The Role of Natriuretic Peptides in Predicting Adverse Outcomes After Cardiac Surgery: An Updated Systematic Review.
The increasing global burden of cardiovascular disease, particularly, in the aging population, has led to an increase in high-risk cardiac surgical procedures. The current preoperative risk stratification scores, such as the European System for Cardiac Operative Risk Evaluation and the Society for Thoracic Surgeons score, have limitations in their predictive accuracy and tend to underestimate the mortality risk in higher-risk populations. This systematic review aimed to evaluate the utility of natriuretic peptides, brain natriuretic peptide (BNP) and its precursor prohormone (N-terminal prohormone BNP), as predictive biomarkers for adverse outcomes after cardiac surgery. A comprehensive search strategy was performed, and 63 studies involving 40,667 patients who underwent major cardiac operations were included for data extraction. Preoperative levels of BNP and N-terminal prohormone BNP seemed to be associated with an increased risk of short- and long-term mortality, postoperative heart failure, kidney injury, and length of intensive care unit stay. However, their predictive value for postoperative arrhythmias and myocardial infarction was less established. Our findings suggest that natriuretic peptides may play an important role in risk prediction in patients who underwent cardiac surgery. The addition of these biomarkers to the existing clinical risk stratification strategies may enhance their predictive accuracy. However, this needs to be endorsed by data derived from wide-scale clinical trials.


Targeting Leishmania major parasite with peptides derived from a combinatorial phage display library.
Cutaneous leishmaniasis (CL) is a global problem caused by intracellular protozoan pathogens of the genus Leishmania for which there are no suitable vaccine or chemotherapy options. Thus, de novo identification of small molecules binding to the Leishmania parasites by direct screening is a promising and appropriate alternative strategy for the development of new drugs. In this study, we used a random linear hexapeptide library fused to the gene III protein of M13 filamentous bacteriophage to select binding peptides to metacyclic promastigotes from a highly virulent strain of Leishmania major (Zymodeme MON-25; MHOM/TN/94/GLC94). After four rounds of stringent selection and amplification, polyclonal and monoclonal phage-peptides directed against L. major metacyclic promastigotes were assessed by ELISA, and the optimal phage-peptides were grown individually and characterized for binding to L. major by monoclonal phage ELISA. The DNA of 42 phage-peptides clones was amplified by PCR, sequenced, and their amino acid sequences deduced. Six different peptide sequences were obtained with frequencies of occurrence ranging from 2.3% to 85.7%. The biological effect of the peptides was assessed in vitro on human monocytes infected with L. major metacyclic promastigotes, and in vivo on susceptible parasite-infected BALB/c mice. The development of cutaneous lesions in the right hind footpads of infected mice after 13 weeks post-infection showed a protection rate of 81.94% with the injected peptide P2. Moreover, Western blots revealed that the P2 peptide interacted with the major surface protease gp63, a protein of 63kDa molecular weight. Moreover, bioinformatics were used to predict the interaction between peptides and the major surface molecule of the L. major. The molecular docking showed that the P2 peptide has the minimum interaction energy and maximum shape complimentarity with the L. major gp63 active site. Our study demonstrated that the P2 peptide occurs at high frequency during the screening procedure, best inhibits L. major growth kinetics in vitro, and reduces cutaneous lesions in BALB/c mice, thus showing great promise in the development of new therapeutic molecules.


Influence of swift heavy ion irradiation on the photoluminescence of Si-nanoparticles and defects in SiO2.
The influence of swift heavy ion (SHI) irradiation on the photoluminescence (PL) of silicon nanoparticles (SiNPs) and defects in SiO2-film is investigated. SiNPs were formed by implantation of 70 keV Si+ and subsequent thermal annealing to produce optically active SiNPs and to remove implantation-induced defects. Seven different ion species with energy between 3-36 MeV and fluence from 1011-1014 cm-2 were employed for irradiation of the implanted samples prior to the thermal annealing. Induced changes in defect and SiNP PL were characterized and correlated with the specific energy loss of the employed SHIs. We find that SHI irradiation, performed before the thermal annealing process, affects both defect and SiNP PL. The change of defect and SiNP PL due to SHI irradiation is found to show a threshold-like behaviour with respect to the electronic stopping power, where a decrease in defect PL and an anticorrelated increase in SiNP PL after the subsequent thermal annealing are observed for electronic stopping exceeding 3-5 keV nm-1. PL intensities are also compared as a function of total energy deposition and nuclear energy loss. The observed effects can be explained by ion track formation as well as a different type of annealing mechanisms active for SHI irradiation compared to the thermal annealing.


Enhanced durability of an iridium-bipyridine complex embedded into organosilica nanotubes for water oxidation.
Heterogeneous metal complex catalysts for the water oxidation reaction have ever been desired for the development of devices simulating photosynthesis. This paper describes the design of highly active and robust heterogeneous iridium complex catalysts for chemical water oxidation. The heterogeneous catalyst (Ir-BPy-NT) was prepared by the post-synthetic metalation of bipyridine-containing mesoporous organosilica nanotubes (BPy-NT) with an [IrCp*Cl(μ-Cl)]2 (Cp* = η5-pentamethylcyclopentadienyl) complex. The as-prepared Ir-BPy-NT catalyst showed enhanced durability with high reaction activity compared to the analogous homogeneous and the conventional heterogeneous ones, due to the stable nanotube structures as well as the isolated active sites. The unique one-dimensional nanotubes with large pore diameters can also reduce the diffusion limitation and facilitate the transport of reactants and products during reactions.


Psychological Treatment of Low Sexual Desire in Women: Protocol for a Randomized, Waitlist-Controlled Trial of Internet-Based Cognitive Behavioral and Mindfulness-Based Treatments.
Psychological therapies are effective treatments for hypoactive sexual desire dysfunction (HSDD; formerly hypoactive sexual desire disorder), a common sexual dysfunction among women. Access to evidence-based treatments, however, remains difficult. Internet-based interventions are effective for a variety of psychological disorders and may be a promising means to close the treatment gap for HSDD. This article describes the treatment protocol and study design of a randomized controlled trial, aiming to study the efficacy of cognitive behavioral and mindfulness-based interventions delivered via the internet for women with HSDD to a waitlist control group. Outcomes are sexual desire (primary) and sexual distress (secondary). Additional variables (eg, depression, mindfulness, rumination) will be assessed as potential moderators or mediators of treatment success. A cognitive behavioral and a mindfulness-based self-help intervention for HSDD will be provided online. Overall, 266 women with HSDD will be recruited and assigned either to one of the intervention groups, or to a waitlist control group (2:2:1). Outcome data will be assessed at baseline, at 12 weeks, and at 6 and 12 months after randomization. Intention-to-treat and completer analyses will be conducted. We expect improvements in sexual desire and sexuality-related distress in both intervention groups compared to the waitlist control. Recruitment has begun in January 2019 and is expected to be completed in August 2021. Results will be published in 2022. This study aims to contribute to the improvement and dissemination of psychological treatments for women with HSDD and to clarify whether cognitive behavioral and/or mindfulness-based treatments for HSDD are feasible and effective when delivered via the internet. ClinicalTrials.gov NCT03780751; https://clinicaltrials.gov/ct2/show/NCT03780751. DERR1-10.2196/20326.


[The evaluation of living skills in forensic-psychiatric patients].
The role of daily living skills in forensic psychiatric patients in relation to psychotherapeutic progress and the potential reduction of dangerous behaviour has been neglected in the scientific discussion about clinical instruments for the evaluation of dangerousness and recidivism. This is mainly due to the lack of adequate observationally based instruments allowing for valid and reliable therapeutic assessments. Therefore, a new means of assessment focusing on daily living skills and social risk (the BEST-Index [Behavioural Status Index] was applied to n = 86 German forensic psychiatric patients. Two widely known actuarial instruments tapping violence risk were administered for cross validation (Psychopathy Checklist Revised [PCL-R], HCR-20). Within intervals of nine months, all instruments were applied three times. Sufficient inter rater reliability and good convergent validity of the sub-scales in relation to the actuarial instruments (HCR-20, PCL-R) could be demonstrated; supported by empirical data, clinicians working with the BEST-Index may use it to monitor behavioural change over long treatment periods. It is suggested that treatment planning and evaluation of mentally ill offenders might profit from its use.


A steerable complex wavelet construction and its application to image denoising.
This work addresses the design of a novel complex steerable wavelet construction, the generation of transform-space feature measurements associated with corner and edge presence and orientation properties, and the application of these measurements directly to image denoising. The decomposition uses pairs of bandpass filters that display symmetry and antisymmetry about a steerable axis of orientation. While the angular characterization of the bandpass filters is similar to those previously described, the radial characteristic is new, as is the manner of constructing the interpolation functions for steering. The complex filters have been engineered into a multirate system, providing a synthesis and analysis subband filtering system with good reconstruction properties. Although the performance of our proposed denoising strategy is currently below that of recently reported state-of-the-art techniques in denoising, it does compare favorably with wavelet coring approaches employing global thresholds and with an "Oracle" shrinkage technique, and presents a very promising avenue for exploring structure-based denoising in the wavelet domain.


DNA binding by epipodophyllotoxins and N-acyl anthracyclines: implications for mechanism of topoisomerase II inhibition.
Previous evidence suggests that epipodophyllotoxins, such as etoposide and teniposide, and the N-acyl anthracycline AD41 inhibit topoisomerase II resealing even though they apparently do not bind to DNA. Using experimental conditions designed to detect limited numbers of DNA binding sites, we now report that both epipodophyllotoxins and the N-acyl anthracyclines AD41 and AD32 bind to DNA. Binding was greater to kinetoplast DNA than to pUC18 plasmid DNA. There was also greater etoposide binding to single-stranded DNA than to double-stranded linear or supercoiled DNA. Based on binding competition experiments, etoposide and teniposide appear to have equal affinity for DNA, in spite of the fact that the latter is more potent as a topoisomerase inhibitor. This suggests that the difference in the drugs relates to protein interaction. There are 3- to 7-fold more binding sites for AD41 than for AD32, depending on the DNA substrate employed, and both drugs, unlike adriamycin, exhibit saturation of binding sites over a concentration range of 0-50 microM when kinetoplast DNA is the substrate. Evidence for DNA intercalation by AD41 is provided by the observation that the drug introduces positive supercoils into covalently closed plasmid DNA. Based on these data, a hypothesis is proposed that would provide a general mechanism whereby intercalating agents and epipodophyllotoxins alter topoisomerase function and presumably exert their antitumor effects.


Non-ketotic hyperglycaemia hemichorea-hemiballismus and acute ischaemic stroke.
Here we describe a patient with a rare movement disorder, hemichorea-hemiballismus, which is described as a complication of non-ketotic hyperglycaemia. This complication may be seen in individuals with poorly controlled long-standing diabetes mellitus. Proper diagnosis is established with CT and MRI of the brain, which typically show classic findings in the basal ganglia. Treatment focuses on improvement of glycaemic control and usually results in rapid resolution of the movement disorder. Nevertheless, recurrent episodes of hemichorea-hemiballismus, and even more ominous complications such as ischaemic stroke may occur.


Use of a corporate needs assessment to define the information requirements of an arthritis resource centre in Birmingham: comparison of patients' and professionals' views.
Education and information are important components of the management of chronic disease, though provision of these in the routine clinic setting may be suboptimal. We carried out a corporate needs assessment, both to evaluate stakeholders' perceived usefulness of potential facilities that could be offered by a community-based arthritis resource centre in Birmingham and to compare the views of patients with rheumatological conditions and health professionals. Rheumatology patients (n = 201 responders/309 contacted) and health professionals (n = 232/430) were asked to complete a questionnaire to assess both current rheumatology service provision and perceived needs for further information that could be offered within the proposed resource centre. Views of patients and professionals were compared using odds ratios. Logistic regression analysis determined patient characteristics associated with perceived usefulness of various information types. The overall response rate was 58%. Most patients were currently receiving medication but only 38% received written information on arthritis. Over 80% of responders felt that more information would be useful, particularly information in written leaflets. Compared with professionals, patients gave higher value to certain types of medical, non-medical, support and skills information, particularly individual information from trained volunteers, and specific information on benefits, diet and alternative therapy, and symptom management. Non-Caucasian patients gave higher value to the provision of material in different languages and the availability of multilingual volunteer staff. Rheumatology patients and professionals identified a relative lack of information for patients. There was wide interest in the provision of more information, with value placed on the provision of material in different languages, at an educational resource centre. This work has been used to develop the facilities currently offered at the Birmingham Arthritis Resource Centre. Further research is needed to investigate the effectiveness of the provision of good quality information to patients with arthritis.


Influences of Social Determinants of Health on African Americans Living With HIV in the Rural Southeast: A Qualitative Meta-synthesis.
Social determinants of health influence health outcomes and contribute to health disparities in diverse populations. A meta-synthesis was conducted to provide emic perspectives of the experiences of African Americans living with HIV in the rural southeastern United States. Analysis of qualitative literature revealed patterns among social determinants of health as upstream factors contributing to health care barriers, poor health outcomes, decreased quality of life, and health disparities. The purpose of our meta-synthesis was the illumination and synthesis of themes describing characteristics of social determinants of health in selected qualitative articles. The nine themes that emerged included living in poverty, enduring unemployment, missing work, lacking transportation, sustaining stress, feeling socially excluded, needing social support, battling substance use, and lacking adequate health care.


p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system.
In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-kappaB, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IkappaB kinase (IKK)-beta and stimulated its abilities to phosphorylate IkappaB and to activate NF-kappaB. MKK6(Glu) induced NF-kappaB-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-alpha, which activates both NF-kappaB and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis. TNF-alpha-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1), which is known to activate p38 and NF-kappaB in other cell types. Thus, by stimulating both p38 and NF-kappaB, Tak1-activating cytokines, like TNF-alpha, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38.


Hypoxia Sensing and Persistence Genes Are Expressed during the Intragranulomatous Survival of Mycobacterium tuberculosis.
Although it is accepted that the environment within the granuloma profoundly affects Mycobacterium tuberculosis (Mtb) and infection outcome, our ability to understand Mtb gene expression in these niches has been limited. We determined intragranulomatous gene expression in human-like lung lesions derived from nonhuman primates with both active tuberculosis (ATB) and latent TB infection (LTBI). We employed a non-laser-based approach to microdissect individual lung lesions and interrogate the global transcriptome of Mtb within granulomas. Mtb genes expressed in classical granulomas with central, caseous necrosis, as well as within the caseum itself, were identified and compared with other Mtb lesions in animals with ATB (n = 7) or LTBI (n = 7). Results were validated using both an oligonucleotide approach and RT-PCR on macaque samples and by using human TB samples. We detected approximately 2,900 and 1,850 statistically significant genes in ATB and LTBI lesions, respectively (linear models for microarray analysis, Bonferroni corrected, P < 0.05). Of these genes, the expression of approximately 1,300 (ATB) and 900 (LTBI) was positively induced. We identified the induction of key regulons and compared our results to genes previously determined to be required for Mtb growth. Our results indicate pathways that Mtb uses to ensure its survival in a highly stressful environment in vivo. A large number of genes is commonly expressed in granulomas with ATB and LTBI. In addition, the enhanced expression of the dormancy survival regulon was a key feature of lesions in animals with LTBI, stressing its importance in the persistence of Mtb during the chronic phase of infection.


Archaeal type IV pilus-like structures--evolutionarily conserved prokaryotic surface organelles.
In both bacteria and Archaea, the biosynthesis of type IV pilus-related structures involves a set of core components, including a prepilin peptidase that specifically processes precursors of pilin-like proteins. Although in silico analyses showed that most sequenced archaeal genomes encode predicted pilins and conserved pilus biosynthesis components, recent in vivo analyses of archaeal pili in genetically tractable crenarchaea and euryarchaea revealed Archaea-specific type IV pilus functions and biosynthesis components. Studies in a variety of archaeal species will reveal which type IV pilus-like structures are common in Archaea and which are limited to certain species within this domain. The insights gleaned from these studies may also elucidate the roles played by these types of structures in adapting to specific environments.


Dynamic compression system for the correction of pectus carinatum.
Between April 2001 and 2007, we treated 208 patients with pectus carinatum by using a specially designed dynamic compression system (DCS) that uses a custom-made aluminum brace. Recently, an electronic pressure measuring device was added to the brace. Results were evaluated by using a double-blinded subjective scale (1 to 10). A total of 208 patients were treated over 6 years; 154 were males (74%) and the mean age was 12.5 years (range 3 to 18 years). Mean utilization time was 7.2 hours daily for 7 months (range 3 to 20 months). A total of 28 (13.4%) patients abandoned treatment and were not evaluated for final results. Of the 180 remaining patients, 112 completed treatment. A total of 99 of 112 (88.4%) had good to excellent results scoring between 7 and 10 points, and 13 (11.6%) patients scored 1 to 6 points and were judged as poor or failed results. The "Pressure for Initial Correction" (PIC) in pounds per square inch (PSI) proved that starting treatment with less than 2.5 PSI avoids skin lesions. Patients who require pressures higher than 7.5 PSI should not be treated with this method. We found a good correlation between PIC versus treatment duration and outcome. DCS is an effective treatment for pectus carinatum with minimal morbidity. We suggest that patients with pectus carinatum have a trial of compression therapy before recommending surgical resection. The use of pressure measurement avoids complications such as skin lesions, partial or poor results, and patient noncompliance.


Characterizing the effects of the protein environment on the reduction potentials of metalloproteins.
The reduction potentials of electron transfer proteins are critically determined by the degree of burial of the redox site within the protein and the degree of permanent polarization of the polypeptide around the redox site. Although continuum electrostatics calculations of protein structures can predict the net effect of these factors, quantifying each individual contribution is a difficult task. Here, the burial of the redox site is characterized by a dielectric radius R(p) (a Born-type radius for the protein), the polarization of the polypeptide is characterized by an electret potential ϕ(p) (the average electrostatic potential at the metal atoms), and an electret-dielectric spheres (EDS) model of the entire protein is then defined in terms of R(p) and ϕ(p). The EDS model shows that for a protein with a redox site of charge Q, the dielectric response free energy is a function of Q(2), while the electret energy is a function of Q. In addition, R(p) and ϕ(p) are shown to be characteristics of the fold of a protein and are predictive of the most likely redox couple for redox sites that undergo different redox couples.


Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta-oxidation.
Glucocorticoid administration may produce fatty liver in humans. We investigated the effects of dexamethasone on hepatic mitochondria and lipid metabolism in mice. Dexamethasone 21-phosphate (20 microM) did not inhibit the mitochondrial inner membrane-bound very-long-chain acyl-CoA dehydrogenase but inhibited the matrixlocated long-, medium-, and short-chain dehydrogenases. Dexamethasone 21-phosphate (20 microM) inhibited the first beta-oxidation cycle of [1-(14C)]butyric acid and [1-(14C)]octanoic acid but not that of [1-(14C)]palmitic acid. Administration of dexamethasone 21-phosphate (100 mg/kg) decreased the in vivo oxidation of [1-(14C)]butyric acid and [1-(14C)]octanoic acid into [14C]CO2 but not that of [1-(14C)]palmitic acid and decreased the hepatic secretion of triglycerides. After 5 days of treatment (100 mg/kg daily), hepatic triglycerides were increased and both microvesicular steatosis and ultrastructural mitochondrial lesions were present. In conclusion, glucocorticoids inhibit medium- and short-chain acyl-CoA dehydrogenation and hepatic lipid secretion in mice. These effects may account for their steatogenic effects in humans.


Retroperitoneal masses mimicking adrenal tumors.
To report 10 cases of neoplasms that were initially thought to be primarily adrenal-derived masses but were later confirmed as tumors of a different origin. Between 2000 and 2011, a total of 229 patients underwent adrenalectomy at our institution. Of this overall group, 10 patients had retroperitoneal pathologic conditions mimicking adrenal tumors. Using an institutional review board-approved database, we reviewed the clinical, biochemical, and radiologic characteristics of these 10 patients. The study cohort consisted of 4 male and 6 female patients. The mean age of these 10 patients was 48 years. The pathologic conditions included schwannoma (n = 3), leiomyosarcoma (n = 2), and 1 each of metastatic angiosarcoma, metastatic granulosa cell tumor, retroperitoneal hematoma, perivascular epithelioid cell tumor, and bronchogenic cyst. The patient with angiosarcoma had elevated plasma and urine catecholamines and a positive metaiodobenzylguanidine scan, whereas the others had normal findings on biochemical work-up. A percutaneous biopsy was performed preoperatively in 2 patients. All patients, except the patient with hematoma, underwent abdominal exploration, which was laparoscopic in 5, open in 2, and robotic in 2. With exclusion of the patients with angiosarcoma and hematoma, resection was possible in all the remaining patients. In this report we describe our experience with retroperitoneal masses mimicking adrenal tumors. Increased awareness of these unusual pathologic conditions is important for appropriate clinical management of these tumors. The presentation of the patients and the surgical management of these individual pathologic entities are highlighted.


Thyroid Disorders in Central Ghana: The Influence of 20 Years of Iodization.
Ghana began mandatory iodization of salt in 1996. This study compares the prevalence of thyroid disorders before and after the introduction of iodization. This is a retrospective study of thyroid cases from the middle belt of Ghana between 1982 and 2014. To demonstrate a link between iodization and hyperthyroidism and autoimmunity, we compared the prevalence of hyperthyroidism and autoimmune thyroid disorders before and after the iodization programme. A total of 10,484 (7548 females, 2936 males) cases were recorded. The rate of thyroid cases seen was 343/100,000. Nontoxic nodular goiters (25.7%) and toxic nodular goiters (22.5%) represented the second commonest thyroid disorders recorded. The prevalence of hyperthyroid disorders seen after 1996 was significantly higher than the prevalence seen before the iodization (40.0 versus 21.1%, p < 0.001). The prevalence of autoimmune disorders recorded after iodization was significantly higher than that before the iodization programme started (22.3% versus 9.6%, p < 0.001). This study has revealed a significant increase in thyroid admissions in Central Ghana over the decades. A connection between iodine fortification and iodine-induced hyperthyroidism and between iodine fortification and autoimmune thyroiditis has been shown in this study.


Contextualising psychological distress among regular ecstasy users: the importance of sociodemographic factors and patterns of drug use.
Considerable concern has been raised about associations between ecstasy use and mental health. Studies of ecstasy users typically investigate varying levels of lifetime use of ecstasy, and often fail to account for other drug use and sociodemographic characteristics of participants, which may explain mixed findings. The current study aimed to examine the relationship between patterns of recent (last six months) ecstasy use and psychological distress among current, regular ecstasy users, controlling for sociodemographic risk factors and patterns of other drug use. Data were collected from regular ecstasy users (n = 752) recruited from each capital city in Australia as part of the Ecstasy and related Drugs Reporting System (EDRS). Psychological distress was assessed using the Kessler Psychological Distress Scale (K10). Data were analysed using multinomial logistic regression. Seven per cent of the sample scored in the 'high' distress category and 55% in the 'medium' distress category. Patterns of ecstasy use were not independently associated with psychological distress. The strongest predictors of distress were female sex, lower education, unemployment, 'binge' drug use including ecstasy (use for >48 h without sleep), frequent cannabis use and daily tobacco use. Regular ecstasy users have elevated levels of psychological distress compared with the general population; however, ecstasy use per se was not independently related to such distress. Other factors, including sociodemographic characteristics and other drug use patterns, appear to be more important. These findings highlight the importance of targeting patterns of polydrug use in order to reduce drug-related harm among regular ecstasy users.


Clinical assessment of a split-shank post system in permanent molar and premolar teeth.
The handling characteristics and use of a new split-shank post system in permanent molar and premolar teeth were assessed. Five general practitioners placed a total of 103 posts and, after each case, reported on the ease of tooth preparation and post placement. Overall, the assessments of the handling and use of the system were favorable.


Alterations in the Reactive Oxygen Species in Peripheral Blood of Chronic Myeloid Leukaemia Patients from Northern India.
There is a significant difference in the Reactive Oxygen Species (ROS) levels of Chronic Myeloid Leukaemia (CML) patients before and during treatment with Tyrosine Kinase Inhibitors (TKIs). This is because high ROS levels support oncogenic phenotype of CML by inducing proliferation pathway and accumulation of further genetic mutations. Often the measurement is done on WBC or serum for ascertaining one type of ROS species, but measurement of global ROS in fresh whole blood will give more accurate estimation of ROS. To measure global ROS in peripheral blood of CML patients. A case control study was undertaken to measure ROS in peripheral blood of CML patients from Northern India. CML patients on TKIs (n=40 on imatinib herein called treated) and untreated (n=17, who were not on any TKIs or alternative medicine, called as treatment naive) and 52 healthy controls were also enrolled. Chemiluminescent assay was carried out using luminol as signal enhancer in 400 µl of blood to measure ROS. The chemiluminescence was measured as Relative Light Units (RLU)/sec/104 WBC. Data was presented in terms of mean±SE or geometric mean (95% Confidence Interval) for continuous variables and percentage for categorical variables. Groups were compared using two sample t-test for continuous variables and chi-square test for categorical variables. The WBC profile and ROS levels of patients taking TKIs were quite similar and showed no significant difference (p<0.999) compared to healthy controls. In contrast, significant increase was observed in the ROS levels of CML patients not on TKIs (untreated) compared to patients under treatment (p<0.029) and healthy controls (p<0.007). We also observed that the absolute ROS values and WBC counts were higher in untreated patients compared to patients on TKIs and healthy controls, even though mean ROS value was less. To ascertain the alterations in ROS levels of CML patients before and during treatment with TKIs, it is better to measure global ROS in fresh whole blood by chemiluminescent method using luminol. Luminol assay is a quick, easy and inexpensive method to measure global ROS. Patient under treatment with TKIs show significant decrease in ROS levels almost similar to the levels measured in healthy controls yet the mechanisms by which this decrease occurs needs to be elucidated.


RRM2 computational phosphoprotein network construction and analysis between no-tumor hepatitis/cirrhotic liver tissues and human hepatocellular carcinoma (HCC).
RRM2 computational phosphoprotein network construction and analysis of human hepatocellular carcinoma (HCC) is very useful to identify novel markers and potential targets for prognosis and therapy. By integration of gene regulatory network infer (GRNInfer) and the database for annotation, visualization and integrated discovery (DAVID) we identified and constructed significant molecule RRM2 phosphoprotein network from 25 no-tumor hepatitis/cirrhotic liver tissues and 25 HCC patients in the same GEO Dataset GSE10140-10141. We gained the negative result of RRM2 phosphoprotein module through the net numbers of activation minus inhibition compared with no-tumor hepatitis/cirrhotic liver tissues and predicted possibly the decrease of RRM2 phosphoprotein module in HCC. Our integrative result showed that RRM2 phosphoprotein cluster of HCC contained both in human no-tumor hepatitis/cirrhotic liver tissues and HCC terms of phosphoprotein (with RRM2) and cell cycle (without RRM2), only in HCC terms of cell-cell signaling, cell projection part, glycoprotein, cell projection, cell adhesion, biological adhesion, integral to plasma membrane, plasma membrane, kinase and phosphorus metabolic process (without RRM2), and none in HCC terms of cell death (without RRM2) and ion binding (with RRM2) compared with human no-tumor hepatitis/cirrhotic liver tissues, all the condition is vital to invasion of HCC. Therefore, we deduced the weaker RRM2 phosphoprotein function in HCC consistent with our above computation. It would be necessary of RRM2 phosphoprotein function decrease to invasion of HCC. RRM2 phosphoprotein interaction module construction in HCC can be a new route for studying the pathogenesis of HCC.


A new modified fluorescein strip: Its repeatability and usefulness in tear film break-up time analysis.
To (i) analyze the repeatability of fluorescein instillation from a modified fluorescein strip (MFS) compared to a standard fluorescein strip (FS), and to (ii) observe its usefulness in the measurement of the fluorescein break-up time (FBUT) in comparison to the Tearscope (NIBUT). In-vitro: Intra- and inter-observer repeatability in fluorescein instillation from the MFS and FS was evaluated by fluorescence analysis (n=10, each). In-vivo: BUT of the right eye of 20 randomly selected subjects (mean age 43.3±11.5, range=21-60 years, 8 males, 12 females) was measured by use of the Tearscope and MFS. Subjects were grouped by the Ocular Surface Disease Index (OSDI) score into 8 OSDI+ and 12 OSDI- by a cut-off value of 15. In-vitro: Intra-observer 95% limit of agreement (LoA) of the MFS was similar to the FS LoA in observer 1 (O1), but better than the FS LoA in observer (O2) (MFS: O1: LoA=±1.98 mW; p=0.179; O2: ±2.71; 0.442; FS: O1: ±1.71; 0.246; O2: ±4.11; 0.512). Inter-observer LoA in fluorescence was better in MFS (±1.42; 0.111) than in FS (±3.71; 0.003). In-vivo: MFS-BUT was significantly shorter than the NIBUT (p=0.002), but significantly correlated (r=0.864, p<0.001). NIBUT and MFS-BUT were significant discriminators (p<0.001) of OSDI±(0.948/8s and 0.938/5s [AUC/cut-off value]; NIBUT and MFS-BUT, respectively). The MFS was better in the repeatability of fluorescein instillation than the FS. NIBUT and MFS-BUT were good discriminators of dry eye symptoms, but differ in their cut-off values.


A robust general phase retrieval method for medical applications.
From medical imaging perspective the robustness of a phase retrieval method is of critical importance. In this presentation we compare the robustness of two general phase retrieval methods, namely the transport of intensity equation inversion (TIE-inversion) method and the attenuation partition based (AP-based) method. We showed that the TIE-inversion method, regardless if being assisted with the Tikhonov regularization, failed to retrieve the phase maps in two experimental studies. The failure exposes this method's weakness as being unstable against the noise. In contrast, the sample phase maps are retrieved successfully by using the AP-based method. The stark performance differences of the two methods are rooted in their different techniques dealing with the singularity problem. This comparison shows that the robust AP-based phase retrieval method will be superior to the TIE-inversion method for medical imaging applications where radiation doses are stringently limited.


Septic arthritis or transient synovitis of the hip in children: the value of clinical prediction algorithms.
The crucial differentiation between septic arthritis and transient synovitis of the hip in children can be difficult. In 1999, Kocher et al introduced four clinical predictors which were highly predictive (99.6%) of septic arthritis. These included fever (temperature > or = 38.5 degrees C), inability to bear weight, white blood-cell count > 12.0 x 10(9) cells/L and ESR > or = 40 mm/hr; CRP > or = 20 mg/L was later added as a fifth predictor. We retrospectively evaluated these predictors to differentiate septic arthritis from transient synovitis of the hip in children over a four-year period in a primary referral general hospital. When all five were positive, the predicted probability of septic arthritis in this study was only 59.9%, with fever being the best predictor. When applied to low-prevalence diseases, even highly specific tests yield a high number of false positives and the predictive value is thereby diminished. Clinical predictors should be applied with caution when assessing a child with an irritable hip, and a high index of suspicion, and close observation of patients at risk should be maintained.


Anesthesia and postoperative pain control-multimodal anesthesia protocol.
Multimodal analgesia (MMA) involves the use of additive or synergistic combinations of analgesics to achieve clinically required analgesia while minimizing significant side effects associated with higher dose of a single equianalgesic medication such as an opioid analgesic. MMA generally involves optimizing non-opioid pharmacologic and non-pharmacologic interventions and reserving opioid use to treat breakthrough pain. Patients receiving medications via MMA protocols are likely to have lower opioid consumption compared to those managed using primarily IV opioid patient-controlled analgesia. MMA pain management strategies have become important components of enhanced recovery after surgery (ERAS) protocols in an effort to optimize care by standardizing analgesic medications in the perioperative setting while minimizing adverse effects and improving quality and patient outcomes. Successful implementation of a MMA requires the input and cooperation of all of the stakeholders including the caregivers as well as the patients. Health system benefits can also be realized from the implementation of an effective MMA, as fewer opioid related side effects can improve patient recovery and lead to faster discharge and improved utilization of resources.


The burden of mental disorders in Nepal between 1990 and 2019: Findings from the Global Burden of Disease Study 2019.
Mental disorders are the leading cause of disease burden, affecting 13% of all people globally in 2019. However, there is scarce evidence on the burden of mental disorders in Nepal. This study used the Global Burden of Disease Study 2019 data to assess the prevalence and disability-adjusted life-years (DALYs) of mental disorders in Nepal between 1990 and 2019. In 2019, there were 3.9 million (95% UI: 3.6-4.3) people with mental disorders in Nepal. Major depressive disorders (1.1 million; 95% UI: 0.9-1.2 million) and anxiety disorders (0.9 million; 95% UI: 0.8-1.2 million) were the most prevalent mental disorders in 2019. Attention deficit hyperactive disorder, conduct disorder, and autism spectrum disorders were present twice as high in males than in females. The proportional contribution of mental disorders to the total disease burden has tripled between 1990 (1.79% of all DALYs) and 2019 (5.5% of all DALYs). In conclusion, the proportional contribution of mental disorders to total disease burden has increased significantly in the last three decades in Nepal, with apparent sex and age differentials in prevalence and DALY rates. Effective program and policy responses are required to prepare the health system for reducing the growing burden of mental health disorders in Nepal.


Mandatory Change From Surgical Skull Caps to Bouffant Caps Among Operating Room Personnel Does Not Reduce Surgical Site Infections in Class I Surgical Cases: A Single-Center Experience With More Than 15 000 Patients.
Surgical site infections (SSIs) are noteworthy and costly complications. New recommendations from a national organization have urged the elimination of traditional surgeon's caps (surgical skull caps) and mandated the use of bouffant caps to prevent SSIs. To report SSI rates for >15 000 class I (clean) surgical procedures 13 mo before and 13 mo after surgical skull caps were banned at a single site with 25 operating rooms. SSI data were acquired from hospital infection control monthly summary reports from January 2014 to March 2016. Based on a change in hospital policy mandating obligatory use of bouffant caps since February 2015, data were categorized into nonbouffant and bouffant groups. Monthly and cumulative infection rates for 13 mo before (7513 patients) and 13 mo after (8446 patients) the policy implementation were collected and analyzed for the groups, respectively. An overall increase of 0.07% (0.77%-0.84%) in the cumulative rate of SSI in all class I operating room cases and of 0.03% (0.79%-0.82%) in the cumulative rate of SSI in all spinal procedures was noted. However, neither increase reached statistical significance (P > .05). The cumulative rate of SSI in neurosurgery craniotomy/craniectomy cases decreased from 0.95% to 0.75%; this was also not statistically significant (P = 1.00). National efforts at improving healthcare performance are laudable but need to be evidence based. Guidelines, especially when applied in a mandatory fashion, should be assessed for effectiveness. In this large, single-center series of patients undergoing class I surgical procedures, elimination of the traditional surgeon's cap did not reduce infection rates.


A Scope of the Social Brain in Multiple Sclerosis: Insights From Neuroimaging Studies.
Multiple sclerosis (MS) is the most common inflammatory neurologic disease in young adults. Its pathological mechanisms include demyelination, neurodegeneration, and synaptopathy. Cognitive deficits occur in up to 65% of individuals with MS and affect both nonsocial (eg, information processing speed, memory, and executive functions) and social (ie, emotion recognition, theory of mind, and empathy) cognitive domains. In the last 3 decades, there has been a growing interest in social cognition and its relationship with neuropsychological, sociodemographic, and disease characteristics in individuals with MS. Uncovering the neuropathological correlates of social cognitive deficits is now a crucial aim that would also help us better understand the underlying mechanisms of social cognition. We reviewed 11 neuroimaging studies to investigate social cognition in MS. These studies focused mainly on facial emotion recognition and theory of mind, with the findings suggesting that a disrupted cortico-subcortical network forms the basis of social deficits involving both domains. We then interpreted these results in the context of multiple disconnection syndrome, which occurs as a result of axonal demyelination and degeneration within the connexome of several neural hubs devoted to social cognition. Heterogeneity in social cognitive performance, observed among our study participants, is discussed with reference to the cognitive reserve and brain reserve hypotheses. These reserves may explain why individuals with comparable clinical characteristics of MS may exhibit different cognitive profiles. Further research is required to generalize these findings to the MS population and to inform the development of effective interventions to improve psychosocial functioning in individuals with MS.


Reliability and Validity of the Japanese Version of the Barriers to Access to Care Evaluation Scale Version 3 for People With Mental Disorders: an Online Survey Study.
It is a serious problem when people with mental disorders avoid, delay, discontinue, or do not use treatment and support, despite the existence of evidence-based treatment and support methods. In this study, we aimed to clarify the factor structure of BACE v3, a scale to measure barriers to accessing mental health care, and to examine its reliability and validity among Japanese people with mental disorders. An online survey with 268 participants, 20 years old and over, who had received care from mental health services in the past 12 months was conducted. Exploratory and confirmatory factor analysis (EFA and CFA) were used to examine the structure of the BACE v3. Internal consistency and test-retest reliability of all subscales were examined. Convergent validity [correlation of one of the subscales of the BACE v3, the treatment stigma subscale with the Stigma Scale for Receiving Psychological Help (SSRPH) and with the Internalized Stigma of Mental Illness Scale (ISMI)] was assessed. EFA identified two factors (treatment stigma and non-stigma), and the results suggested that the factor structure of the Japanese version of BACE v3 was similar to the original 2-factor structure. Regarding the CFA result, the goodness-of-fit indices showed marginal fit (root mean square error of approximation = 0.087; Tucker-Lewis index = 0.842; standardized root mean square residual = 0.078; comparative fit index = 0.86). The internal consistency of the treatment stigma subscale was α = 0.90, and the intraclass correlation coefficient was 0.76 (confidence interval: 0.70-0.81). The internal consistency of the non-stigma subscale was α = 0.83, and the intraclass correlation coefficient was 0.64 (confidence interval: 0.56-0.71). The score of the treatment stigma subscale was significantly and positively correlated with the SSRPH and ISMI. Thus, the BACE v3 has acceptable consistency, reliability and validity for the assessment of barriers to accessing mental health care including treatment stigma among people with mental disorders in Japan.


Parkin null cortical neuronal/glial cultures are resistant to amyloid-β1-42 toxicity: a role for autophagy?
Dementia occurs often in late stages of Parkinson's disease (PD) but its cause is unknown. Likewise there is little information about the interaction between proteins that produce PD and those implicated in Alzheimer's disease (AD). Here we have investigated the interactions between parkin protein and the amyloid-β (Aβ)1-42 peptide. We examined the effects of oligomeric Aβ1-42 peptide on the survival, differentiation, and signaling pathways in cortical cultures from wild type (WT) and parkin null (PK-KO) mice. We discovered that PK-KO cells were more resistant than WT to Aβ1-42. This peptide induced neuronal cell death, astrogliosis, microglial proliferation, and increased total and hyperphosphorylated tau and levels of chaperones HSP-70 and CHIP in WT, but not in Aβ-treated PK-KO cultures. Aβ1-42 decreased proteasome activities in WT and PK-KO cultures, but the ubiquitination of proteins only increased in WT cultures. Aβ1-42 induced a short activation of ERK1/2 and AKT signaling pathways, implicated in cell survival, in PK-KO-treated cells, and a shift in the autophagy marker LC3-II/LC3-I ratio. In addition, the percentage of cells immunoreactive to both HSC70 and LAMP-2A increased in PK-KO cultures versus WT and furthermore in PK-KO cultures treated with Aβ1-42. Pre-treatment with inhibitors of glutathione synthesis or autophagy reverted the resistance to Aβ1-42 of the PK-KO cultures. In conclusion, the loss of parkin protein triggers the compensatory mechanisms of cell protection against Aβ1-42. Parkin suppression, therefore, is not a risk factor for dementia of AD type.


Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses.
MHC proteins that present peptide ligands for recognition by TCR form nanoscale clusters on the cell membrane of APCs. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To evaluate the role of MHC clustering, we exploited nanoscale discoidal membrane mimetics (nanolipoprotein particles) to capture and present peptide-MHC (pMHC) ligands at various densities. We examined the binding of these model membrane clusters to the surface of live human CD8+ T cells and the subsequent triggering of intracellular signaling. The data demonstrate that the proximity of pMHC ligands, high association rate of CD8-MHC interactions, and relatively long lifetime of cognate TCR-pMHC complexes emerge as essential parameters, explaining the significance of MHC clustering. Rapid rebinding of CD8 to MHC suggests a dual role of CD8 in facilitating the T cells' hunt for a rare foreign pMHC ligand and the induction of rapid T cell response. Thus, our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR on live T cells that regulate Ag recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T cell responses.


[Venous thromboembolism and risk factors for deep vein thrombosis in patients with pancreatic cancer undergoing chemotherapy].
Among various types of cancers, pancreatic cancer is known to be prone to venous thromboembolism (VTE). We investigated the complication rate of VTE and risk factors for deep vein thrombosis (DVT) in patients with pancreatic cancer undergoing chemotherapy. We retrospectively analyzed the data of 51 patients with pancreatic cancer who had undergone chemotherapy at our hospital from January 2016 to March 2021, had their D-dimer levels measured at the initial visit, and had undergone venous ultrasonography if D-dimer levels were elevated. At the initial visit, the complication rate of VTE was 35.3% (18/51 patients). Multivariate analysis revealed that the risk factors for DVT were primary tumors in the pancreas's body and tail and elevated D-dimer levels. Patients with DVT tended to have shorter overall survival than those without (218 vs 523 days). Patients with pancreatic cancer frequently develop VTE and should be aggressively screened for thrombosis, particularly in those with primary tumors in the pancreas's body and tail and elevated D-dimer levels.


Proteomic study explores AGR2 as pro-metastatic protein in HCC.
Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors worldwide. The prognosis of patients with HCC still remains very dismal, mainly due to metastasis. We found that high-expression levels of AGR2 existed in metastatic HCC cell lines and patient samples. Overexpression of AGR2 was found to be correlated to the metastatic status of HCC cells, and inhibition of AGR2 by siRNA resulted in a dramatic decline in invasion abilities in metastatic cells in vitro. Overexpression of AGR2 increased the invasion of HCC cells in vitro and also in vivo with a nude mouse model. The tandem affinity purification (TAP) identified 18 AGR2-binding proteins and IPA analysis revealed that these proteins focus on MAPK and Caspase pathway. Therefore, we speculate that the overexpression of AGR2 can promote HCC metastasis, possibly by affecting MAPK and Caspase pathway through AGR2-interacting proteins.


Mitochondrial complex I protein differs among residual feed intake phenotype in beef cattle.
Four experiments were performed to determine if residual feed intake (RFI) was related to mitochondrial complex I (CI) protein. For Exp. 1, crossbred Angus steers (initial BW 270 ± 2.0 kg) were fed for a total of 170 d (n = 72). For Exp. 2, crossbred Braunvieh steers (initial BW 280 ± 3.0 kg) were fed for a total of 150 d (n = 50). For Exp. 3, crossbred Braunvieh heifers (initial BW 260 ± 3.0 kg) were fed for a total of 160 d (n = 40). For Exp. 4, crossbred Angus steers (initial BW 290 ± 3.0 kg) were fed for a total of 160 d (n = 40). All cattle in all experiments were fed the same diet. The variable RFI was calculated as the difference between predicted and actual DMI. Predicted DMI was calculated from regressing intake on ADG and metabolic body weight. Blood was collected, lymphocytes were isolated, and antibody used to capture CI. For Exp. 1, 2, and 3, CI quantity was measured using an ELISA commercial kit (Mitosciences, OR). For Exp. 4, CI subunits were separated by gel electrophoresis and bands were analyzed for differences in concentration (absorbance) among RFI phenotypes. For all 4 experiments, there was a significant difference (P < 0.05) between RFI and DMI but no difference (P > 0.05) was reported for ADG and metabolic midweight. For Exp. 1, 2, and 3, CI concentration in mitochondria was greater (P < 0.05) for low RFI compared with other treatments. For Exp. 4, animals with low RFI had a trend (P = 0.07) for greater concentration of Band I (protein S1) than high RFI. Correlation between RFI and Band I was -0.72 (P = 0.04). We concluded that mitochondrial function was at least in part responsible for differences among animals in metabolic efficiency.


State-level prevalence of anemia in women of reproductive age. Ensanut 2006, 2012 and 2018-19.
To compare the prevalence of anemia and iron deficiency, at state level in non-pregnant women between 20 and 49 years of age from the Encuesta Nacional de Salud y Nutrición (Ensanut, in Spanish) 2006, 2012 and 2018-19. The Ensanut 2006, 2012 and 2018-19 have a probabilistic design. Hb in capillary blood was measured by HemoCue Hb201 and ferritin by venous sample. Anemia was diagnosed with Hb<120g/L and iron deficiency with Ferritin<15ng/mL. At the national level, anemia increased 6.1 (p<0.05) percentage points (pp) from 2006 to 2018-19. Baja California Norte, Campeche, Colima, Chiapas, Quintana Roo, Sinaloa and Sonora, went from low prevalence (5 to 19.9%) to moderate (20 to 39.9%); in Yucatán and Tamaulipas it went from low to severe (>40). In Guanajuato, State of Mexico and Querétaro it was reduced from 2006 to 2018-19 (p<0.05). Anemia continues to be a public health problem that requires actions at the state level, considering level of wellbeing index, food programs and affiliation to medical Services insurance.


A muscarinic cholinergic mechanism underlies activation of the central pattern generator for locust flight.
A central question in behavioural control is how central pattern generators (CPGs) for locomotion are activated. This paper disputes the key role generally accredited to octopamine in activating the CPG for insect flight. In deafferented locusts, fictive flight was initiated by bath application of the muscarinic agonist pilocarpine, the acetylcholine analogue carbachol, and the acetylcholinesterase blocker eserine, but not by nicotine. Furthermore, in addition to octopamine, various other amines including dopamine, tyramine and histamine all induced fictive flight, but not serotonin or the amine-precursor amino acid tyrosine. However, flight initiation was not reversibly blocked by aminergic antagonists, and was still readily elicited by both natural stimulation (wind) and pilocarpine in reserpinized, amine-depleted locusts. By contrast, the muscarinic antagonists atropine and scopolamine reversibly blocked flight initiated by wind, cholinergic agonists, octopamine, and by selective stimulation of a flight-initiating interneurone (TCG). The short delay from TCG stimulation to flight onset suggests that TCG acts directly on the flight CPG, and accordingly that TCG, or its follower cell within the flight generating circuit, is cholinergic. We conclude that acetylcholine acting via muscarinic receptors is the key neurotransmitter in the mechanism underlying the natural activation of the locust flight CPG. Amines are not essential for this, but must be considered as potential neuromodulators for facilitating flight release and tuning the motor pattern. We speculate that muscarinic activation coupled to aminergic facilitation may be a general feature of behavioural control in insects for ensuring conditional recruitment of individual motor programs in accordance with momentary adaptive requirements.


Retinal and peripapillary vascular density in episodic and chronic migraine cases without aura.
Migraine is a neurovascular disease that can cause ocular and systemic ischemic damage. Despite from aura, a limited number of studies have considered the effect of the chronic migraine in cases without aura. Our aim was to evaluate the differences in the retinal and optic disk microvasculature among episodic and chronic migraine cases without aura using optical coherence tomography angiography (OCTA) imaging. 45 cases with migraine, and 25 control subjects were included in this prospective, cross-sectional study. OCTA was performed at 3 × 3 mm and 6 × 6 mm of the macula and at 4.5 × 4.5 mm of the optic disk. Retinal nerve fiber layer (RNFL) thickness, ganglion cell complex thickness, and vessel densities of the optic nerve and macula were compared among the three groups: a control group, an episodic migraine without aura (EMWOA) group, and a chronic migraine without aura (CMWOA) group. In EMWOA group, circumpapillary vascular density (cpVD) was not decreased significantly in any quadrants (all, p>0.05). Compared to the control group, CMWOA group had significantly lower RNFL thickness in superior-temporal quadrants (p = 0.002 and 0.006, respectively), while cpVD differed only in the temporal quadrant and temporal inferior sector (p = 0.002 and p = 0.009, respectively). Temporal peripapillary perfusion is valuable in the follow-up of chronic migraine cases. Longitudinal studies are needed to determine the place of OCTA in the follow-up of migraine.


Rhythmicity and plasticity of digestive physiology in a euryhaline teleost fish, permit (Trachinotus falcatus).
Digestive physiology is considered to be under circadian control, but there is little evidence in teleost fish. The present study explored the rhythmicity and plasticity to feeding schedules of enzymatic digestion in a candidate aquaculture fish, the permit (Trachinotus falcatus). The first experiment identified the rhythms of digestive factors throughout the light-dark (LD) cycle. Gastric luminal pH and pepsin activity showed significant daily variation albeit not rhythmic. These dynamic changes were likewise observed in several digestive enzymes, in which the activities of intestinal protease, chymotrypsin and lipase exhibited significant daily rhythms. In the second experiment, the existence of feed anticipatory activity in the digestive factors was investigated by subjecting the fish to either periodic or random feeding. Anticipatory gastric acidification prior to feeding was identified in periodically fed fish. However, pepsin activity did not exhibit such anticipation but a substantial postprandial increase was observed. Intestinal protease, leucine aminopeptidase and lipase anticipated periodic mealtime with elevated enzymatic activities. Plasma melatonin and cortisol demonstrated robust daily rhythms but feeding time manipulations revealed no significant impact. Plasma ghrelin level remained constant during the LD cycle and appeared to be unaffected by differing feeding regimes as well. Taken together, the digestive factors of permit were highly dynamic during the LD cycle. Periodic feeding entrained digestive physiology and mediated anticipatory gastric acidification and intestinal enzymatic activities. This knowledge will be essential in developing feeding protocols and husbandry-related welfare strategies that will further advance this candidate finfish as an aquaculture species.


Muscle energy technique for non-specific low-back pain.
Low-back pain (LBP) is responsible for considerable personal suffering due to pain and reduced function, as well as the societal burden due to costs of health care and lost work productivity. For the vast majority of people with LBP, no specific anatomical cause can be reliably identified. For these people with non-specific LBP there are numerous treatment options, few of which have been shown to be effective in reducing pain and disability. The muscle energy technique (MET) is a treatment technique used predominantly by osteopaths, physiotherapists and chiropractors which involves alternating periods of resisted muscle contractions and assisted stretching. To date it is unclear whether MET is effective in reducing pain and improving function in people with LBP. To examine the effectiveness of MET in the treatment of people with non-specific LBP compared with control interventions, with particular emphasis on subjective pain and disability outcomes. CENTRAL, MEDLINE, EMBASE, five other databases and two trials registers were searched from inception to May and June 2014 together with reference checking and citation searching of relevant systematic reviews. Randomised controlled trials assessing the effect of MET on pain or disability in patients with non-specific LBP were included. Two authors independently assessed the risk of bias and extracted the data. Meta-analysis was performed where clinical homogeneity was sufficient. The quality of the evidence for each comparison was assessed with the GRADE approach. There were 12 randomised controlled trials with 14 comparisons included in the review, with a total sample of 500 participants across all comparisons. Included studies were typically very small (n = 20 to 72), all except one were assessed as being at high risk of bias, and all reported short-term outcomes. For the purposes of pooling, studies were divided into seven clinically homogenous comparisons according to the patient population (acute or chronic LBP) and the nature of the control intervention. Most of the comparisons (five out of seven) included only one study, one comparison had two studies, and one comparison included seven studies.The meta-analyses provided low-quality evidence that MET provided no additional benefit when added to other therapies on the outcomes of chronic pain and disability in the short-term (weighted mean difference (WMD) for pain 0.00, 95% CI -2.97 to 2.98 on a 100-point scale; standardised mean difference (SMD) for disability -0.18, 95% CI -0.43 to 0.08, 7 studies, 232 participants). There was low-quality evidence that MET produced no clinically relevant differences in pain compared to sham MET (mean difference (MD) 14.20, 95% CI -10.14 to 38.54, 1 study, 20 participants). For the comparison of MET to other conservative therapies for acute non-specific LBP, there was very low-quality evidence of no clinically relevant difference for the outcomes of pain (MD -10.72, 95% CI -32.57 to 11.13, 2 studies, 88 participants) and functional status (MD 0.87, 95% CI -6.31 to 8.05, 1 study, 60 participants). For the comparison of MET to other conservative therapies for chronic non-specific LBP, there was low-quality evidence of no clinically relevant difference for the outcomes of pain (MD -9.70, 95% CI -20.20 to 0.80, 1 study, 30 participants) and functional status (MD -4.10, 95% CI -9.53 to 1.33, 1 study, 30 participants). There was low-quality evidence of no clinically relevant difference for the addition of MET to other interventions for acute non-specific LBP for the outcome of pain (MD -3, 95% CI -11.37 to 5.37, 1 study, 40 participants) and low-quality evidence of an effect in favour of MET for functional status (MD -17.6, 95% CI -27.05 to -8.15, 1 study, 40 participants). For chronic non-specific LBP, there was low-quality evidence of an effect in favour of MET for the addition of MET to other interventions for the outcomes of pain (MD -34.1, 95% CI -38.43 to -29.77, 1 study, 30 participants) and functional status (MD -22, 95% CI -27.41 to -16.59, 1 study, 30 participants). Lastly, there was low-quality evidence of no difference for the addition of MET to another manual intervention compared to the same intervention with other conservative therapies for the outcomes of pain (MD 5.20, 95% CI -3.03 to 13.43, 1 study, 20 participants) and functional status (MD 6.0, 95% CI -0.49 to 12.49, 1 study, 20 participants).No study reported on our other primary outcome of general well-being. Seven studies reported that no adverse events were observed, whereas the other five studies did not report any information on adverse events. The quality of research related to testing the effectiveness of MET is poor. Studies are generally small and at high risk of bias due to methodological deficiencies. Studies conducted to date generally provide low-quality evidence that MET is not effective for patients with LBP. There is not sufficient evidence to reliably determine whether MET is likely to be effective in practice. Large, methodologically-sound studies are necessary to investigate this question.


Fluorometric detection of biological S-nitrosothiols.
A technique is presented for the quantitative detection of S-nitrosothiols formed by model biological thiols, cysteine, glutathione, and serum albumin. The technique is based on the detection of fluorescent compound 1-[H]-naphthotriazole formed between 2,3-diaminonaphthalene and nitrous acid released from S-nitrosothiols by treatment with mercuric chloride in an acidic environment. Concentration of S-nitrosothiols is determined from the difference in fluorescent signal (excitation/emission wavelengths of 363 nm/450 nm, respectively) observed in the presence and absence of 0.18 mM HgCl2. The yield of the reaction between 2,3-diaminonaphthalene and nitrous acid released from the S-NO bond by HgCl2 approaches 90-100% as documented by simultaneous assays of S-nitrosothiols by uv spectrophotometry and by Saville method. The assay can be applied to the analysis of mixtures containing excess of thiol and/or nitrite at neutral pH by pretreatment of samples with N-ethylmaleinimide and/or ammonium sulfamate, respectively. In analysis of S-nitrosothiols in protein-containing mixtures, HgCl2-mediated release of nitrous acid in the presence of 2,3-diaminonaphthalene is followed by neutralization of samples and precipitation of protein with 0.5 M 5-sulfosalicylic acid. The fluorometric assay is carried out at an excitation wavelength of 380 nm to eliminate the background fluorescence of 5-sulfosalicylic acid observed at lower wavelengths. The technique offers simple and rapid determination of S-nitrosothiols in complex reaction mixtures with the detection limit at low nanomolar concentrations.


Polypharmacy management in Medicare managed care: changes in prescribing by primary care physicians resulting from a program promoting medication reviews.
To examine the effects of medication reviews by primary care physicians on prescriptions written for elderly members of a Medicare managed care organization who were at risk for polypharmacy. Prospective study with follow-up survey. We conducted a study in 1995 to demonstrate the prevalence of polypharmacy (defined as receiving 5 or more prescription medications during the 3-month study period) among elderly members of our managed care organization. Two years later, elderly members identified as being at risk for polypharmacy were sent a letter encouraging them to schedule a medication review with their primary care physician. Each primary care physician was provided with clinical practice guidelines on polypharmacy and patient-specific medication management reports. Patients and physicians were subsequently mailed a survey to assess the impact of the medication review program on prescribing practices. Of 37,372 elderly members screened, 5737 (15%) were at risk for polypharmacy. Of these, 2615 (46%) responded to the follow-up survey. Of the survey respondents, 1087 (42%) had gone to their primary care physician for a medication review. During the review, 96% of patients discussed their prescription medications and 72% discussed nonprescription medications they were taking. Twenty percent reported that their physician discontinued medications, 29% reported that the physician changed the dose of a medication, and 17% informed their physician about a new prescription or nonprescription medication they were taking. Of the 275 primary care physicians surveyed, 56 (20%) returned the questionnaire. Of these, 61% reported that the medication review program was "very" or "somewhat useful." Thirty-five percent reported discontinuing unnecessary medications, and 23% reported decreasing the frequency of dosing. Overall, 45% of physicians reported making at least one change in their prescribing to a member at risk for polypharmacy. Our program promoting medication reviews between primary care physicians and their elderly patients resulted in significant changes in prescribing by physicians. This type of program is likely to decrease the risk of polypharmacy among older members of a Medicare managed care organization.


p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells.
Aberrant nuclear factor-kappaB (NF-kappaB) signaling plays a role in cancer initiation and progression; thus, it represents a potential therapeutic target. We previously identified a mechanism of repression of NF-kappaB transcriptional activity and induction of apoptosis in colon cancer cells involving nuclear/nucleolar translocation of the RelA (p65) component of NF-kappaB. This response was stimulated by cellular stress-inducing agents, including aspirin, but not by tumor necrosis factor. Here, we investigate the upstream molecular mechanisms responsible for nucleolar targeting of RelA and show that aspirin activates the p38 mitogen-activated protein kinase (MAPK) pathway in colorectal cancer cells. We also show that aspirin causes rapid, ubiquitin-dependent degradation of cyclin D1, a known p38 target. Aspirin-induced p38 activation preceded cyclin D1 degradation, which was then followed by activation of the NF-kappaB pathway, suggesting a causative link. Indeed, chemical p38 inhibition (PD169316) and small interfering RNA directed against p38 blocked aspirin-induced cyclin D1 degradation, nucleolar translocation of RelA, and apoptosis. Furthermore, chemical inhibition of the cyclin D1/cyclin-dependent kinase 4 (CDK4) kinase complex, used as a surrogate for cyclin D1 degradation, caused nucleolar translocation of RelA, repression of kappaB-driven transcription, and apoptosis, thereby reproducing the effects of aspirin. In addition, we found that aspirin and the CDK4 inhibitor induced nucleolar translocation of RelA and apoptosis through a common mechanism involving the NH(2)-terminal nucleolar localization signal. Collectively, these data suggest that aspirin causes inhibition of cyclin D1/CDK4 through the p38 MAPK pathway. This inhibition stimulates the NF-kappaB pathway to induce nucleolar translocation of RelA and apoptosis. These novel findings have considerable relevance to the rational design of novel chemotherapeutic and chemopreventative strategies.


Bactericidal effects and cytotoxicity of new aromatic dialdehyde disinfectants (ortho-phthalaldehyde).
We investigated the bactericidal effects and cytotoxicity of an ortho-phthalaldehyde product in comparison with those of its predecessor glutaraldehyde products. Bactericidal effects ware examined on Mycobacterium terrae, a standard organism used for investigating the bactericidal effect of high-level disinfectants. Cytotoxicity as determined by the MTT assay was examined by using four cell lines. The colony forming test, a method to examine residual toxicity, and the evaporation test, a newly developed method to examine the toxicity of the evaporated ingredients, were performed. Test solutions were 2.25% and 3.5% glutaraldehyde (GA) products and a 0.55% ortho-phthalaldehyde (OPA) product, and glutaraldehyde itself. All the disinfectants showed sufficient bactericidal effects on M. terrae. Meanwhile, the OPA product was less toxic than GA products and GA itself to all the cell lines tested. The colony forming test showed that GA products and GA itself exerted residual cytotoxicity more potently than did the OPA product. The evaporation test showed that GA products and GA itself exerted cytotoxicity via evaporation more potently than did the OPA product. In conclusion, OPA appears to be less cytotoxic than GA even though bactericidal effects were comparable. This may be due to the lower concentration of the active ingredient (ortho-phthalaldehyde) in the OPA product.


Zinc release and the sequence of biochemical events during triggering of Bacillus megaterium KM spore germination.
Zinc release is the first quantitatively significant event detected during the triggering of Bacillus megaterium KM spore germination. Of the total spore Zn2+ pool 25% is released from non-heat-activated spores within 4 min of triggering germination. During this period only 10% of the spore population becomes irreversibly committed to germinate. The investigation of a putative role for Zn2+ in the germination trigger mechanism has established a relationship between the rate and extent of Zn2+ release and the stimulation of spore germination by heat activation. Furthermore, a correlation can be demonstrated between the extent of zinc release from spore populations and the time required to obtain 50% commitment of these populations to germinate over a wide temperature range. These findings have been used to expand a recently published model for the triggering of bacterial spore germination.


Functional connectivity variations in mild cognitive impairment: associations with cognitive function.
Participants with mild cognitive impairment (MCI) have a higher likelihood of developing Alzheimer's disease (AD) compared to those without MCI, and functional magnetic resonance neuroimaging (fMRI) used with MCI participants may prove to be an important tool in identifying early biomarkers for AD. We tested the hypothesis that functional connectivity differences exist between older adults with and without MCI using resting-state fMRI. Data were collected on over 200 participants of the Rush Memory and Aging Project, a community-based, clinical-pathological cohort study of aging. From the cohort, 40 participants were identified as having MCI, and were compared to 40 demographically matched participants without cognitive impairment. MCI participants showed lesser functional connectivity between the posterior cingulate cortex and right and left orbital frontal, right middle frontal, left putamen, right caudate, left superior temporal, and right posterior cingulate regions; and greater connectivity with right inferior frontal, left fusiform, left rectal, and left precentral regions. Furthermore, in an alternate sample of 113, connectivity values in regions of difference correlated with episodic memory and processing speed. Results suggest functional connectivity values in regions of difference are associated with cognitive function and may reflect the presence of AD pathology and increased risk of developing clinical AD.


Adaptive reuse in the healthcare industry: repurposing abandoned buildings to serve medical missions.
Adaptive reuse-the practice of identifying, acquiring, renovating, and placing back into service a building or similar structure for a purpose different than that for which it was originally designed-offers great potential for addressing the spatial expansion needs of healthcare establishments in a unique and mutually beneficial manner. This repurposing approach, however, has received very little attention in the health sciences literature, diminishing the opportunities of those serving in hospitals, medical clinics, and related care providing institutions to acquire an understanding of the practice. The delivery of healthcare services primarily is site based, requiring physical space for physicians, nurses, administrators, and others to carry out the many duties associated with the provision of medical care and attention. But this space often represents a significant expenditure, consuming financial resources which otherwise could be directed toward patient care. Economies on this front are possible through adaptive reuse, permitting more resources to be directed toward mission fulfillment activities. This article directs attention toward adaptive reuse by profiling Willis-Knighton Health System's associated experiences and implementation strategies. Among other things, opportunities and obstacles are discussed, detailed cases are presented, and an operational framework is provided, permitting healthcare providers to understand and make use of this novel practice for addressing spatial expansion needs more affordably. Since space considerations exist throughout the lives of healthcare establishments, providers must ensure an awareness of methods for productively attending to these requirements. Evidenced by Willis-Knighton Health System's associated experiences and outcomes, adaptive reuse presents an option for more economically addressing spatial requirements, fostering opportunities to expand the delivery of health and medical services.


The amidation step of diphthamide biosynthesis in yeast requires DPH6, a gene identified through mining the DPH1-DPH5 interaction network.
Diphthamide is a highly modified histidine residue in eukaryal translation elongation factor 2 (eEF2) that is the target for irreversible ADP ribosylation by diphtheria toxin (DT). In Saccharomyces cerevisiae, the initial steps of diphthamide biosynthesis are well characterized and require the DPH1-DPH5 genes. However, the last pathway step-amidation of the intermediate diphthine to diphthamide-is ill-defined. Here we mine the genetic interaction landscapes of DPH1-DPH5 to identify a candidate gene for the elusive amidase (YLR143w/DPH6) and confirm involvement of a second gene (YBR246w/DPH7) in the amidation step. Like dph1-dph5, dph6 and dph7 mutants maintain eEF2 forms that evade inhibition by DT and sordarin, a diphthamide-dependent antifungal. Moreover, mass spectrometry shows that dph6 and dph7 mutants specifically accumulate diphthine-modified eEF2, demonstrating failure to complete the final amidation step. Consistent with an expected requirement for ATP in diphthine amidation, Dph6 contains an essential adenine nucleotide hydrolase domain and binds to eEF2. Dph6 is therefore a candidate for the elusive amidase, while Dph7 apparently couples diphthine synthase (Dph5) to diphthine amidation. The latter conclusion is based on our observation that dph7 mutants show drastically upregulated interaction between Dph5 and eEF2, indicating that their association is kept in check by Dph7. Physiologically, completion of diphthamide synthesis is required for optimal translational accuracy and cell growth, as indicated by shared traits among the dph mutants including increased ribosomal -1 frameshifting and altered responses to translation inhibitors. Through identification of Dph6 and Dph7 as components required for the amidation step of the diphthamide pathway, our work paves the way for a detailed mechanistic understanding of diphthamide formation.


Respiratory neuroplasticity following carotid body denervation: Central and peripheral adaptations.
Historically, the role of the carotid bodies in ventilatory control has been understated, but the current view suggests that the carotid bodies (1) provide a tonic, facilitory input to the respiratory network, (2) serve as the major site of peripheral O2 chemoreception and minor contributor to CO2/H(+) chemoreception, and (3) are required for ventilatory adaptation to high altitude. Each of these roles has been demonstrated in studies of ventilation in mammals after carotid body denervation. Following carotid body denervation, many of the compromised ventilatory "functions" show a time-dependent recovery plasticity that varies in the degree of recovery and time required for recovery. Respiratory plasticity following carotid body denervation is also dependent on species, with contributions from peripheral and central sites/mechanisms driving the respiratory plasticity. The purpose of this review is to provide a summary of the data pointing to peripheral and central mechanisms of plasticity following carotid body denervation. We speculate that after carotid body denervation there are altered excitatory and/or inhibitory neuromodulator mechanisms that contribute to the initial respiratory depression and the subsequent respiratory plasticity, and further suggest that the continued exploration of central effects of carotid body denervation might provide useful information regarding the capacity of the respiratory network for plasticity following neurologic injury in humans.


Comparative Analysis of the Conformation, Aggregation, Interaction, and Fibril Morphologies of Human α-, β-, and γ-Synuclein Proteins.
The human synuclein (syn) family is comprised of α-, β-, and γ-syn proteins. α-syn has the highest propensity for aggregation, and its aggregated forms accumulate in Lewy bodies (LB) and Lewy neurites, which are involved in Parkinson's disease (PD). β- and γ-syn are absent in LB, and their exact role is still enigmatic. β-syn does not form aggregates under physiological conditions (pH 7.4), while γ-syn is associated with neural and non-neural diseases like breast cancer. Because of their similar regional distribution in the brain, natively unfolded structure, and high degree of sequence homology, studying the effect of the environment on their conformation, interactions, fibrillation, and fibril morphologies has become important. Our studies show that high temperatures, low pH values, and high concentrations increase the rate of fibrillation of α- and γ-syn, while β-syn forms fibrils only at low pH. Fibril morphologies are strongly dependent on the immediate environment of the proteins. The high molar ratio of β-syn inhibits the fibrillation in α- and γ-syn. However, preformed seed fibrils of β- and γ-syn do not affect fibrillation of α-syn. Surface plasmon resonance data show that interactions between α- and β-syn, β- and γ-syn, and α- and γ-syn are weak to moderate in nature and can be physiologically significant in counteracting several adverse conditions in the cells that trigger their aggregation. These studies could be helpful in understanding collective human synuclein behavior in various protein environments and in the modulation of the homeostasis between β-syn and healthy versus corrupt α- and γ-syn that can potentially affect PD pathology.


Enlarging the Scope of 5-Aminolevulinic Acid-Mediated Photodiagnosis towards Breast Cancers.
Today, most research on treating cancers targets one single cancer, often because of the very specific operation principle of the therapy. For instance, immunotherapies require the expression of a particular antigen, which might not be expressed in all cancers or in all patients. What about metastases? Combination therapies are promising but require treatment personalization and are an expensive approach that many health systems are not willing to pay for. Resection of cancerous tissues may be conducted beforehand. However, the precise location and removal of tumors are in most cases, hurdles that require margins to prevent recurrence. Herein, we further demonstrate the wide application of aminolevulinate-based photodynamic diagnosis and therapy toward breast cancers. By selecting four breast cancer cell lines that represent the main breast tumor subtypes, we investigated their ability to accumulate the fluorescent protoporphyrin IX upon treatment with the marketed 5-aminolevulinic acid hexyl ester (ALA-Hex) or our new and more stable derivative PSI-ALA-Hex. We found that all cell lines were able to accumulate PpIX under a few hours independent of their hormonal status with both treatments. Additionally, this accumulation was less dose-dependent with PSI-ALA-Hex and induced similar or higher fluorescence intensity than ALA-Hex in three out of four cell lines. The toxicity of the two molecules was not different up to 0.33 mM. However, PSI-ALA-Hex was more toxic at 1 mM, even though lower concentrations of PSI-ALA-Hex led to the same PpIX accumulation level. Additional illumination with blue light to induce cell death by generating reactive oxygen species was also considered. The treatments led to a dramatic death of the BT-474 cells under all conditions. In SK-BR-3 and MCF-7, ALA-Hex was also very efficient at all concentrations. However, increasing doses of PSI-ALA-Hex (0.33 and 1 mM) surprisingly led to a higher viability rate. In contrast, the triple-negative breast cancer cells MDA-MB-231 showed a higher death induction with higher concentrations of ALA-Hex or PSI-ALA-Hex. Derivatives of ALA seem promising as fluorescence-guided resection tools and may enable subsequent completion of cancer cell destruction by blue light irradiation.


Unveiling interactions among mitochondria, caspase-like proteases, and the actin cytoskeleton during plant programmed cell death (PCD).
Aponogeton madagascariensis produces perforations over its leaf surface via programmed cell death (PCD). PCD begins between longitudinal and transverse veins at the center of spaces regarded as areoles, and continues outward, stopping several cells from these veins. The gradient of PCD that exists within a single areole of leaves in an early stage of development was used as a model to investigate cellular dynamics during PCD. Mitochondria have interactions with a family of proteases known as caspases, and the actin cytoskeleton during metazoan PCD; less is known regarding these interactions during plant PCD. This study employed the actin stain Alexa Fluor 488 phalloidin, the actin depolymerizer Latrunculin B (Lat B), a synthetic caspase peptide substrate and corresponding specific inhibitors, as well as the mitochondrial pore inhibitor cyclosporine A (CsA) to analyze the role of these cellular constituents during PCD. Results depicted that YVADase (caspase-1) activity is higher during the very early stages of perforation formation, followed by the bundling and subsequent breakdown of actin. Actin depolymerization using Lat B caused no change in YVADase activity. In vivo inhibition of YVADase activity prevented PCD and actin breakdown, therefore substantiating actin as a likely substrate for caspase-like proteases (CLPs). The mitochondrial pore inhibitor CsA significantly decreased YVADase activity, and prevented both PCD and actin breakdown; therefore suggesting the mitochondria as a possible trigger for CLPs during PCD in the lace plant. To our knowledge, this is the first in vivo study using either caspase-1 inhibitor (Ac-YVAD-CMK) or CsA, following which the actin cytoskeleton was examined. Overall, our findings suggest the mitochondria as a possible upstream activator of YVADase activity and implicate these proteases as potential initiators of actin breakdown during perforation formation via PCD in the lace plant.


Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma.
We have generated transgenic mice that constitutively express murine interleukin (IL)-5 in the lung epithelium. Airway expression of this cytokine resulted in a dramatic accumulation of peribronchial eosinophils and striking pathologic changes including the expansion of bronchus-associated lymphoid tissue (BALT), goblet cell hyperplasia, epithelial hypertrophy, and focal collagen deposition. These changes were also accompanied by eosinophil infiltration of the airway lumen. In addition, transgenic animals displayed airway hyperresponsiveness to methacholine in the absence of aerosolized antigen challenge. These findings demonstrate that lung-specific IL-5 expression can induce pathologic changes characteristic of asthma and may provide useful models to evaluate the efficacy of potential respiratory disease therapies or pharmaceuticals.


A morphological study of the neostriatum of aged mice with particular reference to neuroglia.
The most prominent feature of the aged mouse neostriatum is the presence of large vacuoles. Careful inspection showed that these are vacuolated myelin sheaths and are invariably found in, or at the periphery of, the nerve fibre bundles which traverse the neostriatum. Oligodendrocytes showed little evidence of ageing but satellite oligodendrocytes contain more lipofuscin than oligodendrocytes associated with myelin sheaths. Most astrocytes contain pigment-prominent lipofuscin granules but a small minority contain numerous large pigment lipofuscin granules, and are packed with microfilaments and glycogen granules. A few astrocytes have circular nuclear inclusions filled with a fine granular material. Microglial cells contain the largest amount and variety of lipofuscin; in most cases, however, the lipofuscin is of the lipid-pigment type.


Acceptability of two colorectal cancer screening tests: pain as a key determinant in sigmoidoscopy.
Background Participants' experience with a screening test can influence adherence, and therefore the efficacy of screening programs. We compared screening with unsedated flexible sigmoidoscopy and fecal immunochemical testing (FIT) for participants' satisfaction with the decision and for willingness to repeat colorectal cancer screening. Methods In a prospective, randomized trial 3257 individuals (50 - 74 years) were invited to either flexible sigmoidoscopy or FIT (1:1), of whom 1650 took up the offer (52.6 %). In total, 1497 screening participants completed at least one questionnaire, either before screening, and/or at three time points in the following year, that measured willingness to repeat screening, willingness to recommend screening, and satisfaction with decision to attend. There were 769 and 728 responders in the flexible sigmoidoscopy and FIT group, respectively. Additionally, 581 flexible sigmoidoscopy participants also completed a pain questionnaire. Results 1 year later, 10 % of the flexible sigmoidoscopy participants were not willing to repeat screening, compared to 5 % of FIT participants. A higher percentage of women compared to men would not repeat flexible sigmoidoscopy screening (adjusted odds ratio [OR] 2.52, 95 % confidence interval [95 %CI] 1.48 to 4.28). Notably, 22 % of women reported pain during flexible sigmoidoscopy compared to 5 % of men. When we added pain to the statistical model, pain was significantly associated with unwillingness to repeat flexible sigmoidoscopy (OR 3.15, 95 %CI 1.68 to 5.87), while gender was no longer associated (OR 1.53, 95 %CI 0.82 to 2.88). Conclusion Acceptability for flexible sigmoidoscopy and for FIT was high among Norwegian screening participants, though FIT participants were more willing to repeat screening. Women were less willing to repeat screening with flexible sigmoidoscopy compared to men. This gender difference seemed partly due to pain, and therefore preventable.This study is registered at ClinicalTrials.gov: NCT01538550.


Is the ADHD brain wired differently? A review on structural and functional connectivity in attention deficit hyperactivity disorder.
In recent years, a change in perspective in etiological models of attention deficit hyperactivity disorder (ADHD) has occurred in concordance with emerging concepts in other neuropsychiatric disorders such as schizophrenia and autism. These models shift the focus of the assumed pathology from regional brain abnormalities to dysfunction in distributed network organization. In the current contribution, we report findings from functional connectivity studies during resting and task states, as well as from studies on structural connectivity using diffusion tensor imaging, in subjects with ADHD. Although major methodological limitations in analyzing connectivity measures derived from noninvasive in vivo neuroimaging still exist, there is convergent evidence for white matter pathology and disrupted anatomical connectivity in ADHD. In addition, dysfunctional connectivity during rest and during cognitive tasks has been demonstrated. However, the causality between disturbed white matter architecture and cortical dysfunction remains to be evaluated. Both genetic and environmental factors might contribute to disruptions in interactions between different brain regions. Stimulant medication not only modulates regionally specific activation strength but also normalizes dysfunctional connectivity, pointing to a predominant network dysfunction in ADHD. By combining a longitudinal approach with a systems perspective in ADHD in the future, it might be possible to identify at which stage during development disruptions in neural networks emerge and to delineate possible new endophenotypes of ADHD.


A Twin Study into the Genetic and Environmental Influences on Academic Performance in Science in nine-year-old Boys and Girls.
We investigated for the first time the genetic and environmental aetiology behind scientific achievement in primary school children, with a special focus on possible aetiological differences for boys and girls. For a representative community sample of 2,602 twin pairs assessed at age nine years, scientific achievement in school was rated by teachers based on National Curriculum criteria in three domains: Scientific Enquiry, Life Processes, and Physical Processes. Results indicate that genetic influences account for over 60% of the variance in scientific achievement, with environmental influences accounting for the remaining variance. Environmental influences were mainly of the non-shared variety, suggesting that children from the same family experience school environments differently. An analysis of sex differences considering differences in means, variances, and aetiology of individual differences found only differences in variance between the sexes, with boys showing greater variance in performance than girls.


Diverse monogenic subforms of human spermatogenic failure.
Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.


The isolation of demolybdo xanthine oxidase from bovine milk.
It was deduced many years ago from indirect evidence that demolybdo xanthine oxidase is present in normal bovine milk. This has now been confirmed by isolation of this enzyme form by a method based on the folate-gel affinity-chromatography procedure described Nishino & Tsushima [(1986) J. Biol. Chem. 261, 11242-11246]. Enzymic and spectroscopic properties of demolybdo xanthine oxidase, which retains flavin and iron-sulphur centres, are generally in accordance with expectations. Like the normal enzyme, it yields on denaturation material fluorescing at 460 nm. Molybdenum cofactor activity measured by the Neurospora crassa nit-1 assay in the presence of added molybdate was 33% of that of the normal enzyme. The absorption spectrum in the near-u.v. region differs slightly, but significantly, from that of the active and desulpho forms of the enzyme. It is concluded that the molybdenum cofactor site contains a pterin-like material not identical with that in the normal enzyme. The significance of the occurrence of demolybdo xanthine oxidase in milk is discussed, and evidence in the literature for demolybdo forms of other molybdoenzymes is briefly reviewed. Additional studies on the use of the affinity procedure for large-scale preparation of high-activity xanthine oxidase are described. In agreement with our ability to isolate the demolybdo enzyme, the procedure appears less effective in eliminating the demolybdo than the desulpho enzyme.


Phase Transition and Thermal Expansion of MgSiO3 Perovskite.
Results from in situ x-ray diffraction experiments with a DIA-type cubic anvil apparatus (SAM 85) reveal that MgSiO(3) perovskite transforms from the orthorhombic Pbnm symmetry to another perovskite-type structure above 600 kelvin (K) at pressures of 7.3 gigapascals; the apparent volume increase across the transition is 0.7%. Unit-cell volume increased linearly with temperature, both below (1.44 x 10(-5) K(-1)) and above (1.55 x 10(-5) K(-1)) the transition. These results indicate that the physical properties measured on the Pbnm phase should be used with great caution because they may not be applicable to the earth's lower mantle. A density analysis based on the new data yields an iron content of 10.4 weight percent for a pyrolite composition under conditions corresponding to the lower mantle. All current equation-of-state data are compatible with constant chemical composition in the upper and lower mantle; thus, these data imply that a chemically layered mantle is unnecessary, and whole-mantle convection is possible.