N-(2-mercaptopropionyl)-glycine was added either alone or with Intralipid®. Left ventricular work and activation of Akt, STAT3, and ERK1/2 were used to evaluate cardioprotection. ROS production was assessed by measuring the loss of aconitase activity and the release of hydrogen peroxide using Amplex Red. Electron transport chain complex activities and proton leak were measured by high-resolution respirometry in permeabilized cardiac fibers. Titration experiments using the fatty acid intermediates of Intralipid® palmitoyl-, oleoyl- and linoleoylcarnitine served to determine concentration-dependent inhibition of complex IV activity and mitochondrial ROS release. Intralipid® enhanced postischemic recovery and activated Akt and Erk1/2, effects that were abolished by the ROS scavenger N-(2-mercaptopropionyl)glycine. Palmitoylcarnitine and linoleoylcarnitine, but not oleoylcarnitine concentration-dependently inhibited complex IV. Only palmitoylcarnitine reached high tissue concentrations during early reperfusion and generated significant ROS by complex IV inhibition. Palmitoylcarnitine (1 µM), administered at reperfusion, also fully mimicked Intralipid®-mediated protection in an N-(2-mercaptopropionyl)-glycine -dependent manner. Our data describe a new mechanism of postconditioning cardioprotection by the clinically available fat emulsion, Intralipid®. Protection is elicited by the fatty acid intermediate palmitoylcarnitine, and involves inhibition of complex IV, an increase in ROS production and activation of the RISK pathway.


The yield of screening symptomatic contacts of multidrug-resistant tuberculosis cases at a tertiary hospital in Addis Ababa, Ethiopia.
Early detection and treatment of multidrug-resistant tuberculosis (MDR-TB, resistant to isoniazid and rifampicin) is an urgent global priority. Identifying and tracing close contacts of patients with MDR-TB could be a feasible strategy to achieve this goal. However, there is limited experience with contact tracing among patients with drug-resistant tuberculosis both globally and in Ethiopia. Here we present our findings on the extent of screening symptomatic contacts and its yield in a tertiary hospital in a major urban setting in Ethiopia. Symptomatic household contacts were identified in 29 (5.7%) of 508 index cases treated at the hospital. There were a total of 155 family members in the households traced of whom 16 (10%) had confirmed MDR-TB. At least one confirmed MDR-TB cases was identified in 15 (51.7%) of the 29 traced households. Tracing symptomatic contacts of MDR-TB cases could be a high yield strategy for early detection and treatment of MDR-TB cases in the community. The approach should be promoted for wider adoption and dissemination. Larger scale studies should be done to determine its effectiveness and sustainability in similar settings.


Targeting erythroblast-specific apoptosis in experimental anemia.
Erythrocyte production is regulated by balancing precursor cell apoptosis and survival signaling. Previously, we found that BH3-only proapoptotic factor, Nix, opposed erythroblast-survival signaling by erythropoietin-induced Bcl-xl during normal erythrocyte formation. Since erythropoietin treatment of human anemia has limitations, we explored the therapeutic potential of abrogating Nix-mediated erythroblast apoptosis to enhance erythrocyte production. Nix gene ablation blunted the phenylhydrazine-induced fall in blood count, enhanced hematocrit recovery, and reduced erythroblast apoptosis, despite lower endogenous erythropoietin levels. Similar to erythropoietin, Nix ablation increased early splenic erythroblasts and circulating reticulocytes, while maintaining a pool of mature erythroblasts as erythropoietic reserve. Erythrocytes in Nix-deficient mice showed morphological abnormalities, suggesting that apoptosis during erythropoiesis not only controls red blood cell number, but also serves a "triage" function, preferentially eliminating abnormal erythrocytes. These results support the concept of targeting erythroblast apoptosis to maximize erythrocyte production in acute anemia, which may be of value in erythropoietin resistance.


Akt3-Mediated Protection Against Inflammatory Demyelinating Disease.
Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis and insulin signaling, respectively, the role for Akt3 remains uncertain. Akt3 is predominantly expressed in the brain, and total deletion of Akt3 in mice results in a reduction in brain size and neurodegeneration following injury. Previously, we found that Akt3-/- mice have a significantly worse clinical course during myelin-oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model in which autoreactive immune cells enter the CNS, resulting in inflammation, demyelination, and axonal injury. Spinal cords of Akt3-/- mice are severely demyelinated and have increased inflammation compared to WT, suggesting a neuroprotective role for Akt3 during EAE. To specifically address the role of Akt3 in neuroinflammation and maintaining neuronal integrity, we used several mouse strains with different manipulations to Akt3. During EAE, Akt3 Nmf350 mice (with enhanced Akt3 kinase activity) had lower clinical scores, a lag in disease onset, a delay in the influx of inflammatory cells into the CNS, and less axonal damage compared to WT mice. A significant increased efficiency of differentiation toward FOXP3 expressing iTregs was also observed in Akt3 Nmf350 mice relative to WT. Mice with a conditional deletion of Akt3 in CD4+ T-cells had an earlier onset of EAE symptoms, increased inflammation in the spinal cord and brain, and had fewer FOXP3+ cells and FOXP3 mRNA expression. No difference in EAE outcome was observed when Akt3 expression was deleted in neurons (Syn1-CKO). These results indicate that Akt3 signaling in T-cells and not neurons is necessary for maintaining CNS integrity during an inflammatory demyelinating disease.


Enhanced nonlinear optical characteristics of copper-ion-doped double crossover DNAs.
The modification of deoxyribonucleic acid (DNA) samples by sequencing the order of bases and doping copper ions opens the possibility for the design of novel nanomaterials exhibiting large optical nonlinearity. We investigated the nonlinear characteristics of copper-ion doped double crossover DNA samples for the first time to the best of our knowledge by using Z-scan and four-wave mixing methods. To accelerate the nonlinear characteristics, we prepared two types of unique DNA nanostructures composed of 148 base pairs doped with copper ions with a facile annealing method. The outstanding third-order nonlinear optical susceptibility of the copper-ion-doped DNA solution, 1.19 × 10(-12) esu, was estimated by the conventional Z-scan measurement, whereas the four-wave mixing experiment was also investigated. In the visible spectral range, the copper-ion-doped DNA solution samples provided competent four-wave mixing signals with a remarkable conversion efficiency of -4.15 dB for the converted signal at 627 nm. The interactions between DNA and copper ions contribute to the enhancement of nonlinearity due to structural and functional changes. The present study signifies that the copper-ion-doped double crossover DNA is a potential candidate as a highly efficient novel material for further nonlinear optical applications.


Prevalence and characteristics of pseudohypertension in patients with "resistant hypertension".
Pseudohypertension has been described as a cause of resistant hypertension, due to medial hypertrophy of the artery from atherosclerosis. This phenomenon results in an elevated cuff pressure compared with intra-arterial measurements and is found primarily in populations with advanced age and atherosclerotic disease. The purpose of this review was to investigate the clinical picture and medical outcomes of patients with this phenomenon. We conducted a retrospective chart review between April 2009 and October 2011 of 244 patients seen in our Hypertension clinic. Baseline characteristics and outcomes of pharmacologic and lifestyle modifications were analyzed. There were 17/244 (7%) patients found to have pseudohypertension among patients enrolled. The mean number of antihypertensive medications decreased from 3.7 to 2.7, following a mean of 4.1 visits. All patients had a brachial artery bruit and triphasic blood pressure readings via Doppler. Our findings suggest that elderly patients with concomitant history of atherosclerotic disease, renal insufficiency, and diabetes mellitus have the highest risk of developing pseudohypertension. This condition should be considered in patients with resistant hypertension. Blood pressure measurement with Doppler can be considered as a noninvasive investigation. Recognition of this entity may result in potential cost reduction with fewer medications prescribed.


Review of dental implant rat research models simulating osteoporosis or diabetes.
Osteoporosis and diabetes are physiologic determinants that affect the process of osseointegration. The demand for dental implants is high in these patients, who have benefited from progress in preclinical research. Osseointegration has been extensively studied in rat models of osteoporosis and diabetes. The aim of this study is to present an assessment of the published data and provide consideration for future studies. The present study summarizes information through a systematic review of the literature from 1997 to 2008 available through PUBMED. The authors found 20 and 13 articles that report on osseointegration of implants in osteoporotic and diabetic rats, respectively. The survey was extended to recent publications on relevant aspects related to species, strains, and quality of endpoint data. Differences in experimental variables such as timing of implant insertion, location of implants, or duration of disease prior to implant placement were reported and can be justified based on the experimental questions. Moreover, heterogeneity was further caused by variations in the age of rats and in reporting of the main parameters of osseointegration in the cortical and medullary compartments. Regardless of these differences, the evidence indicates consistently that ovariectomy results in reduced osseointegration, while there is only moderate evidence for impaired osseointegration in diabetic rats. Selection of the appropriate protocol is critical when studying implant osseointegration in rats. This overview highlights the demand for quality endpoint data related to animal numbers, data collection, and the way to establish osseointegration. Because of the differences in research questions, general recommendations for uniform models for osteoporosis and diabetes cannot be made.


Intergovernmental collaboration for the health and wellbeing of refugees settling in Australia.
As outlined in the Department of Immigration and Border Protection Annual report 2016-17, Australia granted 21 928 humanitarian visas in 2016-17, 13 760 of them offshore. This number will increase in future to a planned offshore program of 18 750 in 2018-19. The report notes that the United Nations High Commissioner for Refugees ranks Australia third for the number of refugees resettled. With such a massive program and commitment by the Australian Government, the need to ensure that health and wellbeing are maintained or gained during the settlement process is paramount. This article outlines how collaboration between like-minded national governments can improve premigration health screening through information sharing, collaborative learning and increased capability in countries of origin to not only screen for illness and disability, but to more effectively put measures in place to address these before, during and after arrival. Australia, Canada, New Zealand, the UK and the US have worked together for more than a decade on migration health screening policies to ensure better management of health needs and successful resettlement. A case study about the Syrian refugee cohort, which began arriving in Australia in late 2015, illustrates how intergovernmental collaboration can improve settlement.


Population Health Metrics Research Consortium gold standard verbal autopsy validation study: design, implementation, and development of analysis datasets.
Verbal autopsy methods are critically important for evaluating the leading causes of death in populations without adequate vital registration systems. With a myriad of analytical and data collection approaches, it is essential to create a high quality validation dataset from different populations to evaluate comparative method performance and make recommendations for future verbal autopsy implementation. This study was undertaken to compile a set of strictly defined gold standard deaths for which verbal autopsies were collected to validate the accuracy of different methods of verbal autopsy cause of death assignment. Data collection was implemented in six sites in four countries: Andhra Pradesh, India; Bohol, Philippines; Dar es Salaam, Tanzania; Mexico City, Mexico; Pemba Island, Tanzania; and Uttar Pradesh, India. The Population Health Metrics Research Consortium (PHMRC) developed stringent diagnostic criteria including laboratory, pathology, and medical imaging findings to identify gold standard deaths in health facilities as well as an enhanced verbal autopsy instrument based on World Health Organization (WHO) standards. A cause list was constructed based on the WHO Global Burden of Disease estimates of the leading causes of death, potential to identify unique signs and symptoms, and the likely existence of sufficient medical technology to ascertain gold standard cases. Blinded verbal autopsies were collected on all gold standard deaths. Over 12,000 verbal autopsies on deaths with gold standard diagnoses were collected (7,836 adults, 2,075 children, 1,629 neonates, and 1,002 stillbirths). Difficulties in finding sufficient cases to meet gold standard criteria as well as problems with misclassification for certain causes meant that the target list of causes for analysis was reduced to 34 for adults, 21 for children, and 10 for neonates, excluding stillbirths. To ensure strict independence for the validation of methods and assessment of comparative performance, 500 test-train datasets were created from the universe of cases, covering a range of cause-specific compositions. This unique, robust validation dataset will allow scholars to evaluate the performance of different verbal autopsy analytic methods as well as instrument design. This dataset can be used to inform the implementation of verbal autopsies to more reliably ascertain cause of death in national health information systems.


Cabozantinib: An evolving therapy for hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is rising in incidence and remains a leading cause of cancer-related death. After a decade of disappointing trials following the approval of sorafenib for patients with advanced HCC, a number of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting angiogenesis and immune checkpoints have recently been approved. The phase 3 CELESTIAL trial demonstrated improved progression-free and overall survival with the TKI cabozantinib compared to placebo, supporting it as a treatment option for patients with advanced HCC previously treated with sorafenib. Cabozantinib blocks multiple key pathways of HCC pathogenesis, including VEGFR, MET, and the TAM (TYRO3, AXL, MER) family of receptor kinases, and promotes an immune-permissive tumor microenvironment. Here, we review the mechanisms of action of cabozantinib, including effects on tumor growth and its immunomodulatory properties, providing pre-clinical rationale for combination strategies with checkpoint inhibitors. We discuss the design and outcomes of CELESTIAL including improved survival across subgroups defined by age, disease etiology, baseline AFP level, prior therapies (including duration of prior sorafenib), and tumor burden. Cabozantinib had a manageable safety profile with dose modification. Studies combining cabozantinib with atezolizumab (COSMIC-312) and durvalumab (CAMILLA) in the first and second-line settings are ongoing, as well as a neoadjuvant study of cabozantinib with nivolumab. Future investigations are warranted to define the use of cabozantinib in patients with Child-Pugh B liver function and identify markers predictive of clinical benefit. The role of cabozantinib in HCC continues to evolve with an anticipated role in immunotherapy combinations.


C7 extension crosswise osteotomy: a novel osteotomy for correction of chin-on-chest deformity in a patient with ankylosing spondylitis.
Extension crosswise osteotomy at C7 (C7 ECO) was developed for the correction of forward gaze in patients with chin-on-chest deformity due to ankylosing spondylitis. A modification of cervicothoracic extension osteoclasis (C/T EO), C7 ECO replaces osteoclasis of the anterior column with a crosswise cut of the C7 vertebral body to eliminate the risks of unintended dislocation of the cervical spine. C7 ECO also eliminates the risks of C7 and T1 pedicle subtraction osteotomies (C/T PSOs), in which a posteriorly based wedge excision may lead to stretching injuries of the lower cervical roots and/or failure to achieve the exact angle of excision required for an optimal correction. Furthermore, opening the osteotomy anteriorly, as in the authors' method, instead of closing it posteriorly, as in PSO, eliminates the risks related to shortening of the posterior column, such as buckling of the dura, kinking of the spinal cord, and stretching of the lower cervical nerve roots. Here, the authors report the use of C7 ECO for the surgical treatment of a 69-year-old man with severe compromise of his forward gaze due to chin-on-chest deformity in the course of ankylosing spondylitis. After uneventful correction surgery, the patient regained the ability to see objects, namely faces of people, at the level of his head while standing and to perform work tasks at a desk.


Cross-Talk between Gut Microbiota and Heart via the Routes of Metabolite and Immunity.
Considering the prevalence of cardiovascular disease (CVD), significant interest has been focused on the gut microbiota-heart interaction because the gut microbiota has been recognized as a barometer of human health. Dysbiosis, characterized by changes in the gut microbiota in CVD, has been reported in cardiovascular pathologies, such as atherosclerosis, hypertension, and heart failure. Conversely, gut microbiota-derived metabolites, such as trimethylamine/trimethylamine N-oxide (TMA/TMAO), can impact host physiology. Further, bacterial dysbiosis can disturb gut immunity, which increases the risk of acute arterial events. Moreover, studies of germ-free mice have provided evidence that microbiota diversity and the presence of a specific microbe in the gut can affect immune cells in hosts. Therefore, the changes in the composition of the gut microbiota can affect host metabolism and immunity. Importantly, these effects are not only confined to the gut but also spreaded to distal organs. The purpose of the current review is to highlight the complex interplay between the microbiota and CVD via TMAO and different immune cells and discuss the roles of probiotics and nutrition interventions in modulating the intestinal microbiota as novel therapeutic targets of CVD.


Therapeutic potential of 90Y- and 131I-labeled anti-CD20 monoclonal antibody in treating non-Hodgkin's lymphoma with pulmonary involvement: a Monte Carlo-based dosimetric analysis.
Pulmonary involvement is common in patients with non-Hodgkin's lymphoma (NHL). (90)Y- and (131)I-anti-CD20 antibodies (ibritumomab tiuxetan and tositumomab, respectively) have been approved for the treatment of refractory low-grade follicular NHL. In this work, we used Monte Carlo-based dosimetry to compare the potential of (90)Y and (131)I, based purely on their emission properties, in targeted therapy for NHL lung metastases of various nodule sizes and tumor burdens. Lung metastases were simulated as spheres, with radii ranging from 0.2 to 5.0 cm, which were randomly distributed in a voxelized adult male lung phantom. Total tumor burden was varied from 0.2 to 1,641 g. Tumor uptake and retention kinetics of the 2 radionuclides were assumed equivalent; a uniform distribution of activity within tumors was assumed. Absorbed dose to tumors and lung parenchyma per unit activity in lung tumors was calculated by a Monte Carlo-based system using the MCNP4B package. Therapeutic efficacy was defined as the ratio of mean absorbed dose in the tumor to that in normal lung. Dosimetric analysis was also performed for a lung-surface distribution of tumor nodules mimicking pleural metastatic disease. The therapeutic efficacy of both (90)Y and (131)I declined with increasing tumor burden. In treating tumors with radii less than 2.0 cm, (131)I targeting was more efficacious than (90)Y targeting. (90)Y yielded a broader distribution of tumor absorbed doses, with the minimum 54.1% lower than the average dose; for (131)I, the minimum absorbed dose was 33.3% lower than the average. The absorbed dose to normal lungs was reduced when the tumors were distributed on the lung surface. For surface tumors, the reductions in normal-lung absorbed dose were greater for (90)Y than for (131)I, but (131)I continued to provide a greater therapeutic ratio across different tumor burdens and sizes. Monte Carlo-based dosimetry was performed to compare the therapeutic potential of (90)Y and (131)I targeting of lung metastases in NHL patients. (131)I provided a therapeutic advantage over (90)Y, especially in tumors with radii less than 2.0 cm and at lower tumor burdens. For both (90)Y- and (131)I-labeled antibodies, treatment is more efficacious when applied to metastatic NHL cases with lower tumor burdens. (131)I has advantages over (90)Y in treating smaller lung metastases.


SI-SHY: Dysregulated Fear in Toddlerhood Predicts Kindergarten Social Withdrawal through Protective Parenting.
Two recent advances in the study of fearful temperament (behavioral inhibition) include the validation of dysregulated fear as a temperamental construct that more specifically predicts later social withdrawal and anxiety, and the use of conceptual and statistical models that place parenting as a mechanism of development from temperament to these outcomes. The current study further advances these areas by examining whether protective parenting mediated the relation between dysregulated fear in toddlerhood and social withdrawal in kindergarten. Participants included 93 toddlers and their mothers, who engaged in laboratory tasks assessing traditional fearful temperament, dysregulated fear, and protective parenting. When children reached kindergarten, they returned to the laboratory for a multimethod assessment of social withdrawal. Results confirmed the hypothesis that dysregulated fear predicted social withdrawal through protective parenting, and this occurred above and beyond the effect of traditional fearful temperament. These findings bolster support for the use of dysregulated fear as a temperamental construct related to, but perhaps more discerning of risk than traditionally measured fearful temperament/behavioral inhibition and highlight the importance of transactional influences between the individual and the caregiving environment in the development of social withdrawal.