Age-related fatigue is associated with reduced mitochondrial function in peripheral blood mononuclear cells.
Fatigue is a complex syndrome associated with exhaustion not relieved by sleep. It occurs frequently in older adults in the context of chronic disease and is associated with decreased physical capacity. Whether a mitochondrial dysfunction and therefore an impaired energy production might contribute to the development of fatigue during aging is yet unknown. The aim of this study was to evaluate mitochondrial respiration of peripheral blood mononuclear cells (PBMCs) in older patients with and without fatigue. Fatigue was determined according to the Brief Fatigue Inventory. Mitochondrial respiration of freshly isolated PBMCs was investigated by high-resolution respirometry using the Oroboros Oxygraph-O2k. Functional impairment and depressive symptoms were assessed using questionnaires. 23 geriatric patients (77.8 ± 4.9 years; 43.5% female) with fatigue and 22 without fatigue (75.4 ± 5.4 years; 45.5% female) were analyzed. Patients with fatigue exhibited more functional limitations and more depressive symptoms. High-resolution respirometry of intact PBMCs revealed a lower routine (4.82 ± 1.14 pmol/s versus 5.89 ± 1.90 pmol/s, p = 0.041) and maximum (6.55 ± 1.51 pmol/s versus 8.43 ± 3.67 pmol/s, p = 0.013) oxygen consumption rate, resulting in a reduced ATP-linked respiration (4.26 ± 1.00 pmol/s versus 5.09 ± 1.53 pmol/s, p = 0.035) of PBMCs from geriatric patients with fatigue compared to controls without. This short report shows that in this group of older patients, fatigue is associated with lower PBMC mitochondrial respiration. Whether the impaired mitochondrial respiration is accompanied by a reduced mitochondrial activity in other organs (e.g. muscle) remains to be elucidated.


Techniques for intraoperative graft assessment in coronary artery bypass surgery.
Early graft patency is a major determinant of morbidity and mortality following coronary artery bypass surgery. Long-term graft failure is caused by intimal hyperplasia and atherosclerosis, while early failure, especially in the first year, has been attributed, in part, to surgical error. The need for intraoperative graft evaluation is paramount to determine need for revision and ensure future functioning grafts. Transit time flowmetry (TTFM) is the most commonly used intraoperative modality, however, only about 20% of cardiac surgeons in North America use TTFM. When combined with high resolution epicardial ultrasonography, TTFM provides high diagnostic yield. Fluorescence imaging can provide excellent visualization of the coronary and graft vasculature; however, data on this subject is limited. We herein examine the literature and discuss the available techniques for graft assessment along with their limitations.


PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.
A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.


A comparative study of efficacy of atorvastatin alone and its combination with fenofibrate on lipid profile in type 2 diabetes mellitus patients with hyperlipidemia.
Mixed dyslipidemia is characterized by increased low-density lipoprotein cholesterol (LDL-C) elevated triglycerides (TGs) and decrease high-density lipoprotein cholesterol (HDL-C). It is more common in diabetes and is associated with an increased risk of coronary artery disease. Monotherapy with statins or fibrates may not effectively control all lipid parameters. The atorvastatin-fenofibrate combination has been shown to have highly beneficial effect on lipid parameters in type 2 diabetes associated with combined hyperlipidemia (CHL). In an open-label study, we evaluated the efficacy of atorvastatin alone and in combination with fenofibrate in 60 types 2 diabetes mellitus patients associated with hyperlipidemia. Patients were randomly assigned to receive atorvastatin 10 mg (Group 1) or combination of atorvastatin 10 mg and fenofibrate 145 mg (Group 2) once daily for 12 weeks. The effect of drugs on lipid profile was evaluated before and after treatment. After 12 weeks, the reduction in total cholesterol (TC), TGs, LDL-C, VLDL-C was 28%, 20%, 37% and 20% in Group 1 (P < 0.001 for all) as compared with 31%, 39%, 33% and 40% in Group 2 (P < 0.001 for all). There was insignificant rise in HDL-C in Group 1 (P = 0.71) and insignificant decrease in HDL-C (P = 0.70) in Group 2. During the combination therapy, the decrease in TC, TGs and VLDL-C was greater than atorvastatin alone. The combination of atorvastatin with fenofibrate in type 2 diabetes patients with CHL may have a favorable effect on some major coronary artery disease risk factors.


Genome-wide analysis of adolescent psychotic-like experiences shows genetic overlap with psychiatric disorders.
This study aimed to test for overlap in genetic influences between psychotic-like experience traits shown by adolescents in the community, and clinically-recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic-like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self- and parent-ratings in three European community samples aged 15-19 years (Final N incl. siblings = 6,297-10,098). A mega-genome-wide association study (mega-GWAS) for each psychotic-like experience domain was performed. Single nucleotide polymorphism (SNP)-heritability of each psychotic-like experience domain was estimated using genomic-relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium- (LD-) score regression. Genetic overlap between specific psychotic-like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD-score regression. GREML returned SNP-heritability estimates of 3-9% for psychotic-like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent-rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic-like experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic-like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically-recognized psychiatric disorders, specifically schizophrenia and major depression.


The impact of a supervised injecting facility on ambulance call-outs in Sydney, Australia.
Supervised injecting facilities (SIFs) are effective in reducing the harms associated with injecting drug use among their clientele, but do SIFs ease the burden on ambulance services of attending to overdoses in the community? This study addresses this question, which is yet to be answered, in the growing body of international evidence supporting SIFs efficacy. Ecological study of patterns in ambulance attendances at opioid-related overdoses, before and after the opening of a SIF in Sydney, Australia. A SIF opened as a pilot in Sydney's 'red light' district with the aim of accommodating a high throughput of injecting drug users (IDUs) for supervised injecting episodes, recovery and the management of overdoses. A total of 20,409 ambulance attendances at opioid-related overdoses before and after the opening of the Sydney SIF. Average monthly ambulance attendances at suspected opioid-related overdoses, before (36 months) and after (60 months) the opening of the Sydney Medically Supervised Injecting Centre (MSIC), in the vicinity of the centre and in the rest of New South Wales (NSW). The burden on ambulance services of attending to opioid-related overdoses declined significantly in the vicinity of the Sydney SIF after it opened, compared to the rest of NSW. This effect was greatest during operating hours and in the immediate MSIC area, suggesting that SIFs may be most effective in reducing the impact of opioid-related overdose in their immediate vicinity. By providing environments in which IDUs receive supervised injection and overdose management and education SIF can reduce the demand for ambulance services, thereby freeing them to attend other medical emergencies within the community.


Genetic Polymorphisms and the Risk of Diabetic Foot: A Systematic Review and Meta-Analyses.
Diabetic foot (DF) is a dangerous complication of diabetes. The aim of the study was to synthesize all the published single nucleotide polymorphisms (SNPs) of DF to objectively evaluate the relationship of SNPs and DF risks. The HuGE database and CNKI were searched for eligible publications on genetic polymorphisms and the risk of DF systematically. The quality of literatures was evaluated by the Newcastle-Ottawa scale. Pooled odds ratios with a 95% confidence interval for SNPs were evaluated through 3 genetic models. Citing 29 different polymorphisms from 24 articles and the study met our selection criteria. There were 24 polymorphisms summarized systematically, and 5 merged polymorphisms for a meta-analysis: 9 positively associated with DF: HIF-1α rs11549465, TNF-α rs1800629, TLR-9 rs5743836, FIB rs6056, HSP70-2437C/T, VDR rs2228570, LOX rs1800449, ITLN1 rs2274907, and OPG rs2073617, but OPG rs3134069 was not a risk factor in DF; 6 negatively associated with DF: VEGF rs833061 and rs2010963, MCP-1 rs1024611, SDF-1 rs1801157, SIRT1 rs12778366, and OPG rs2073617. In addition, 13 polymorphisms were not associated with DF: MMP-9 rs3918242, eNOS rs1799983, VEGF rs3025039, -7C/T, rs1570360, rs13207351, and rs699947, IL-6 rs1800795, HIF-1α rs11549467, TNF-α rs361525, TLR-2 rs3804100, SIRT1 rs3758391, and TIMP-1 rs2070584. The study provided some evidence for SNPs to the development of diabetic foot. The meta-analysis showed that rs1024611 of MCP-1 may be regarded as a protective factor, especially in Asian populations. Other loci indicated inconsistent results.


Kv1.1 and Kv1.2: similar channels, different seizure models.
Voltage-gated K(+) channels (Kv) represent the largest family of genes in the K(+) channel family. The Kv1 subfamily plays an essential role in the initiation and shaping of action potentials, influencing action potential firing patterns and controlling neuronal excitability. Overlapping patterns with differential expression and precise localization of Kv1.1 and Kv1.2 channels targeted to specialized subcellular compartments contribute to distinctive patterns of neuronal excitability. Dynamic regulation of the components in these subcellular domains help to finely tune the cellular and regional networks. Disruption of the expression, distribution, and density of these channels through deletion or mutation of the genes encoding these channels, Kcna1 and Kcna2, is associated with neurologic pathologies including epilepsy and ataxia in humans and in rodent models. Kv1.1 and Kv1.2 knockout mice both have seizures beginning early in development; however, each express a different seizure type (pathway), although the channels are from the same subfamily and are abundantly coexpressed. Voltage-gated ion channels clustered in specific locations may present a novel therapeutic target for influencing excitability in neurologic disorders associated with some channelopathies.


Relationship between declared funding support and level of evidence.
The relationship between industry and the orthopaedic community is under increasing scrutiny. Industry traditionally has funded a substantial amount of the orthopaedic research published in this and other journals. The objective of the present study was to investigate associations between the level of evidence and declared source(s) of funding in papers published in the American volume of The Journal of Bone and Joint Surgery. All articles published in the American volume of The Journal of Bone and Joint Surgery from January 2003 to December 2007 were reviewed by a single individual. Primary research papers with an assigned level of evidence were assessed with regard to source of funding, subject area, and results. The association between source of funding and level of evidence was described with use of contingency tables and chi-square tests. Of 886 studies with an assigned level of evidence, 246 were funded by industry, of which 124 (50%) were graded as Level-IV evidence. Among 274 studies funded by governments, foundations, or universities, only seventy-nine (29%) were graded as Level-IV evidence. Among 366 studies with no funding declared, 209 (57%) were graded as Level-IV evidence. The association between industry funding and a lower level of evidence was significant (p < 0.0001). While industry funded a larger number of studies than any other single source in this journal, the level of evidence of industry-funded studies was lower that that for studies funded by governments, foundations, or universities. Improving the scientific quality of industry-funded research might increase the quality of evidence for making orthopaedic decisions.


Effects of immunotherapies and clinical outcomes in neurosarcoidosis: a retrospective cohort study.
Neurosarcoidosis is associated with a significant degree of morbidity and mortality and its treatments are varied and complex. There is a paucity of information in current literature on patterns of treatment and long term outcomes. This study aimed to evaluate the clinical outcomes and responses to immunosuppressive therapy in a large cohort of neurosarcoidosis patients . We enrolled 80 patients with a diagnosis of neurosarcoidosis. Prescription patterns and clinical outcomes before and after treatment and differences between the treatment groups were compared using Kruskal-Wallis and Mann-Witney U tests. Patients with cranial mononeuropathy other than optic neuropathy were more likely to be treated with steroids alone whereas patients with other presentations were likely to require second and third level treatments. These included azathioprine, methotrexate, mycophenolate, infliximab, and cyclophosphamide often used in combination. Prednisolone alone at onset failed in 67% of patients but appeared most effective in those with isolated facial nerve palsy. Patients treated with prednisolone plus a standard immunosuppression first line generally did well except for those with brain parenchymal disease and /or hydrocephalus who responded better to the addition of infliximab, or cyclophosphamide. Triple therapy with prednisolone + azathioprine + infliximab was associated with significantly greater improvement on the Modified Rankin Scale than prednisolone alone whether used first line (p = 0.001 corrected) or subsequently (p = 0.021 corrected). Overall favourable outcomes in the form of improvement of MRS were reported in 87%, CONCLUSIONS: Our results provides evidence that early immunosuppressive treatments, with azathioprine, methotrexate and infliximab could effectively improve clinical outcomes in many patients with neurosarcoidosis.


Recent advances in β-lactam synthesis.
During the past century, β-lactams have been identified as the core of penicillin and since then several strategies have been developed for their synthesis. Traditional methods for β-lactam synthesis usually involved amide bond formation and the Staudinger reaction. In recent years, by the advancement of photo- and transition metal-catalysis, several new methods have been reported for β-lactam synthesis. For instance: ligand assisted metal catalyzed C-H activation/intermolecular oxidative amidation draws attention for β-lactam synthesis. In this review we introduce methods for β-lactam synthesis and present newly developed reactions. We approach the synthesis of β-lactams according to different retro synthesis strategies.


Somatosensory evoked potential changes in neuroendovascular procedures: incidence and association with clinical outcome in 873 patients.
Neurophysiological monitoring is routinely used during neurosurgical procedures. Use of neurophysiological monitoring has extended to neuroendovascular procedures, but evidence of its impact on clinical outcome in this arena is limited. To report the incidence of significant intraoperative somatosensory evoked potential (SSEP) changes during neuroendovascular surgery and to correlate SSEP changes with clinical outcomes. Patients who underwent neuroendovascular surgery at our institution between 2011 and 2013 were included in the analysis. Medical charts and imaging studies were reviewed retrospectively for sex, age, lesion type and size, clinical presentation, type of endovascular procedure, duration of SSEP change, reversibility of SSEP change, incidence of intraoperative complications and related mortalities, presence of new infarction within 72 hours of intervention, and discharge outcome. Of 873 consecutive patients, 52 (6%) had clinically significant intraoperative SSEP changes. Twenty-four patients (46%) had SSEP changes that were corrected, and 28 patients (54%) had changes that were not reversed before the end of surgery. Both decreased duration and reversal of SSEP changes were associated with a lower incidence of postoperative infarction and more favorable clinical outcome on discharge. The positive predictive value of an irreversible SSEP change for postoperative infarction in our study was 21%, and the negative predictive value was 83%. The approximate incidence of SSEP changes is 6% during neuroendovascular procedures. Rapid reversal of SSEP changes is associated with better outcomes. SSEP monitoring may be a valuable tool for preventing complications after neuroendovascular interventions.


Current Trends in the Use of Irrigant Activation Techniques Among Endodontists & Post-Graduate Dental Students in India -A Knowledge, Attitude and Practice Based Survey.
The aim of this survey was to examine the practice/use of Irrigant Activation Techniques (IAT) among Endodontists and post-graduate dental students in India. An invitation to participate in this survey was sent by electronic mail to 902 members of Indian Endodontic society. A total of 32 questions were finalized for the survey after validation by five endodontic experts. Survey contained 2 demographic questions, 7 knowledge based questions, 11 questions on attitude and 12 questions on practice of IAT. The reliability was checked by randomly asking 10 participants to fill the survey forms again after 15 days. The data was analyzed using chi-square test (P<0.05). The overall response rate for the survey was 30.5%. The content validity ratio for the questionnaire was 0.972 & the reliability calculated using Kappa scores was 0.978. Most of the respondents (87.3%) use IAT, while 4.7% do not use IAT. Most commonly used IAT was Manual dynamic agitation (MDA) used by 28.7%, followed by Ultrasonics in 17.2%. Sonic & negative pressure (EndoVac) was used by less than 10% of respondents. Combination of IAT was used by 39%. In 23 (5 on knowledge, 9 on attitude & 9 on practice) out of the 32 questions in this survey, there was a statistically significant difference (P<0.05) in the answers between the groups, with post-graduate dental students opting the correct choices. Sodium hypochlorite (NaOCl) is the preferred choice of irrigant for IAT according to 48.6%, Chlorhexidine (CHX) is used by 4.2% & Ethylene diamine tetra acetic acid (EDTA) by 2.4%. Combination of two irrigants is used by 28.7% and 6% use all the three irrigants. Vast majority of the Endodontist in India use some form of IAT to improve the efficacy of irrigation. MDA is the most commonly used IAT.


Solution-processed titanium carbide MXene films examined as highly transparent conductors.
MXenes, a new family of two-dimensional structures, have recently gained significant attention due to their unique physical properties suitable for a wide range of potential applications. Here we introduce Ti3C2Tx delaminated monolayers as ultrathin transparent conductors with properties exceeding comparable reduced graphene oxide films. Solution processed Ti3C2Tx films exhibit sheet resistances as low as 437 Ω sq-1 with 77% transmittance at 550 nm. Field effect transistor measurements confirm that these films have a metallic nature, which makes them suitable as electrodes. We show using Kelvin Probe Atomic Force Microscopy that the work function of delaminated Ti3C2Tx flakes (with OH terminal groups) is 5.28 ± 0.03 eV. These results demonstrate that solution-processed Ti3C2Tx conducting films could open up a new direction for the next generation of transparent conductive electrodes.


Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes.
Detailed metabolic studies were carried out to compare major regulatory steps in glucose metabolism in vivo between 25 normal pregnant Latino women without and 150 pregnant Latino women with gestational diabetes mellitus (GDM). The two groups were frequency-matched for age, BMI, and gestational age at testing in the third trimester. After an overnight fast, women with GDM had higher fasting plasma glucose (P = 0.0001) and immunoreactive insulin (P = 0.0003) concentrations and higher glucose production rates (P = 0.01) but lower glucose clearance rates (P = 0.001) compared with normal pregnant women. During steady-state hyperinsulinemia (approximately 600 pmol/l) and euglycemia (approximately 4.9 mmol/l), women with GDM had lower glucose clearance rates (P = 0.0001) but higher glucose production rates (P = 0.0001) and plasma free fatty acid (FFA) concentrations (P = 0.0002) than the normal women. These intergroup differences persisted when a subgroup of 116 women with GDM who were not diabetic < or = 6 months after pregnancy were used in the analysis. When all subjects were considered, there was a very close correlation between glucose production rates and plasma FFA concentrations throughout the glucose clamps in control (r = 0.996) and GDM (r = 0.995) groups. Slopes and intercepts of the relationships were nearly identical, suggesting that blunted suppression of FFA concentrations contributed to blunted suppression of glucose production in the GDM group. In addition to these defects in insulin action, women with GDM had a 67% impairment of pancreatic beta-cell compensation for insulin resistance compared with normal pregnant women. These results demonstrate that women with GDM have multiple defects in insulin action together with impaired compensation for insulin resistance. Our findings suggest that defects in the regulation of glucose clearance, glucose production, and plasma FFA concentrations, together with defects in pancreatic beta-cell function, precede the development of type 2 diabetes in these high-risk women.


When log-dwellers meet loggers: impacts of forest fragmentation on two endemic log-dwelling beetles in southeastern Australia.
Anthropogenic activities continue to cause massive fragmentation and reduction of forest area worldwide. With fragmentation and reduction of habitat recognized as the greatest threats to biodiversity, the implementation of improved, informed and conservation-based forestry practices is essential, and requires a greater understanding of the responses of different organisms to forest fragmentation. While genetic techniques can add invaluable insights to fragmentation studies they have rarely been employed, particularly for multiple species. In the present study, we combined genetic information, obtained from allozyme loci and anonymous single copy nuclear DNA markers, with ecological data to investigate the impacts of forest fragmentation on two log-dwelling beetles with different life histories, in an 'islands of bush in a sea of pine' model, at Tumut in New South Wales, Australia. Both the relatively mobile (i.e. has high dispersal ability and/or broad habitat range) Adelium calosomoides and the less mobile Apasis puncticeps showed reduced mobility and gene flow in fragmented compared to continuous forest: there was significantly greater isolation by distance and stronger local structure revealed by spatial autocorrelation in fragmented forest. Analysis of patch and species characteristics revealed that genetic and demographic structure may be influenced by log degradation class for both species, and number of potential dispersal barriers, distance from continuous forest and desiccation intolerance/moisture preference for Ap. puncticeps. Thus the pine plantation matrix poses a barrier or filter for gene flow and mobility in both beetle species.


Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production.
Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99. We found that Zn2+ induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC50 value of 15 μm Importantly, at this concentration, Zn2+ also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn2+-dependent APP-C99 dimerization and inhibition of Aβ production, whereas the increased Aβ43:Aβ40 ratio is substrate dimerization-independent and involves the known Zn2+ binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD.


In vitro activities of novel 4-HPR derivatives on a panel of rhabdoid and other tumor cell lines.
Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis. N-(4-hydroxy phenyl) retinamide (4-HPR or fenretinide) is a potential chemotherapeutic for RTs with activity correlated to its ability to down-modulate Cyclin D1. Previously, we synthesized novel halogen-substituted and peptidomimetic-derivatives of 4-HPR that retained activity in MON RT cells. Here we analyzed the effect of 4-HPR in inhibiting the growth of several RT, glioma, and breast cancer cell lines and tested their effect on cell cycle, apoptosis and Cyclin D1 expression. Effect of compounds on RT cell cycle profiles, and cell death were assessed by MTS cell survival assays and FACS analysis. The effects of treatment on Cyclin D1 expression were determined by immunoblotting. The efficacy of these compounds on glioma and breast cancer cell lines was also determined using MTS assays. Low micromolar concentrations of 4-HPR derivatives inhibited cell survival of all RT cells tested. The 4-HPR derivatives altered RT cell cycle profiles and induced high levels of cell death that was correlated with their potency. ATRA exhibited high IC50 values in all cell lines tested and did not cause cell death. In MON RT cells, the iodo-substituted compounds were more active than 4-HPR in inducing cell cycle arrest and apoptosis. Additionally, the activity of the compounds correlated with their ability to down-modulate Cyclin D1: while active compounds reduced Cyclin D1 levels, inactive ATRA did not. In glioma and breast cancer cell lines, 4-HPR and 4-HPR derivatives showed variable efficacy. Here we demonstrate, for the first time, that the inhibitory activities of novel halogen-substituted and peptidomimetic derivatives of 4-HPR are correlated to their ability to induce cell death and down-modulate Cyclin D1. These 4-HPR derivatives showed varied potencies in breast cancer and glioma cell lines. These data indicate that further studies are warranted on these derivatives of 4-HPR due to their low IC50s in RT cells. These derivatives are of general interest, as conjugation of halogen radioisotopes such as 18F, 124I, or 131I to 4-HPR will allow us to combine chemotherapy and radiotherapy with a single drug, and to perform PET/SPECT imaging studies in the future.


Monitoring of the electrical status of the ventricle during cardioplegic arrest.
Present methods used to assess the status of myocardial preservation during cardioplegic arrest include monitoring the peripheral electrocardiogram (ECG) and ventricular myocardial temperature, and visual inspection of the heart to verify complete mechanical arrest. This study was designed to determine if these parameters are adequate to ensure complete electromechanical arrest after the application of standard cardioplegic techniques. The electrical status of the ventricle in adult mongrel dogs was monitored continuously during elective hyperkalemic hypothermic arrest for the presence of electrical activity in either the atrium or ventricle with 25 intramural electrodes, three epicardial reference electrodes, a His bundle catheter, and three peripheral ECGs. Occurrence of ventricular electrical activity was documented in the arrested heart (determined visually) when the peripheral ECG was quiescent; the activity persisted for a significant period of time before electromechanical activity could be detected by standard monitoring techniques. This electrical activity is believed to originate in the lower atrial septum and to conduct through the AV node to the ventricles at myocardial temperatures previously thought to be safe. Thus, continuous monitoring of intramural electrical activity would appear to be a more reliable technique than those currently used to determine the adequacy of myocardial preservation during elective cardioplegic arrest.


Strong Exciton-Plasmon Coupling in Silver Nanowire Nanocavities.
The interaction between plasmonic and excitonic systems and the formation of hybridized states is an area of intense interest due to the potential to create exotic light-matter states. We report herein coupling between the leaky surface plasmon polariton (SPP) modes of single Ag nanowires and excitons of a cyanine dye (TDBC) in an open nanocavity. Silver nanowires were spin-cast onto glass coverslips, and the wavevector of the leaky SPP mode was measured by back focal plane (BFP) microscopy. Performing these measurements at different wavelengths allows the generation of dispersion curves, which show avoided crossings after deposition of a concentrated TDBC-PVA film. The Rabi splitting frequencies (Ω) determined from the dispersion curves vary between nanowires, with a maximum value of Ω = 390 ± 80 meV. The experiments also show an increase in attenuation of the SPP mode in the avoided crossing region. The ability to measure attenuation for the hybrid exciton-SPP states is a powerful aspect of these single nanowire experiments because this quantity is not readily available from ensemble experiments.


Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia.
Brief forebrain ischemia in rodents induces selective and delayed neuronal death, particularly of hippocampal CA1 pyramidal neurons. Neuronal death is preceded by down-regulation specific to CA1 of GluR2, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit that limits Ca(2+) influx. This alteration is hypothesized to cause neurodegeneration by permitting a lethal influx of Ca(2+) and/or Zn(2+) through newly formed GluR2-lacking AMPA receptors. Two days of mild hypothermia induced 1 h after ischemia potently and lastingly protects against ischemic injury. We examined molecular mechanisms underlying hypothermia-induced neuroprotection. We report that hypothermia rescues most hippocampal CA1 neurons from ischemia-induced cell death and attenuates ischemia-induced down-regulation of mRNA encoding the AMPA receptor subunit GluR2. Ischemia induced a marked down-regulation of GluR2 mRNA and a small down-regulation of GluR1 mRNA in CA1 at 2 days, as assessed by quantitative in situ hybridization. The ischemia-induced changes in gene expression were cell-specific in that GluR2 was not significantly altered in CA3 or dentate gyrus. After ischemia treated by hypothermia GluR2 mRNA expression was modestly reduced at 2 days and exhibited complete recovery to control levels at 7 days. Hypothermia prevented ischemia induced changes in GluR1 mRNA expression. These findings suggest that intervention at the level of transcriptional regulation of the GluR2 gene may be a mechanism by which prolonged postischemic cooling rescues CA1 neurons otherwise "destined to die."


An innovative OSCE clinical log station: a quantitative study of its influence on Log use by medical students.
A Clinical Log was introduced as part of a medical student learning portfolio, aiming to develop a habit of critical reflection while learning was taking place, and provide feedback to students and the institution on learning progress. It was designed as a longitudinal self-directed structured record of student learning events, with reflection on these for personal and professional development, and actions planned or taken for learning.As incentive was needed to encourage student engagement, an innovative Clinical Log station was introduced in the OSCE, an assessment format with established acceptance at the School. This study questions: How does an OSCE Clinical Log station influence Log use by students? The Log station was introduced into the formative, and subsequent summative, OSCEs with careful attention to student and assessor training, marking rubrics and the standard setting procedure. The scoring process sought evidence of educational use of the log, and an ability to present and reflect on key learning issues in a concise and coherent manner. Analysis of the first cohort's Log use over the four-year course (quantified as number of patient visits entered by all students) revealed limited initial use. Usage was stimulated after introduction of the Log station early in third year, with some improvement during the subsequent year-long integrated community-based clerkship. Student reflection, quantified by the mean number of characters in the 'reflection' fields per entry, peaked just prior to the final OSCE (mid-Year 4). Following this, very few students continued to enter and reflect on clinical experience using the Log. While the current study suggested that we can't assume students will self-reflect unless such an activity is included in an assessment, ongoing work has focused on building learner and faculty confidence in the value of self-reflection as part of being a competent physician.


Geographical inequalities in use of improved drinking water supply and sanitation across Sub-Saharan Africa: mapping and spatial analysis of cross-sectional survey data.
Understanding geographic inequalities in coverage of drinking-water supply and sanitation (WSS) will help track progress towards universal coverage of water and sanitation by identifying marginalized populations, thus helping to control a large number of infectious diseases. This paper uses household survey data to develop comprehensive maps of WSS coverage at high spatial resolution for sub-Saharan Africa (SSA). Analysis is extended to investigate geographic heterogeneity and relative geographic inequality within countries. Cluster-level data on household reported use of improved drinking-water supply, sanitation, and open defecation were abstracted from 138 national surveys undertaken from 1991-2012 in 41 countries. Spatially explicit logistic regression models were developed and fitted within a Bayesian framework, and used to predict coverage at the second administrative level (admin2, e.g., district) across SSA for 2012. Results reveal substantial geographical inequalities in predicted use of water and sanitation that exceed urban-rural disparities. The average range in coverage seen between admin2 within countries was 55% for improved drinking water, 54% for use of improved sanitation, and 59% for dependence upon open defecation. There was also some evidence that countries with higher levels of inequality relative to coverage in use of an improved drinking-water source also experienced higher levels of inequality in use of improved sanitation (rural populations r = 0.47, p = 0.002; urban populations r = 0.39, p = 0.01). Results are limited by the quantity of WSS data available, which varies considerably by country, and by the reliability and utility of available indicators. This study identifies important geographic inequalities in use of WSS previously hidden within national statistics, confirming the necessity for targeted policies and metrics that reach the most marginalized populations. The presented maps and analysis approach can provide a mechanism for monitoring future reductions in inequality within countries, reflecting priorities of the post-2015 development agenda. Please see later in the article for the Editors' Summary.


The Role of the Microbiome in Cancer and Therapy Efficacy: Focus on Lung Cancer.
The microbiome is extremely important for human health; more recently its role in the context of cancer became clear. Microbial effects range from enhancing cancer immunity and cancer therapy efficacy, to promoting cancer progression and inhibiting treatment efficacy. These broad implications led researchers to investigate these specific interactions, as well as how modification of the microbiome can improve cancer survival and treatment efficacy. While these interactions are better established for cancers such as gastric cancer, they are far less understood in others. As non-small cell lung cancer (NSCLC) makes up the majority of lung cancer cases, and is among the top causes of cancer deaths worldwide, understanding the mechanisms by which the microbiome may impact progression and treatment is crucial to improve patient survival and treatment response. A literature review was conducted to reveal the crosslink between human microbiome and lung cancer. This includes immune priming, induction of pro- or anti-tumor response, and the local effects of intra-tumoral microbiota. Overall, this is a complex multifactorial relationship, and there are broad implications as to how this knowledge can improve cancer treatment. Solutions include manipulation of the microbiome using probiotics, bacterial vaccines and antibiotics. Bacteria biomarkers may also be used as a diagnostic tool.


Open reduction and internal fixation compared with circular fixator application for bicondylar tibial plateau fractures. Results of a multicenter, prospective, randomized clinical trial.
Standard open reduction and internal fixation techniques have been successful in restoring osseous alignment for bicondylar tibial plateau fractures; however, surgical morbidity, especially soft-tissue infection and wound necrosis, has been reported frequently. For this reason, several investigators have proposed minimally invasive methods of fracture reduction followed by circular external fixation as an alternative approach. To our knowledge, there has been no direct comparison of the two operative approaches. We performed a multicenter, prospective, randomized clinical trial in which standard open reduction and internal fixation with medial and lateral plates was compared with percutaneous and/or limited open fixation and application of a circular fixator for displaced bicondylar tibial plateau fractures (Schatzker types V and VI and Orthopaedic Trauma Association types C1, C2, and C3). Eighty-three fractures in eighty-two patients were randomized to operative treatment (forty-three fractures were randomized to circular external fixation and forty to open reduction and internal fixation). Follow-up consisted of obtaining a history, physical examination, and radiographs; completion of the Hospital for Special Surgery (HSS) knee score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Short Form-36 (SF-36) General Health Survey; and recording of complication and reoperation rates. There were no significant differences between the groups in terms of demographic variables, mechanism of injury, or fracture severity and/or displacement. However, patients in the circular fixator group had less intraoperative blood loss than those in the open reduction and internal fixation group (213 mL and 544 mL, respectively; p=0.006) and spent less time in the hospital (9.9 days and 23.4 days, respectively; p=0.024). The quality of osseous reduction was similar in the groups. There was a trend for patients in the circular fixator group to have superior early outcome in terms of HSS scores at six months (p=0.064) and the ability to return to preinjury activities at six months (p=0.031) and twelve months (p=0.024). These outcomes were not significantly different at two years. There was no difference in total arc of knee motion, and the WOMAC scores at two years after the injury were not significantly different between the groups with regard to the pain (p=0.923), stiffness (p=0.604), or function (p=0.827) categories. The SF-36 scores at two years after the injury were significantly decreased compared with the controls for both groups (p=0.001 for the circular fixator group and p=0.014 for the open reduction and internal fixation group), although there was less impairment in the circular fixator group in the bodily pain category (a score of 46) compared with the open reduction and internal fixation group (a score of 35) (p=0.041). Seven (18%) of the forty patients in the open reduction and internal fixation group had a deep infection. The number of unplanned repeat surgical interventions, and their severity, was greater in the open reduction and internal fixation group (thirty-seven procedures) compared with the circular fixator group (sixteen procedures) (p=0.001). Both techniques provide a satisfactory quality of fracture reduction. Because percutaneous reduction and application of a circular fixator results in a shorter hospital stay, a marginally faster return of function, and similar clinical outcomes and because the number and severity of complications is much higher with open reduction and internal fixation, we believe that circular external fixation is an attractive option for these difficult-to-treat fractures. Regardless of treatment method, patients with this injury have substantial residual limb-specific and general health deficits at two years of follow-up.


A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder.
Two parallel, 8-week double-blind studies compared olanzapine/fluoxetine combination, olanzapine, and fluoxetine in outpatients with treatment-resistant depression (TRD). Treatment-resistant depression was defined as a documented history of current-episode antidepressant failure plus a prospective failure on fluoxetine. Following an 8-week fluoxetine lead-in, 605 nonresponders with DSM-IV major depressive disorder were randomly assigned to olanzapine/fluoxetine combination, olanzapine, or fluoxetine. The primary outcome measure was baseline-to-endpoint mean change on the Montgomery-Asberg Depression Rating Scale (MADRS). The study was conducted from April 2002 to May 2005. After 8 weeks of double-blind treatment, Study 1 revealed no statistically significant therapy differences in MADRS mean change (olanzapine/fluoxetine combination: -11.0, fluoxetine: -9.4, olanzapine: -10.5). In Study 2, olanzapine/fluoxetine combination demonstrated significantly greater MADRS improvement (-14.5) than fluoxetine (-8.6, p < .001) and olanzapine (-7.0, p < .001). Pooled study results revealed significant differences for olanzapine/ fluoxetine combination (-12.7) versus fluoxetine (-9.0, p < .001) and olanzapine (-8.8, p < .001). Pooled remission rates were 27% for olanzapine/ fluoxetine combination, 17% for fluoxetine, and 15% for olanzapine. Adverse events were consistent with previous studies. Cholesterol mean change (mg/dL) was +15.1 for olanzapine/ fluoxetine combination, +0.8 for fluoxetine, and +2.7 for olanzapine. Mean weight change (kg) was +4.9 for olanzapine/fluoxetine combination, +0.4 for fluoxetine, and +5.5 for olanzapine. Nonfasting glucose mean change (mg/dL) was +11.4 for olanzapine/fluoxetine combination, +4.9 for fluoxetine, and +9.9 for olanzapine. Patients with TRD (defined as treatment failure on 2 antidepressants) taking olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis. When considered within the context of all available evidence, olanzapine/fluoxetine combination is an efficacious therapy for patients with TRD. ClinicalTrials.gov identifier: NCT00035321.


Elongation factor-1 alpha is an overexpressed actin binding protein in metastatic rat mammary adenocarcinoma.
Overexpression of elongation factor-1 alpha (EF1 alpha) mRNA has been correlated with increased metastatic potential in mammary adenocarcinoma; however, this relationship was not explored at the level of protein expression. As EF1 alpha has been shown in other cell types to be a component of the actin cytoskeleton, a likely effector in metastasis, the actin binding activity of EF1 alpha from metastatic and nonmetastatic rat breast tumors and cell lines was investigated. We have shown that EF1 alpha protein is overexpressed in metastatic compared to nonmetastatic cells and whole tumors. Similarly to other EF1 alpha s, both types of tumor EF1 alpha bind to F-actin, but EF1 alpha from metastatic cells has a reduced affinity for actin. In addition, there is a high correlation between the intracellular distribution of filamentous actin and EF1 alpha in those cytoskeletal structures thought to be important for supporting the cellular motility required for metastasis. Following stimulation with EGF, there is a parallel increase in the amount of F-actin and EF1 alpha associated with the cytoskeleton. The response to EGF can be blocked with cytochalasin D indicating that the binding of EF1 alpha to the cytoskeleton is mediated by F-actin. We propose that a weakened association of EF1 alpha with actin may be related to the metastatic process via an altered organization of the actin cytoskeleton and the differential translation of mRNAs associated with the cytoskeleton.


Influence of oat components on lipid digestion using an in vitro model: Impact of viscosity and depletion flocculation mechanism.
Depletion flocculation is a well-known instability mechanism that can occur in oil-in-water emulsions when the concentration of non-adsorbed polysaccharide exceeds a certain level. This critical flocculation concentration depends on the molecular characteristics of the polysaccharide molecules, such as their molecular weight and hydrodynamic radius. In this study, a range of analytical methods (dynamic shear rheology, optical microscopy, and static light-scattering) were used to investigate the interaction between lipid droplets and polysaccharides (guar gum and β-glucans) of varying weight-average molecular weight and hydrodynamic radius, and concentration. The aim of this work was to see if the health benefits of soluble fibers like β-glucans could be explained by their influence on the structure and digestibility of lipid emulsions. The apparent viscosity of the emulsions increased with increasing polysaccharide concentration, molecular weight, and hydrodynamic radius. Droplet flocculation was observed in the emulsions only at certain polysaccharide concentrations, which was attributed to a depletion effect. In addition, the water-soluble components in oat flakes, flour, and bran were extracted using aqueous solutions, to examine their impact on emulsion stability and properties. Then, the rate and extent of lipolysis of a sunflower oil-in-water emulsion in the presence of these oat extracts were monitored using the pH-stat method. However, the inhibition of lipolysis was not linearly related to the viscosity of the oat solutions. The water-soluble extracts of β-glucan collected from oat flakes had a significant inhibitory effect on lipolysis. The results of this study increase our understanding of the possible mechanisms influencing the impact of oat constituents on lipid digestion. This work also highlights the importance of considering the molecular properties of polysaccharides, and not just their impact on solution viscosity.


Syringolin-mediated activation of the Pir7b esterase gene in rice cells is suppressed by phosphatase inhibitors.
Inoculation of rice plants (Oryza sativa) with the nonhost pathogen Pseudomonas syringae pv. syringae leads to the activation of defense-related genes and ultimately to induced resistance against the rice blast fungus Pyricularia oryzae. One of the molecular determinants of P. syringae pv. syringae that is recognized by the plant cells and evokes these defense responses is syringolin A, an elicitor that is secreted by the bacteria under appropriate conditions. In order to investigate signal transduction events elicited by syringolin A, the response of cultured rice cells to syringolin A application was analyzed. Cultured rice cells were able to sense syringolin A at concentrations in the nanomolar range as observed by the transient accumulation of Pir7b esterase transcripts. Syringolin A-mediated Pir7b transcript accumulation was inhibited by cycloheximide, indicating that de novo protein synthesis was required. Calyculin and okadaic acid, two protein phosphatase inhibitors, blocked Pir7b gene induction, whereas the serine/threonine protein kinase inhibitors staurosporine and K-252a had no effect on Pir7b transcript levels. Actin transcript levels were essentially not affected by inhibitor treatments over the experimental time span. These results imply that dephosphorylation of a phosphoprotein is an important step in the syringolin A-triggered signal transduction pathway.


Insight into the effects of modifying π-bridges on the performance of dye-sensitized solar cells containing triphenylamine dyes.
Herein we prepare four novel D-π-A dyes based on triphenylamine (ZHG1, ZHG2, ZHG3 and ZHG4) by modifying the π-bridges. Compared with ZHG1, the power conversion efficiency (PCE) of ZHG2 is improved to 6.1% after the introduction of ethynyl. But further extension of the conjugation of the π-bridges by introducing the chromophore 4,8-bis(n-octyloxy)-benzo[1,2-b:4,5-b']dithiophene (BDT) into ZHG3 conversely decreases the PCE to 4.6%. Improving the coplanarity by replacing cyclobenzene with thiophene in ZHG4 after introducing BDT further decreases the PCE of ZHG4 to 4.3%. Theoretical calculations indicate that the LUMOs of ZHG3 and ZHG4 were mainly delocalized over benzothiadiazole which is far from the anchoring groups. Cyclic voltammetry experiments indicate that the LUMO energy levels of ZHG3 and ZHG4 are lower than those of ZHG1 and ZHG2. Both of these results affect the ability to inject electrons into the TiO2 conduction band. X-ray photoelectron spectroscopy (XPS) analysis shows that the mean thickness of the dye coverage for ZHG1, ZHG2, ZHG3 and ZHG4 is 16 Å, 18 Å, 27 Å and 24 Å, respectively. So the tilt angle of the dye backbone anchored on the TiO2 film is in the order of ZHG1 > ZHG2 > ZHG4 > ZHG3, which is consistent with the dye coverage of the outermost TiO2 surfaces. This result indicates that the intermolecular π-π aggregation in ZHG3 and ZHG4 with overlong π-bridges is more serious compared with that in ZHG1 and ZHG2. Perhaps the above two factors are the reason that the PCEs of ZHG3 and ZHG4 are lower than those of ZHG1 and ZHG2. So it is very important to find a balance point between the electron injection ability, intermolecular π-π aggregation and the expansion of the light absorption range.


Involvement of PPARγ in the Anticonvulsant Activity of EP-80317, a Ghrelin Receptor Antagonist.
Ghrelin, des-acyl ghrelin and other related peptides possess anticonvulsant activities. Although ghrelin and cognate peptides were shown to physiologically regulate only the ghrelin receptor, some of them were pharmacologically proved to activate the peroxisome proliferator-activated receptor gamma (PPARγ) through stimulation of the scavenger receptor CD36 in macrophages. In our study, we challenged the hypothesis that PPARγ could be involved in the anticonvulsant effects of EP-80317, a ghrelin receptor antagonist. For this purpose, we used the PPARγ antagonist GW9662 to evaluate the modulation of EP-80317 anticonvulsant properties in two different models. Firstly, the anticonvulsant effects of EP-80317 were studied in rats treated with pilocarpine to induce status epilepticus (SE). Secondly, the anticonvulsant activity of EP-80317 was ascertained in the repeated 6-Hz corneal stimulation model in mice. Behavioral and video electrocorticographic (ECoG) analyses were performed in both models. We also characterized levels of immunoreactivity for PPARγ in the hippocampus of 6-Hz corneally stimulated mice. EP-80317 predictably antagonized seizures in both models. Pretreatment with GW9662 counteracted almost all EP-80317 effects both in mice and rats. Only the effects of EP-80317 on power spectra of ECoGs recorded during repeated 6-Hz corneal stimulation were practically unaffected by GW9662 administration. Moreover, GW9662 alone produced a decrease in the latency of tonic-clonic seizures and accelerated the onset of SE in rats. Finally, in the hippocampus of mice treated with EP-80317 we found increased levels of PPARγ immunoreactivity. Overall, these results support the hypothesis that PPARγ is able to modulate seizures and mediates the anticonvulsant effects of EP-80317.


Suicidal phenomena and abuse in adolescents: a review of epidemiological studies.
To conduct a systematic review of the international literature to determine whether adolescents who had experienced abuse were more likely to also experience suicidal thoughts and behaviors than other adolescents, and to investigate the nature of this association. Reports of community- or school-based studies of adolescents on the association between the prevalence of suicidal phenomena and abuse were searched for via electronic databases, reviewing reference lists and contacting experts in the field. Ten relevant studies were identified. Adolescents who had been physically or sexually abused were significantly more likely to experience suicidal thoughts and behaviors than other adolescents. This association appeared to be direct in most studies in which multivariate analyses were conducted. There is evidence that other factors (e.g., low self-esteem) may play a mediating role in the relationship between abuse and suicidal phenomena. There is a clear link between abuse and suicidal phenomena occurring during childhood and adolescence.


Prevalence of depression and its correlates in Hong Kong's Chinese older adults.
Because of the rapid aging of the population and inconsistent findings of previous epidemiological studies in Hong Kong, a prevalence study of depression among older adults was timely. The authors assessed the prevalence of depression among older adults and identified factors associated with it. The authors interviewed a random representative sample of 917 community-dwelling Chinese adults age 60 and over. The 15-item Chinese Geriatric Depression Scale with a cutoff of > or = 8 was used to identify clinically significant depression in the older adults. The authors found that 11.0% and 14.5% of older Chinese men and women, respectively, scored above the cutoff, a prevalence rate similar to those found in other countries, including the United States, England, and Finland. Factors that were associated with an increased likelihood of depression among older adults included poor self-rated health, long-term pain, vision problems, higher level of impairment in activities of daily living, residing in Hong Kong less than 20 years, financial strain, and having less social support. The prevalence rate of depression among older Chinese adults in Hong Kong is more or less similar to rates found in Western countries. The data suggest that older adults who receive less social support are more likely to be depressed.


Cretaceous origin and repeated tertiary diversification of the redefined butterflies.
Although the taxonomy of the ca 18 000 species of butterflies and skippers is well known, the family-level relationships are still debated. Here, we present, to our knowledge, the most comprehensive phylogenetic analysis of the superfamilies Papilionoidea, Hesperioidea and Hedyloidea to date based on morphological and molecular data. We reconstructed their phylogenetic relationships using parsimony and Bayesian approaches. We estimated times and rates of diversification along lineages in order to reconstruct their evolutionary history. Our results suggest that the butterflies, as traditionally understood, are paraphyletic, with Papilionidae being the sister-group to Hesperioidea, Hedyloidea and all other butterflies. Hence, the families in the current three superfamilies should be placed in a single superfamily Papilionoidea. In addition, we find that Hedylidae is sister to Hesperiidae, and this novel relationship is supported by two morphological characters. The families diverged in the Early Cretaceous but diversified after the Cretaceous-Palaeogene event. The diversification of butterflies is characterized by a slow speciation rate in the lineage leading to Baronia brevicornis, a period of stasis by the skippers after divergence and a burst of diversification in the lineages leading to Nymphalidae, Riodinidae and Lycaenidae.


Health-related quality of life in women patients with borderline personality disorder.
The aims of the study were to: (i) test the reliability of a health-related quality of life (HRQOL) instrument [Swedish Health-Related Quality of Life Survey (SWED-QUAL)] on women patients with borderline personality disorder (BPD); (ii) compare their HRQOL to a normal population group comparable in age; and (iii) test for subgroup differences in HRQOL considering psychiatric DSM axis-I comorbidity. The study was conducted in connection to a randomized, controlled trial of psychotherapy for women BPD patients. Seventy-five women with BPD diagnosis were administered the SWED-QUAL. Statistic reliability was evaluated with inter-item correlations, total-item correlations and internal consistency criterions. The BPD patients' SWED-QUAL results were compared with data extracted from a published study and subgroup differences due to axis-I comorbidity were analysed. SWED-QUAL could be considered as an instrument with acceptable reliability when assessing HRQOL in BPD patients. The BPD patients suffered significant impairments in HRQOL overall health dimensions compared to normal population. There were no subgroup differences due to axis-I comorbidity, which indicate that BPD in itself might be a predictor of substantial HRQOL impairment.


Eight-Step Enantiodivergent Synthesis of (+)- and (-)-Lingzhiol.
An eight-step enantioselective synthesis of lingzhiol is described herein. The sense of an asymmetric Michael reaction is reversed by the choice of metal source, enabling facile access to both enantiomers. A spontaneous semipinacol ring contraction enables mild construction of the lingzhiol core, and radical-mediated benzylic oxidation proceeds in the presence of an unprotected secondary alcohol. This represents the shortest enantioselective synthesis of lingzhiol to date and the only enantiodivergent approach to both enantiomers of this meroterpenoid natural product.


Integrative network analysis identifies key genes and pathways in the progression of hepatitis C virus induced hepatocellular carcinoma.
Incidence of hepatitis C virus (HCV) induced hepatocellular carcinoma (HCC) has been increasing in the United States and Europe during recent years. Although HCV-associated HCC shares many pathological characteristics with other types of HCC, its molecular mechanisms of progression remain elusive. To investigate the underlying pathology, we developed a systematic approach to identify deregulated biological networks in HCC by integrating gene expression profiles with high-throughput protein-protein interaction data. We examined five stages including normal (control) liver, cirrhotic liver, dysplasia, early HCC and advanced HCC. Among the five consecutive pathological stages, we identified four networks including precancerous networks (Normal-Cirrhosis and Cirrhosis-Dysplasia) and cancerous networks (Dysplasia-Early HCC, Early-Advanced HCC). We found little overlap between precancerous and cancerous networks, opposite to a substantial overlap within precancerous or cancerous networks. We further found that the hub proteins interacted with HCV proteins, suggesting direct interventions of these networks by the virus. The functional annotation of each network demonstrates a high degree of consistency with current knowledge in HCC. By assembling these functions into a module map, we could depict the stepwise biological functions that are deregulated in HCV-induced hepatocarcinogenesis. Additionally, these networks enable us to identify important genes and pathways by developmental stage, such as LCK signalling pathways in cirrhosis, MMP genes and TIMP genes in dysplastic liver, and CDC2-mediated cell cycle signalling in early and advanced HCC. CDC2 (alternative symbol CDK1), a cell cycle regulatory gene, is particularly interesting due to its topological position in temporally deregulated networks. Our study uncovers a temporal spectrum of functional deregulation and prioritizes key genes and pathways in the progression of HCV induced HCC. These findings present a wealth of information for further investigation.


Changes in leg pain after bilateral fasciotomy to treat chronic compartment syndrome: a case series study.
Intracompartmental pressure (ICP) as the diagnostic gold standard in the management of chronic compartment syndrome (CCS) is debated. We present a diagnostic protocol in which the decision to operate can be based upon clinical findings alone. The aim of this study was to examine whether patients who underwent surgery for CCS based on clinical findings experienced significant long-term pain relief. A standardized clinical examination, including skin sensitivity, was performed in patients with bilateral leg pain and/or cramps. Before and after a symptom-provoking step test, ICPs were measured. The primary outcome was self-reported leg pain measured on a visual analogue scale. Secondary outcomes were satisfaction with the treatment result and health-related quality of life (HRQL) measured with the SF-8 questionnaire. Postoperative data were collected after 2 years. Follow-up was completed for 37 of 40 patients. ICP was increased in 80.5% of the compartments examined before surgery, but did not correlate with the degree of leg pain. The remaining compartments were diagnosed as CCS based on clinical findings, despite ICPs below the threshold. Leg cramps occurred in 32 of 37 (86.5%) patients during physical activity and at night. Leg pain improved from a score of 8.0±1.5 to 2.3±2.1, P<0.001. Satisfaction with the treatment result was reported by 81.1% of the patients, accompanied by normalized HRQL. The diagnostic protocol led to a fasciotomy in all compartments of both legs, which was associated with substantial and sustained relief of leg pain, improved HRQL, and patient satisfaction.


Neuroprotective antioxidants from marijuana.
Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist delta 9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.


Reproducibility of long-term ambulatory esophageal combined pH/manometry.
Long-term ambulatory esophageal manometry is used increasingly, but normal values and data on the reproducibility of the method are not available. Thus, studies were conducted using paired 24-hour recordings, separated by 1-4 weeks, in 24 healthy volunteers (aged 19-50). Computerized analysis of each two-channel pressure recording (5 and 15 cm above lower esophageal sphincter) determined mean contraction amplitude, duration, area under the curve, contractility and propagation velocity, and the proportion of propagated contractions during day and night periods. A combined glass pH electrode (5 cm above lower esophageal sphincter) was used to register acid reflux. Visual analysis of the 24-hour contractility patterns showed marked intraindividual reproducibility but, although most subjects showed similar meal-associated increases and sleep-associated decreases in contraction frequency and amplitude, considerable interindividual variation was observed. This was confirmed by comparing the variation between subjects in the first and second recordings with the variation between recordings in the same subject; for all pH and manometry variables, the coefficient of variation was two to three times greater between subjects than between recordings in the same subject. The recordings were highly reproducible within subjects (nighttime contraction duration, P less than 0.05; all other variables, P less than 0.01). Thus, computerized ambulatory pH manometry is reproducible and because healthy volunteers have a characteristic individual pattern of esophageal motility, the method is perfectly suitable for repeated-measure design physiological and pharmacological studies. However, generally applicable normal values are difficult to define.


Participation of microRNAs in human interactome: extraction of microRNA-microRNA regulations.
To date, a significant amount of research has been conducted for computational modeling of the microRNA (miRNA)-target gene interactions and inferring different kinds of biologically relevant association from their variable expressions, available from microarray experiments. However, topological organization of the miRNA-transcription factor (TF) induced regulatory network has not yet been analyzed at a genome scale. Evidently, by ignoring the regulatory relationship among the constituent molecules, we expose our model to a great deal of noise. Besides this, the miRNA-TF regulatory network also helps extract a putative set of regulations among miRNAs and hypothesize the miRNA-miRNA regulatory network. We constructed the miRNA and TF induced regulatory network for humans by combining all possible regulations between miRNAs and TFs. Topological analysis of the network revealed some of its non-trivial and intrinsic properties. The concept of topological overlap has been extended to formulate a novel dissimilarity measure that is capable of mining groups of closely interacting molecules from a weighted digraph such that the molecules in each group regulate each other to a large extent. Many of the identified TF modules are found to be enriched in different functional categories. On the other hand, many of the identified miRNA modules displayed significant associations with common diseases. Finally, the miRNA-TF induced regulatory network yields a putative miRNA inter-regulatory network which may be considered as the first step towards the understanding of the regulatory relationship amongst miRNAs. A large number of the validated regulations were found in the predicted set of regulations, having a significantly high average score. A web application is created to facilitate the search of the Putative miRNA-miRNA Regulations (PmmR). It can be accessed through the following link: .


The role of the private sector in delivering essential packages of health services: lessons from country experiences.
Many countries are adopting essential packages of health services (EPHS) to implement universal health coverage (UHC), which are mostly financed and delivered by the public sector, while the potential role of the private health sector (PHS) remains untapped. Currently, many low-income and lower middle-income countries (LLMICs) have devised EPHS; however, guidance on translating these packages into quality, accessible and affordable services is limited. This paper explores the role of PHS in achieving UHC, identifies key concerns and presents the experience of the Diseases Control Priorities 3 Country Translation project in Afghanistan, Ethiopia, Pakistan, Somalia, Sudan and Zanzibar. There are key challenges to engagement of the PHS, which include the complexity and heterogeneity of private providers, their operation in isolation of the health system, limitations of population coverage and equity when left to PHS's own choices, and higher overall cost of care for privately delivered services. Irrespective of the strategies employed to involve the PHS in delivering EPHS, it is necessary to identify private providers in terms of their characteristics and contribution, and their response to regulatory tools and incentives. Strategies for regulating private providers include better statutory control to prevent unlicensed practice, self-regulation by professional bodies to maintain standards of practice and accreditation of large private hospitals and chains. Potentially, purchasing delivery of essential services by engaging private providers can be an effective 'regulatory approach' to modify provider behaviour. Despite existing experience, more research is needed to better explore and operationalise the role of PHS in implementing EPHS in LLMICs.


What do health authorities think of population based health outcome indicators?
To determine the role of population based indicators of health outcome in local health outcome assessments; the constraints of using such indicators; how they could be made more useful; and whether health authorities had developed their own indicators of health outcome. A structured telephone interview with representatives of 91 of the 100 English health authorities. Interviewees, asked to give details on two clinical areas in which population health outcome assessments had been of most value, nominated 147 examples in over 30 clinical areas. They chose 50 (34%) of the examples because of an outlying national indicator, and 20 (14%) because of local variations in a national indicator. The main perceived constraints in the use of population based indicators of health outcome were: data validity and timeliness; the attributability of these health outcomes to the quality of health care; the difficulties of changing clinical behavior; and organisational change within health authorities. To make these indicators more useful interviewees wanted an increased use of process indicators as proxies for health outcome, indicator trend data, and indicator comparisons of districts with similar population structures. Some recent publications have started to consider some of these issues. 27 (30%) health authorities had developed their own indicators, mostly provider based process indicators. 10 of these used their own indicators to manage the performance of local provider units. Population based indicators of health outcome had an important role in prompting districts to undertake population health outcome assessments. Health authorities also used these indicators to examine local variations in health outcome. They helped to highlight areas for further investigation, initiated data validation, and enabled the monitoring of changes to services. Comparative population based indicators of health outcome may have an increasing part to play in assessing the performance of health authorities.


Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells.
Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor BACH2 is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and Bach2 depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells.


A novel interaction between the FLJ33534 locus and smoking in obesity: a genome-wide study of 14 131 Pakistani adults.
Obesity is a complex disease caused by the interplay of genetic and lifestyle factors, but identification of gene-lifestyle interactions in obesity has remained challenging. Few large-scale studies have reported use of genome-wide approaches to investigate gene-lifestyle interactions in obesity. In the Pakistan Risk of Myocardial Infraction Study, a cross-sectional study based in Pakistan, we calculated body mass index (BMI) variance estimates (square of the residual of inverse-normal transformed BMI z-score) in 14 131 participants and conducted genome-wide heterogeneity of variance analyses (GWHVA) for this outcome. All analyses were adjusted for age, age(2), sex and genetic ancestry. The GWHVA analyses identified an intronic variant, rs140133294, in the FLJ33544 gene in association with BMI variance (P-value=3.1 × 10(-8)). In explicit tests of gene × lifestyle interaction, smoking was found to significantly modify the effect of rs140133294 on BMI (Pinteraction=0.0005), whereby the minor allele (T) was associated with lower BMI in current smokers, while positively associated with BMI in never smokers. Analyses of ENCODE data at the FLJ33534 locus revealed features indicative of open chromatin and high confidence DNA-binding motifs for several transcription factors, providing suggestive biological support for a mechanism of interaction. In summary, we have identified a novel interaction between smoking and variation at the FLJ33534 locus in relation to BMI in people from Pakistan.


Emigration flows from North Africa to Europe.
The region of North Africa (NA) represents a striking locality regarding migration with several migration patterns, namely emigration in the form of labour export to Europe and North America and, to a lesser extent, to the Arab Gulf area. The latter has increased enormously in the last decade because of the political instability in most of the NA countries. The aim of the present chapter was to explore the patterns of migration stocks and flows in NA countries, based on several websites, systematic review of journals, comparable data available by the United Nations and by the International Organization of Migration. The NA region has become an area of transit migration and labour migration. Emigrant flows from NA countries towards Europe and North America are increasing this decade more than towards the Arab Gulf countries after being replaced by Asian labour. The recent increase in the proportion of women among the migrant population is remarkable. Remittances sent by African migrants have become an important source of external finance for countries of origin. Transient and irregular migration to Egypt originates at the borders with Sudan, Palestine and Libya with destination to the Euro Mediterranean countries. In Tunisia and Morocco, irregular migrants originate from Sub-Saharan Africa to the northern borders. The NA countries serve as departure rather than destination countries, and migration flows to the Euro-Mediterranean countries through legal or illegal routes.


Exposure to Engineered Nanomaterials: Impact on DNA Repair Pathways.
Some engineered nanomaterials (ENMs) may have the potential to cause damage to the genetic material in living systems. The mechanistic machinery functioning at the cellular/molecular level, in the form of DNA repair processes, has evolved to help circumvent DNA damage caused by exposure to a variety of foreign substances. Recent studies have contributed to our understanding of the various DNA damage repair pathways involved in the processing of DNA damage. However, the vast array of ENMs may present a relatively new challenge to the integrity of the human genome; therefore, the potential hazard posed by some ENMs necessitates the evaluation and understanding of ENM-induced DNA damage repair pathways. This review focuses on recent studies highlighting the differential regulation of DNA repair pathways, in response to a variety of ENMs, and discusses the various factors that dictate aberrant repair processes, including intracellular signalling, spatial interactions and ENM-specific responses.


Lymphokine-activated killer T-cell-originated protein kinase phosphorylation of histone H2AX prevents arsenite-induced apoptosis in RPMI7951 melanoma cells.
Arsenic is a valuable therapeutic tool in cancer treatment. Lymphokine-activated killer T-cell-originated protein kinase (TOPK) is highly expressed in cancer cells, but its specific function is still unknown. We investigated the role of TOPK in arsenic-induced apoptosis in RPMI7951 human melanoma cells. Expression of TOPK was evaluated in different melanoma cell lines, and liquid chromatography-tandem mass spectrometry analysis was used to identify proteins binding with TOPK. Immunofluorescence, Western blot, and flow cytometry were used to assess the effect of arsenic on TOPK, histone H2AX, and apoptosis in RPMI7951 cells. Melanoma cell lines expressing high levels of TOPK were more resistant to arsenite (As(3+))-induced apoptosis. As(3+) treatment induced phosphorylation of TOPK and histone H2AX in RPMI7951 human melanoma cells. Liquid chromatography-tandem mass spectrometry results indicated that TOPK could bind with histone H2AX, and in vitro and in vivo assays confirmed that TOPK binds with and phosphorylates histone H2AX. As(3+) treatment caused phosphorylation of TOPK, which colocalized with phosphorylated histone H2AX in the nucleus. TOPK small interfering RNA cells exhibited a decreased phosphorylation of histone H2AX with As(3+) treatment. As(3+)-induced apoptosis was decreased in H2AX(-/-) cells but increased in TOPK small interfering RNA cells. TOPK binds with histone H2AX and inhibits As(3+)-induced apoptosis through phosphorylation of histone H2AX. Melanoma cell lines with high levels of TOPK are more resistant to As(3+)-induced apoptosis. Therefore, inhibition of TOPK activity combined with As(3+) treatment may be helpful in the treatment of melanomas.


Knowledge, Awareness and Practices Regarding Cystic Echinococcosis among Livestock Farmers in Basrah Province, Iraq.
Cystic echinococcosis (CE) is an endemic neglected parasitic zoonosis in many of the countries of the Middle East. The disease poses a remarkable economic burden for both animals and humans. In this study, we conducted a questionnaire survey among livestock farmers in Basrah province, southern Iraq, in order to evaluate their knowledge and awareness about CE, and to understand some of the risky practices that could contribute to spread and persistence of such disease. Of the interviewed participants (N = 314), 27.4% owned dogs on their farms. Among farmers owning dogs, 76.7% (66/86) never tied up their dogs, and 43% (37/86) indicated feeding uncooked animal viscera to their dogs. The majority (96.5%) of the farmers indicated that they did not de-worm their dogs at all. Only 9.8% (31/314) of the respondents indicated eating raw leafy vegetables without washing. Added to that, 32% of the interviewees indicated that they source water for domestic use from a river; meanwhile 94.3% (296/314) of them do not boil water before using it for domestic purposes. Half of the interviewed livestock farmers in Basrah were not aware about how humans get infected with CE disease, and 41.4% (130/314) did not even realize that CE is a dangerous disease to human health. Almost one in three of the respondents who owned dogs on their farms viewed de-worming of their dogs as a low priority practice. This study highlights the gap in knowledge and awareness about CE among the study population. Risky practices associated with dog keeping management and food and water handling practices were identified. The insight from this research could be used to improve the delivery of a health education message relevant to cystic echinococcosis control at the human-animal interface in Iraq.


The effect of July admission on inpatient outcomes following spinal surgery.
The presence of a "July effect," where the influx of new residents and fellows at teaching hospitals every July may negatively affect patient care and outcomes, is widely debated. The authors used the Nationwide Inpatient Sample (NIS) to identify all cases of spinal surgery and examine outcomes among patients who underwent surgery in July compared with those who underwent surgery in other months. Spinal surgery hospitalizations from 2001 to 2008 were identified in the NIS by extracting relevant ICD-9 codes. Rates of in-hospital mortality, discharge to a long-term care facility, and postoperative complications were compared between admission months and between teaching and nonteaching hospitals using the Wilcoxon rank-sum test, Fisher exact test, and multivariate regression analysis. Compared with patients admitted in other months, patients who were admitted to teaching hospitals in July for spinal surgery showed a similar likelihood of in-hospital mortality (OR 0.94 [95% CI 0.78-1.11], p = 0.46), reaction to implanted device/instrumentation (OR 0.88 [95% CI 0.77-1.02], p = 0.09), and postoperative wound dehiscence (OR 1.12 [95% CI 0.94-1.33], p = 0.25). A significantly higher likelihood of discharge to a long-term care facility (OR 1.03 [95% CI 1.00-1.07], p = 0.0467) and postoperative infection (OR 1.11 [95% CI 1.05-1.17], p = 0.0341) was observed in teaching hospitals in July compared with other months; however, incidence rates were similar regardless of admission month. Higher-risk patients (Charlson score ≥ 2) admitted to teaching hospitals in July had a similar likelihood of all outcomes regardless of admission month. This study of nationwide hospitalizations demonstrates that the influx of new residents and fellows in July has a negligible effect on periprocedural outcomes following spinal surgery.


Activity-Based Detection of Cannabinoids in Serum and Plasma Samples.
Synthetic cannabinoids are the largest group of new psychoactive substances monitored by the European Monitoring Centre of Drugs and Drug Addiction. The rapid proliferation of novel analogs makes the detection of these new derivatives challenging and has initiated considerable interest in the development of so-called "untargeted" screening strategies to detect these compounds. We developed new, stable bioassays in which cannabinoid receptor activation by cannabinoids led to recruitment of truncated β-arrestin 2 (βarr2) to the cannabinoid receptors, resulting in functional complementation of a split luciferase, allowing readout via bioluminescence. Aliquots (500 μL) of authentic serum (n = 45) and plasma (n = 73) samples were used for simple liquid-liquid extraction with hexane:ethyl acetate (99:1 v/v). Following evaporation and reconstitution in 100 μL of Opti-MEM® I/methanol (50/50 v/v), 10 μL of these extracts was analyzed in the bioassays. Truncation of βarr2 significantly (for both cannabinoid receptors; P = 0.0034 and 0.0427) improved the analytical sensitivity over the previously published bioassays applied on urine samples. The new bioassays detected cannabinoid receptor activation by authentic serum or plasma extracts, in which synthetic cannabinoids were present at low- or sub-nanogram per milliliter concentration or in which Δ9-tetrahydrocannabinol was present at concentrations >12 ng/mL. For synthetic cannabinoid detection, analytical sensitivity was 82%, with an analytical specificity of 100%. The bioassays have the potential to serve as a first-line screening tool for (synthetic) cannabinoid activity in serum or plasma and may complement conventional analytical assays and/or precede analytical (mass spectrometry based) confirmation.


Localized Structural Alterations Underlying a Subset of Unexplained Sudden Cardiac Death.
Sudden cardiac death because of ventricular fibrillation (VF) is commonly unexplained in younger victims. Detailed electrophysiological mapping in such patients has not been reported. We evaluated 24 patients (29±13 years) who survived idiopathic VF. First, we used multielectrode body surface recordings to identify the drivers maintaining VF. Then, we analyzed electrograms in the driver regions using endocardial and epicardial catheter mapping during sinus rhythm. Established electrogram criteria were used to identify the presence of structural alterations. VF occurred spontaneously in 3 patients and was induced in 16, whereas VF was noninducible in 5. VF mapping demonstrated reentrant and focal activities (87% versus 13%, respectively) in all. The activities were dominant in one ventricle in 9 patients, whereas they had biventricular distribution in others. During sinus rhythm areas of abnormal electrograms were identified in 15/24 patients (62.5%) revealing localized structural alterations: in the right ventricle in 11, the left ventricle in 1, and both in 3. They covered a limited surface (13±6 cm2) representing 5±3% of the total surface and were recorded predominantly on the epicardium. Seventy-six percent of these areas were colocated with VF drivers (P<0.001). In the 9 patients without structural alteration, we observed a high incidence of Purkinje triggers (7/9 versus 4/15, P=0.033). Catheter ablation resulted in arrhythmia-free outcome in 15/18 patients at 17±11 months follow-up. This study shows that localized structural alterations underlie a significant subset of previously unexplained sudden cardiac death. In the other subset, Purkinje electrical pathology seems as a dominant mechanism.


Screening for previous refractive surgery in eye bank corneas by using optical coherence tomography.
To use optical coherence tomography (OCT) to detect previous refractive surgery in donor corneas. We constructed a tabletop OCT scanner operating at 1310-nm wavelength. Donor corneas at the Cleveland Eye Bank were scanned while sealed within the sterile container immersed in Optisol GS. OCT scanning was performed with 7.6-mm-long lines (512 axial scans) along 8 meridians. Anterior and posterior corneal surfaces were automatically mapped using image processing software that we developed. Curvature was computed from the best parabolic fit in the central 5-mm diameter. Layered analysis of the stromal reflectivity was also performed. Twenty-nine corneas from 19 donors were examined. Five had a history of laser in situ keratomileusis (LASIK). The flap interfaces could not be visualized on slit-lamp or OCT images but were confirmed by histology. The death-to-scan time was 22.1 +/- 11.4 (SD) hours for normal corneas and 100.6 +/- 57.5 hours for LASIK corneas. The anterior surface power was 67.5 +/- 2.5 D in control corneas and 64.5 +/- 2.4 D in LASIK corneas (P = 0.023). There was no significance between the 2 groups in terms of posterior curvature and thickness parameters. The anterior/posterior reflectivity ratio in the central 4-mm diameter was significantly lower in post-LASIK corneas than in control (P < 0.05). OCT provides thickness, topography, and reflectivity maps of donor corneas without taking them out of preservation medium and container. The anterior curvature and the anterior/posterior stromal reflectivity ratio may be useful for detecting previous LASIK.


Modelling the world in real time: how robots engineer information.
Programming robots and other autonomous systems to interact with the world in real time is bringing into sharp focus general questions about representation, inference and understanding. These artificial agents use digital computation to interpret the data gleaned from sensors and produce decisions and actions to guide their future behaviour. In a physical system, however, finite computational resources unavoidably impose the need to approximate and make selective use of the information available to reach prompt deductions. Recent research has led to widespread adoption of the methodology of Bayesian inference, which provides the absolute framework to understand this process fully via modelling as informed, fully acknowledged approximation. The performance of modern systems has improved greatly on the heuristic methods of the early days of artificial intelligence. We discuss the general problem of real-time inference and computation, and draw on examples from recent research in computer vision and robotics: specifically visual tracking and simultaneous localization and mapping.


Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.
Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.


Award for Distinguished Contributions to the International Advancement of Psychology.
This award is given to individuals who have made sustained and enduring contributions to international cooperation and the advancement of knowledge in psychology. The 2020 recipient of the APA Award for Distinguished Contributions to the International Advancement of Psychology was selected by the Board of Directors, as recommended by the Committee on International Relations in Psychology (CIRP). (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Characterization of nitrogen species incorporated into graphite using low energy nitrogen ion sputtering.
The electronic structures of nitrogen species incorporated into highly oriented pyrolytic graphite (HOPG), prepared by low energy (200 eV) nitrogen ion sputtering and subsequent annealing at 1000 K, were investigated by X-ray photoelectron spectroscopy (XPS), angle-dependent X-ray absorption spectroscopy (XAS), and Raman spectroscopy. An additional peak was observed at higher binding energy of 401.9 eV than 400.9 eV for graphitic1 N (graphitic N in the basal plane) in N 1s XPS, where graphitic2 N (graphitic N in the zigzag edge and/or vacancy sites) has been theoretically expected to appear. N 1s XPS showed that graphitic1 N and graphitic2 N were preferably incorporated under low nitrogen content doping conditions (8 × 10(13) ions cm(-2)), while pyridinic N and graphitic1 N were dominantly observed under high nitrogen content doping conditions. In addition, angle-dependent N 1s XAS showed that the graphitic N and pyridinic N atoms were incorporated into the basal plane of HOPG and thus were highly oriented. Furthermore, Raman spectroscopy revealed that low energy sputtering resulted in almost no fraction of the disturbed graphite surface layers under the lowest nitrogen doping condition. The suitable nitrogen doping condition was discovered for realizing the well-controlled nitrogen doped HOPG. The electrochemical properties for the oxygen reduction reaction of these samples in acidic solution were examined and discussed.


Partnering and parenting transitions in Australian men and women: associations with changes in weight, domain-specific physical activity and sedentary behaviours.
Partnering and parenting are important life-stage transitions often accompanied by changes in social networks, roles and responsibilities. There have been no longitudinal studies examining associations of partnering and parenting with changes in domain-specific physical activity (PA) and sedentary behaviours, and our understanding of whether these transitions are associated with weight change is limited. Two thousand one hundred and twenty-four Australian adults from a national cohort (mean age 31.7 (2.7) years, 47.5% male) completed questionnaires at baseline (2004-06) and follow-up (2009-11), reporting marital and parental status. Weight (kg) was measured at baseline and self-reported at follow-up. PA and sedentary behaviours (sitting and television (TV) viewing) were self-reported in a subset (n = 1221). Linear regression estimated the longitudinal associations of parenting and partnering transitions with PA, sedentary behaviours and weight at follow-up, adjusted for baseline value of the respective outcome variable, age, education, follow-up duration and other life-stage transition. During the 5-year follow-up, 17.3% men and 12.9% women partnered, and 27.3% men and 19.1% women had their first child. Compared to staying not partnered, partnering was associated with an increase in total PA (177.5mins/week, 95% Confidence Interval (CI) 18.0 to 337.0) among men and a greater weight gain (2.2 kg, 95% CI 0.6 to 3.7) among women. Compared to remaining child-free, having a first child was associated with greater reductions in total PA (- 123.9mins/week, 95% CI - 248.8 to 1.1) and TV viewing time (- 27.0mins/day, 95% CI - 50.6 to - 3.3) among men. Women who had their first child had greater weight gain (1.4 kg, 95% CI 0.1 to 2.7) but spent less time sitting (- 103.8mins/day, 95% CI - 135.5 to - 72.1) than those remaining child-free. For women, having additional children was associated with less sitting time (- 39.4mins/week, 95% CI - 66.0 to - 12.8) than having the same number of children. Partnering was associated with an increase in men's total PA and women's weight. Transitions into parenthood with a first child or additional children were associated with potentially health-impairing changes in weight and PA, but health-promoting changes in sedentary behaviours. Future PA promotion strategies should pay attention to men who had their first child to mitigate declining total PA.