I-LAMM FOR SPARSE LEARNING: SIMULTANEOUS CONTROL OF ALGORITHMIC COMPLEXITY AND STATISTICAL ERROR.
We propose a computational framework named iterative local adaptive majorize-minimization (I-LAMM) to simultaneously control algorithmic complexity and statistical error when fitting high dimensional models. I-LAMM is a two-stage algorithmic implementation of the local linear approximation to a family of folded concave penalized quasi-likelihood. The first stage solves a convex program with a crude precision tolerance to obtain a coarse initial estimator, which is further refined in the second stage by iteratively solving a sequence of convex programs with smaller precision tolerances. Theoretically, we establish a phase transition: the first stage has a sublinear iteration complexity, while the second stage achieves an improved linear rate of convergence. Though this framework is completely algorithmic, it provides solutions with optimal statistical performances and controlled algorithmic complexity for a large family of nonconvex optimization problems. The iteration effects on statistical errors are clearly demonstrated via a contraction property. Our theory relies on a localized version of the sparse/restricted eigenvalue condition, which allows us to analyze a large family of loss and penalty functions and provide optimality guarantees under very weak assumptions (For example, I-LAMM requires much weaker minimal signal strength than other procedures). Thorough numerical results are provided to support the obtained theory.


Dynamic construction of the neural networks underpinning empathy for pain.
When people witness or imagine the pain of another person, their nervous system may react as if they were feeling that pain themselves. Early neuroscientific evidence indicates that the firsthand and vicarious experiences of pain share largely overlapping neural structures, which typically correspond to the lateral and medial brain regions that encode the sensory and the affective qualities of pain. Such neural circuitry is highly malleable and allows people to flexibly adjust the empathic behavior depending on social and personal factors. Recent views posit, however, that the brain can be conceptualized as a complex system, in which behavior emerges from the interaction between functionally connected brain regions, organized into large-scale networks. Beyond the classical modular view of the brain, here we suggest that empathic behavior may be understood through a dynamic network-based approach where the cortical circuits associated with the experience of pain flexibly change in order to code self- and other-related emotions and to intrinsically map our mentality to empathetically react to others.


Outcomes of a Family Based Pediatric Obesity Program - Preliminary Results.
Children that are classified as obese (body mass index (BMI) > 95th percentile for age and sex, Centers for Disease Control and Prevention) have an increased risk for metabolic and cardiovascular complications. Family based programs that focus on physical activity (PA) and healthy eating are recommended for treatment of pediatric obesity. The purpose of the current study is to determine the outcomes of Building Healthy Families (BHF), a family-based pediatric weight loss treatment program composed of nutrition, physical activity and behavioral modification strategies. In addition, mediating variables that are associated with weight loss in children, in order to enhance the retention and success of this program will be identified. Twenty-two obese (>95th percentile BMI) children (age: 9.94 ± 1.58 yrs) volunteered to participate. Children and their parents (20 moms, 20 dads, 68% obese; BMI > 30 kg·m-2) participated in weekly nutrition education, family lifestyle PA, and one-on-one meetings with a behavioral psychologist. Overall, child participants lost an average of 2.3 ± 2.0 kg of body mass in 12 weeks while parents lost 6.4 ± 4.3 kg of their body mass. There was a significant inverse association between percentage of program goals met and weight loss (r = - 0.67, p < 0.05). Decreases in the child participants intake of high fat, high calorie foods significantly predicted weight change (R2=0.98, p<0.05). In conclusion, family based pediatric obesity programs may offer significant benefits and lead to healthier lifestyles for obese children and their parents.


Prevalence and factors associated with tinnitus: a community-based study of Japanese elders.
The prevalence of tinnitus is reported to be high in older Western populations, and several risk factors have been suggested. However, community-based evidence on prevalence is limited and, to our knowledge, there is no such information from older non-Western populations. The purpose of this study was to determine the prevalence and factors associated with tinnitus in community-dwelling Japanese elders. In this community-based cross-sectional study, 1320 residents of Kurabuchi Town aged 65 years or older (584 men and 736 women; participation proportion = 98.7%) were interviewed at home in 2006, and information on tinnitus and factors associated with tinnitus was collected. We estimated the prevalence of tinnitus by age group and sex and used a logistic regression model to investigate associated factors. The prevalence of tinnitus was 18.6% (men: 18.0%; women: 19.0%); there were no statistically significant differences by age group or sex. Hearing difficulty, depressive mood, prescribed medication, past/current history of coronary heart disease, and knee joint pain requiring medical consultation were associated with tinnitus. These findings suggest that tinnitus is common in Japanese aged over 65 years. Because the factors associated with tinnitus in this cross-sectional study are potentially modifiable, they should be thoroughly investigated in a longitudinal study.


BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations.
A variety of immunohistochemical (IHC) stains have been proposed to mark either benign or malignant mesothelial proliferations. Loss of the p16 tumor suppressor (CDKN2A), through homozygous deletions of 9p21, is a good marker of mesotheliomas but lacks sensitivity. Recent reports indicate that some mesotheliomas are associated with loss of BRCA-associated protein 1 (BAP1) expression. Here we investigate BAP1 and p16 as potential markers of malignancy and compare test characteristics with previously proposed markers using a well-characterized tissue microarray. BAP1 protein expression was interrogated by IHC. The p16 locus was examined by fluorescence in situ hybridization (FISH) directed toward chromosome 9p21. Loss of BAP1 was identified in 7/26 mesotheliomas and 0/49 benign proliferations. Loss of p16 was identified in 14/27 mesotheliomas and 0/40 benign proliferations, yielding 100% specificity and positive predictive value for each marker. Together, BAP1 IHC and p16 FISH were 58% sensitive for detecting malignancy. Various combinations of p53, EMA, IMP3, and GLUT1 showed reasonably high specificity (96% to 98%) but poor to extremely poor sensitivity. Combined BAP1 IHC/p16 FISH testing is a highly specific method of diagnosing malignant mesotheliomas when the question is whether a mesothelial proliferation is benign or malignant and is particularly useful when tissue invasion by mesothelial cells cannot be demonstrated. However, combined BAP1/p16 FISH testing is not highly sensitive, and negative results do not rule out a mesothelioma. The test characteristics of previously proposed markers EMA, p53, GLUT1, IMP3 suggest that, even in combination, these markers are not useful tools in this clinical setting.


Rethinking rehabilitation after percutaneous coronary intervention: a protocol of a multicentre cohort study on continuity of care, health literacy, adherence and costs at all care levels (the CONCARDPCI).
Percutaneous coronary intervention (PCI) aims to provide instant relief of symptoms, and improve functional capacity and prognosis in patients with coronary artery disease. Although patients may experience a quick recovery, continuity of care from hospital to home can be challenging. Within a short time span, patients must adjust their lifestyle, incorporate medications and acquire new support. Thus, CONCARDPCI will identify bottlenecks in the patient journey from a patient perspective to lay the groundwork for integrated, coherent pathways with innovative modes of healthcare delivery. The main objective of the CONCARDPCI is to investigate (1) continuity of care, (2) health literacy and self-management, (3) adherence to treatment, and (4) healthcare utilisation and costs, and to determine associations with future short and long-term health outcomes in patients after PCI. This prospective multicentre cohort study organised in four thematic projects plans to include 3000 patients. All patients undergoing PCI at seven large PCI centres based in two Nordic countries are prospectively screened for eligibility and included in a cohort with a 1-year follow-up period including data collection of patient-reported outcomes (PRO) and a further 10-year follow-up for adverse events. In addition to PROs, data are collected from patient medical records and national compulsory registries. Approval has been granted by the Norwegian Regional Committee for Ethics in Medical Research in Western Norway (REK 2015/57), and the Data Protection Agency in the Zealand region (REG-145-2017). Findings will be disseminated widely through peer-reviewed publications and to patients through patient organisations. NCT03810612.


A causal test of the strength of weak ties.
The authors analyzed data from multiple large-scale randomized experiments on LinkedIn's People You May Know algorithm, which recommends new connections to LinkedIn members, to test the extent to which weak ties increased job mobility in the world's largest professional social network. The experiments randomly varied the prevalence of weak ties in the networks of over 20 million people over a 5-year period, during which 2 billion new ties and 600,000 new jobs were created. The results provided experimental causal evidence supporting the strength of weak ties and suggested three revisions to the theory. First, the strength of weak ties was nonlinear. Statistical analysis found an inverted U-shaped relationship between tie strength and job transmission such that weaker ties increased job transmission but only to a point, after which there were diminishing marginal returns to tie weakness. Second, weak ties measured by interaction intensity and the number of mutual connections displayed varying effects. Moderately weak ties (measured by mutual connections) and the weakest ties (measured by interaction intensity) created the most job mobility. Third, the strength of weak ties varied by industry. Whereas weak ties increased job mobility in more digital industries, strong ties increased job mobility in less digital industries.


Phylogenetic analysis of fungal centromere H3 proteins.
Centromere H3 proteins (CenH3's) are variants of histone H3 specialized for packaging centromere DNA. Unlike canonical H3, which is among the most conserved of eukaryotic proteins, CenH3's are rapidly evolving, raising questions about orthology and conservation of function across species. To gain insight on CenH3 evolution and function, a phylogenetic analysis was undertaken on CenH3 proteins drawn from a single, ancient lineage, the Fungi. Using maximum-likelihood methods, a credible phylogeny was derived for the conserved histone fold domain (HFD) of 25 fungal CenH3's. The collection consisted mostly of hemiascomycetous yeasts, but also included basidiomycetes, euascomycetes, and an archaeascomycete. The HFD phylogeny closely recapitulated known evolutionary relationships between the species, supporting CenH3 orthology. The fungal CenH3's lacked significant homology in their N termini except for those of the Saccharomyces/Kluyveromyces clade that all contained a region homologous to the essential N-terminal domain found in Saccharomyces cerevisiae Cse4. The ability of several heterologous CenH3's to function in S. cerevisiae was tested and found to correlate with evolutionary distance. Domain swapping between S. cerevisiae Cse4 and the noncomplementing Pichia angusta ortholog showed that species specificity could not be explained by the presence or absence of any recognized secondary structural element of the HFD.


Regulation of G protein-coupled receptor signaling: specific dominant-negative effects of melanocortin 2 receptor accessory protein 2.
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), which constitute the largest family of membrane proteins, mediate responses to diverse physiological stimuli. The presence of melanocortin 2 receptors (MC2Rs) on the plasma membrane requires the presence of either MC2R accessory protein (MRAP) or MRAP2, which are homologous accessory proteins. Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). ACTH bound with high affinity to MC2Rs in the presence of MRAP, but not MRAP2. The ability of MRAP and MRAP2 to influence ligand-binding affinity was specific to MC2R, because these proteins had little effect on the binding of NDP-alpha-melanocyte-stimulating hormone to MC4R or on its stimulation of cAMP responses. These results demonstrate that the balance of stimulatory and inhibitory accessory proteins can control the sensitivity of a GPCR to its natural agonist.


Usefulness of non-invasive markers for predicting significant fibrosis in patients with chronic liver disease.
The purpose of this prospective study was to verify and compare the strengths of various blood markers and fibrosis models in predicting significant liver fibrosis. One hundred fifty-eight patients with chronic liver disease who underwent liver biopsy were enrolled. The mean age was 41 yr and male patients accounted for 70.2%. The common causes of liver disease were hepatitis B (67.7%) and C (16.5%) and fatty liver (9.5%). Stages of liver fibrosis (F0-4) were assessed according to the Batts and Ludwig scoring system. Significant fibrosis was defined as > or =F2. Sixteen blood markers were measured along with liver biopsy, and estimates of hepatic fibrosis were calculated using various predictive models. Predictive accuracy was evaluated with a receiver-operating characteristics (ROC) curve. Liver biopsy revealed significant fibrosis in 106 cases (67.1%). On multivariate analysis, alpha2-macroglobulin, hyaluronic acid, and haptoglobin were found to be independently related to significant hepatic fibrosis. A new predictive model was constructed based on these variables, and its area under the ROC curve was 0.91 (95% confidence interval, 0.85-0.96). In conclusion, alpha2-macroglobulin, hyaluronic acid, and haptoglobin levels are independent predictors for significant hepatic fibrosis in chronic liver disease.


Regulation of proBACE1 by glycosaminoglycans.
The beta-secretase (BACE1) is initially synthesized as a partially active zymogen containing a prodomain which can be further activated through proteolytic cleavage of the prodomain by a furin-like protease. The active site of BACE1 is large and although a number of high-affinity active-site inhibitors of BACE1 have been described, most of these compounds are large, polar and do not cross the blood-brain barrier. However, it may be possible to target other regions of the protein which regulate BACE1 allosterically. We have found that proBACE1 can be stimulated by relatively low concentrations (e.g. 1 microg/ml) of heparin. Heparin initially increases proBACE1 activity, probably by binding to the prodomain, which decreases steric inhibition at the active site. However, the heparin-activated zymogen also undergoes autocatalysis, which ultimately leads to a loss of enzyme activity. We speculate that proBACE1 can be regulated by endogenous heparan sulfate proteoglycans and that drugs which target this interaction may have value in the treatment of Alzheimer's disease.


Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection.
Staphylococcus aureus is a frequent cause for serious, chronic and therapy-refractive infections in spite of susceptibility to antibiotics in vitro. In chronic infections, altered bacterial phenotypes, such as small colony variants (SCVs), have been found. Yet, it is largely unclear whether the ability to interconvert from the wild-type to the SCV phenotype is only a rare clinical and/or just laboratory phenomenon or is essential to sustain an infection. Here, we performed different long-term in vitro and in vivo infection models with S. aureus and we show that viable bacteria can persist within host cells and/or tissues for several weeks. Persistence induced bacterial phenotypic diversity, including SCV phenotypes, accompanied by changes in virulence factor expression and auxotrophism. However, the recovered SCV phenotypes were highly dynamic and rapidly reverted to the fully virulent wild-type form when leaving the intracellular location and infecting new cells. Our findings demonstrate that bacterial phenotype switching is an integral part of the infection process that enables the bacteria to hide inside host cells, which can be a reservoir for chronic and therapy-refractive infections.


Effects of selenium feed supplements on functional properties of eggs.
The aim of the present study was to assess the effects of selenium feed supplements on the functional properties of eggs. The hens in experimental groups were fed diets supplemented with 0.2 mg/kg selenium from sodium selenite (Group 1), selenium-enriched yeast (Group 2), synthetic L-selenomethionine (Group 3), or hydroxy analog of selenomethionine (Group 4). The Control Group (Group C) was fed with basal feed without supplementation. The highest values of albumen gel firmness were shown in Group C eggs; differences with all experimental groups were significant (p < 0.001 to p = 0.009). It was ascertained that albumen gel firmness correlated with albumen pH (rs = 0.490; p < 0.001), which was highest in eggs from non-supplemented hens. Group 1 eggs and Group C eggs showed lower albumen foaming capacity (p < 0.001) compared to eggs from other groups. Both albumen foaming capacity and albumen foam stability were higher in Group 2 eggs than in Group C eggs (p < 0.001). The highest yolk foaming capacity was found in Group 2 eggs (p < 0.001). Sponge cakes baked with Group C eggs had a smaller volume than those baked with eggs from Group 2 (p = 0.005), Group 3 (p = 0.004) and Group 4 (p = 0.024). The results of the study confirmed that selenium added to the laying hen feed significantly affected the monitored functional properties of both albumen and yolk. The most distinctive effect of selenium was shown in eggs from the group supplemented with selenium-enriched yeast, for which the results of albumen foam capacity and stability and yolk foaming capacity were the best.


Response in hepatic removal of amino acids by the sheep to short-term infusions of varied amounts of an amino acid mixture into the mesenteric vein.
Under conditions of chronic supply the liver removes most amino acids (AA) in excess of net anabolic needs. Little information is available, however, on how acute alterations in AA supply (as might occur with once-daily feeding regimens) are controlled by the liver. Are these also extracted completely in a 'first-pass' manner or are there limitations to hepatic uptake? Furthermore, is the rate of removal 'saturable' (by Michaelis-Menten kinetics) over the range of supply experienced under normal feeding conditions? These questions have been addressed in a study that involved acute (4.5 h) increases in AA supply. Four sheep were prepared with trans-hepatic vascular catheters and were offered a basal diet (equivalent to 1.6xenergy maintenance) throughout. On four occasions, at 7 d intervals, they were infused with various amounts of an AA mixture into the mesenteric vein over a 4.5 h period. The mixture contained fourteen AA in the proportions present in rumen microbial protein. The amounts infused were calculated to provide an additional one, two, three and four times that absorbed from the basal diet. Continuous blood collections were removed over 2 h intervals before (basal diet only) and at 0.5-2.5 and 2.5-4.5 h of AA infusion. Transfers of AA, from the digestive tract and to the liver, were calculated for both plasma and total blood. The recovery of the infused AA across the portal-drained viscera (PDV) was quantitative (100%) only for histidine and proline, the remaining AA were recovered at 56-83 %. These losses correlated with the arterial concentrations and were probably due to removal of AA from the systemic circulation by the tissues of the digestive tract. Despite the wide range of net PDV appearances (i.e. absorbed plus infused), the percentage of most AA removed by the liver remained constant, but the percentage varied with AA (from 34 for proline to 78 for tryptophan for blood transfers). Thus, even when supply was increased 5-fold over baseline there was no indication that the transport into the liver declined, indeed the absolute removals continued to increase. In contrast, the branched-chain AA (isoleucine, leucine and valine) did not exhibit constant percentage extractions. Their percentage extractions were always the lowest (16, 10 and 25 respectively) and tended to decline at the highest infusion rates, indicative of saturation in hepatic transport and/or metabolism. The arterial concentrations of all infused AA increased with rate of infusion, again indicative that the liver did not extract all the net AA available across the PDV. Absolute amounts removed were similar between plasma and blood, indicating that most of the hepatic transfers occurred from plasma. The fractional rates of transfer from total inflow to the liver (i.e. with re-circulated AA included) were 3- to 4-fold lower than rates based on the amounts absorbed plus infused. The highest percentage extraction for total blood inflows was for serine (27), but most were between 6 and 16, except for the branched-chain AA, which were all <1. Use of percentage extractions based on total inflows are probably more appropriate for development of mathematical models of liver metabolism, and the current data suggest that constant values may be applied. The needs of the liver for specific mechanisms involving phenylalanine and histidine (plasma protein synthesis), glycine (detoxification of xenobiotics) and alanine (gluconeogenesis) probably also require to be included in such models.


The evolving role of interferons in viral eradication strategies.
Interferons (IFNs) are a family of pleiotropic cytokines that are released when viral infection is sensed by pattern recognition receptors. They induce an antiviral state in target cells through influencing the expression of hundreds of genes termed IFN-stimulated genes (ISGs), which interfere with the replication of viruses in wide-ranging ways, and they have stimulatory effects on antiviral cell-mediated immunity. Although the role of therapeutic IFNs in the management of infectious diseases has predominantly been restricted to the treatment of chronic hepatotropic viruses, IFNs have effects on the replication of diverse families of viruses in cell culture models, and the potential to harness our endogenous defence system through therapeutic modulation of IFN pathways remains a tantalising prospect for both the broad-spectrum and tailored treatment of viral infections. Additionally, the study of the IFN system has become crucial to our understanding of host/pathogen molecular interactions, which provides plentiful targets for small molecule inhibitors of infection. Although the emergence of directly acting antivirals (DAAs) has resulted in the displacement of pegylated IFNα (pegIFNα) for the treatment of HCV, recent findings have suggested potential roles for IFNs and IFN-related therapies in HIV and HBV eradication strategies, opening up a new avenue of research for this important family of cytokines.


Immunopharmacology of the atopic diseases.
The atopic conditions, atopic dermatitis, asthma, and allergic rhinitis, may arise as a result of infiltrating bone marrow-derived cells into skin or respiratory mucosae. Release of inflammatory factors from these cells could account for cutaneous vascular instability and pruritus in atopic dermatitis. Erythema and itch have been induced by experimental stress interviews and by blind food challenges. In the latter, increased plasma histamine was detected and correlated with cutaneous reactions. Basophils from patients with atopic dermatitis have increased histamine release after exposure to immunologic or nonimmunologic lectin stimuli. This increased releasability may relate to inadequate cyclic AMP regulation of cell function. We have found that leukocytes of patients with atopic dermatitis have elevated phosphodiesterase activity and consequently reduced intracellular cyclic AMP. Exposure of the cells to a phosphodiesterase inhibitor caused considerable reduction in histamine release. Similarly, exposure of atopic B lymphocytes to a phosphodiesterase inhibitor greatly reduced the high spontaneous IgE synthesis in mononuclear leukocyte cultures. Elevated leukocyte phosphodiesterase activity may also serve as a marker for the atopic diathesis. We have found elevated enzyme activity in umbilical cord blood from newborns with atopic parents, suggesting that this defect may relate to a genetically determined defect. These studies have provided insight into basic abnormalities associated with atopic dermatitis and the atopic diathesis. Defects of regulatory mechanisms in immune and inflammatory cells may help explain the seemingly disparate disorders of physiologic, pharmacologic, and immunologic systems in atopy.


Long-Term Survival in Adults Treated With Extracorporeal Membrane Oxygenation for Respiratory Failure and Sepsis.
The use of extracorporeal membrane oxygenation in adults with respiratory failure and sepsis is steadily increasing, but the knowledge on long-term survival in this group is scarce. The aim of the present study was to investigate the 5-year survival rates and causes of late death in this group of patients. Single-center retrospective cohort study. Karolinska University Hospital, Stockholm, Sweden. Adult patients treated with extracorporeal membrane oxygenation for respiratory failure and sepsis between the service being established for adults in 1995 and December 2013. None. Survival status was attained from a national Causes of Death registry. Minimal patient background data, along with data on survival and causes of death were collected. Survival rates were calculated using the Kaplan-Meier method. Of 255 subjects, 64% survived to discharge. The median follow-up time in survivors was 4.4 years. There was a high mortality rate within the first months after discharge. In the group of patients who survived the first 90 days after treatment, the 5-year survival rate was 87% and was particularly beneficial in patients treated for infectious diseases (88-100%). Late deaths were seen in most diagnostic groups, but the Kaplan-Meier curves flattened out over time. Extracorporeal membrane oxygenation treatment in adult patients with respiratory failure and sepsis can be lifesaving in appropriately selected patients. For patients who survive the first months after extracorporeal membrane oxygenation treatment, long-term survival seems good, especially in patients treated for infections.


A comparison between visual, intraoral scanner, and spectrophotometer shade matching: A clinical study.
Visual shade matching is subjective and a cause of concern for clinicians. Different measurement devices have been developed to assist in tooth color selection and to achieve better esthetic results. However, consensus is lacking as to which method of tooth shade selection provides more predictable results. The purpose of this clinical study was to compare the reliability of different visual and instrumental methods for dental shade matching. Visual shade matching was performed by 3 experienced clinicians using 2 different shade guides (VITA Classical A1-D4 and VITA Toothguide 3D-MASTER with 29 tabs; VITA Zahnfabrik) with and without the aid of a light-correcting device (Smile Lite; Smile Line). An intraoral scanner (TRIOS; 3Shape A/S) and a spectrophotometer (VITA Easyshade Advance 4.0; VITA Zahnfabrik) were also used for color shade matching. The instrumental methods were repeated 3 times to determine repeatability. Shade-matching sessions for each method were performed under controlled lighting on the middle third of the maxillary right central incisor of 28 participants. The Fleiss' kappa statistical test was used to assess the reliability of each method. The weighted kappa statistical test was used to assess the agreement between the shades matched by different methods (α=.05). Instrumental methods were more accurate than visual methods. The best performance was found for the intraoral scanner configured for the 3D-MASTER scale (Fleiss' kappa value of .874) and for the spectrophotometer configured for the VITA Classical scale (Fleiss' kappa value of .805). The best visual shade-matching method was the VITA Classical scale associated with the light-correcting device (Fleiss' kappa value of .322). The Classical scale without the light-correcting device showed the poorest reliability (Fleiss' kappa value of .177) (P<.05). Instrumental methods for color shade matching were more reliable than the visual methods tested.


Structure of a New Palatal Plate and the Artificial Tongue for Articulation Disorder in a Patient with Subtotal Glossectomy.
A palatal augmentation prosthesis (PAP) is used to facilitate improvement in the speech and swallowing functions of patients with tongue resection or tongue movement disorders. However, a PAP's effect is limited in cases where articulation disorder is severe due to wide glossectomy and/or segmental mandibulectomy. In this paper, we describe speech outcomes of a patient with an articulation disorder following glossectomy and segmental mandibulectomy. We used a palatal plate (PP) based on a PAP, along with an artificial tongue (KAT). Speech improvement was evaluated by a standardized speech intelligibility test consisting of 100 syllables. The speech intelligibility score was significantly higher when the patient wore both the PP and KAT than when he wore neither (p=0.013). The conversational intelligibility score was significantly improved with the PP and KAT than without PP and KAT (p=0.024). These results suggest that speech function can be improved in patients with hard tissue defects with segmental mandibulectomy using both a PP and a KAT. The nature of the design of the PP and that of the KAT will allow these prostheses to address a wide range of tissue defects.


Effect of haptic supplementation on postural stabilization: A comparison of fixed and mobile support conditions.
It is well known in the literature of haptic supplementation that a "light touch" (LT) with the index finger on a stable surface increases postural stability. In view of potential application in the domain of mobility aids, it should however be demonstrated that haptic supplementation is effective even when provided by an unstable stick support. The present study aimed to explore the stabilizing effect of a three-digit "light grip" (LG) of different supports (fixed or mobile stick) in young people. Eleven participants (M=25.9 years) were tested in an upright standing task in six experimental conditions in which the mobility of the given support and its resistance in opposite direction to the body movement were manipulated. The RMS variability and the range of postural oscillations were measured. The results confirmed that the stabilizing effect of haptic supplementation is independent from the nature of the support (fixed or mobile) when sufficiently large sway-related contact forces on the fingers are provided. Future applications of this "mobile stick paradigm" to complex situations while targeting different groups of participants may help to approach everyday life situations in which an informational stick could potentially be of assistance to gain stability and mobility.


Community assessment workshops: a group method for gathering client experiences of health services.
Community assessment workshops were developed to gather client experiences of primary health care services in Australia. Primary health care services are particularly concerned with working with disadvantaged populations, for whom traditional client survey methods such as written surveys may not be inclusive and accessible. Service staff at six Australian primary health care services, including two Aboriginal-specific services, invited participants to attend workshops in 2011-2012. Participants were offered transport, childcare and an interpreter, and provided with reimbursement for their time. Ten workshops were run with a total of 65 participants who accessed a variety of services and programmes. A mix of age and gender was achieved. The workshops yielded detailed qualitative data and quantitative rankings for nine service qualities: holistic, effective, efficient, culturally respectful, used by those most in need, responsive to the local community, increasing individual control, supports and empowers the community, and mix of treatment, prevention and promotion. Discussions were audio recorded and transcribed for qualitative analysis. The workshop approach succeeded in being (i) inclusive, reaching users from disadvantaged sections of the community; (ii) comprehensive, providing ratings and discussion that took account of the whole service; (iii) richly descriptive, with researchers able to generate detailed feedback; and (iv) more empowering than traditional client survey methods, by allowing more control to participants and greater benefits than surveys of individuals. The community assessment workshops are a method that could be widely applied to health service evaluation research where the goal is to reach disadvantaged communities and provide ratings and detailed analysis of the experience of users. The participants and the research benefited from the group approach, and the workshops provided valuable, actionable information to the health services. Recruitment of users, particularly those from culturally diverse backgrounds, remains one of the key challenges facing evaluators.


Nonsuicidal Self-Injury in Adolescents: Characterization of the Disorder and the Issue of Distress and Impairment.
Nonsuicidal self-injury disorder (NSSID) is a condition in need of further study to assess the validity of the potential diagnosis and its suggested criteria. This study examined the NSSID diagnosis and investigated the distress/impairment criterion by comparing community adolescents who met all criteria for NSSID (n = 186) to adolescents with five or more nonsuicidal self-injury (NSSI) episodes (n = 314), and to a group of adolescents who met all criteria but negated that their NSSI caused them any distress or impairment, thus failing to meet criterion E (n = 29). The NSSID group delimited from the ≥ 5 NSSI group by reporting significantly more frequent and severe self-injurious thoughts and behaviors, as well as having more experiences of negative life events and higher levels of trauma symptoms. There were also some differences between the NSSID group and adolescents without distress/impairment, which together contribute valuable information on the potential NSSID diagnosis, as well as the discussion of criterion E.


Gallium plasmonics: deep subwavelength spectroscopic imaging of single and interacting gallium nanoparticles.
Gallium has recently been demonstrated as a phase-change plasmonic material offering UV tunability, facile synthesis, and a remarkable stability due to its thin, self-terminating native oxide. However, the dense irregular nanoparticle (NP) ensembles fabricated by molecular-beam epitaxy make optical measurements of individual particles challenging. Here we employ hyperspectral cathodoluminescence (CL) microscopy to characterize the response of single Ga NPs of various sizes within an irregular ensemble by spatially and spectrally resolving both in-plane and out-of-plane plasmonic modes. These modes, which include hybridized dipolar and higher-order terms due to phase retardation and substrate interactions, are correlated with finite difference time domain (FDTD) electrodynamics calculations that consider the Ga NP contact angle, substrate, and native Ga/Si surface oxidation. This study experimentally confirms previous theoretical predictions of plasmonic size-tunability in single Ga NPs and demonstrates that the plasmonic modes of interacting Ga nanoparticles can hybridize to produce strong hot spots in the ultraviolet. The controlled, robust UV plasmonic resonances of gallium nanoparticles are applicable to energy- and phase-specific applications such as optical memory, environmental remediation, and simultaneous fluorescence and surface-enhanced Raman spectroscopies.


Association of histone deacetylase with COUP-TF in tumorigenic Ad12-transformed cells and its potential role in shut-off of MHC class I transcription.
Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) is an orphan nuclear receptor that represses transcription of many genes. In adenovirus type 12 (Ad12) transformed cells, a high level of binding activity of COUP-TF to the major histocompatibility complex (MHC) class I enhancer correlates with the down-regulation of class I transcription, which, in turn, contributes to tumorigenesis. The mechanism by which COUP-TF represses transcription has yet to be elucidated. Here we show that COUP-TF represses transcription through its association with histone deacetylase. This was demonstrated using reciprocal binding assays that determined that the interaction between COUP-TF and histone deacetylase requires the COUP-TF C-terminal repression domain. Moreover, a histone deacetylase enzymatic activity was found to be associated with COUP-TF in Ad12-transformed cells. Transfection experiments further revealed that exogenous histone deacetylase facilitates transcriptional repression by COUP-TF. Also, supershift assays suggest that the transcriptional corepressor N-CoR, which is known to associate with histone deacetylases, is a part of the COUP-TF complex bound to the MHC class I enhancer R2 site. Finally, we provide evidence that inhibition of histone deacetylases relieves the repression of MHC class I expression in Ad12-transformed cells. Taken together these results support the notion that deacetylation of histones, mediated through COUP-TF, serves to down-regulate MHC class I transcription in Ad12-transformed cells.


Immune responses in cystic fibrosis: are they intrinsically defective?
Cystic fibrosis (CF), the most common lethal single-gene disorder affecting Northern Europeans and North Americans, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cftr is a chloride channel and a regulator of other ion channels, and many aspects of the CF phenotype are directly related to ion channel abnormalities attributable to CFTR mutation. Lung disease is the most common limitation to the quantity and quality of life for patients with CF. One aspect that continues to be enigmatic is the observed alterations in innate and adaptive immune responses to certain pathogens. Altered responses to Pseudomonas aeruginosa and Aspergillus fumigatus, with an increase in neutrophil chemoattractants in the former case and a hyper-IgE-like state in the latter, are common in CF. Several lines of evidence suggest that the proinflammatory cytokine response to bacterial infection is exaggerated in CF. A literature search reveals that, although the abnormalities in CF immune cells have been recognized since the 1970s, few studies until recently have appreciated the role that CFTR plays in these cell types. A growing body of evidence has emerged that points to neutrophils, macrophages, and T cells as being central to the infectious and pulmonary pathology, accounting for the majority of CF mortality. Primary CFTR defects in T cells are providing new insights into the misorchestration of the CF immune system due to aberrant signaling pathways. Defective CFTR function disrupts the balance of intracellular ion concentrations, including [Ca(2+)], which is known to drive gene expression pathways. New evidence links this hypothesis to anomalies in immune activation observed across CF cell types, which could shed light on the inability of individuals with CF to effectively clear pathogens. This review focuses on the emerging role of Cftr in gene expression and other functions in cells of the innate and adaptive immune system.


Effects of physical exercise during pregnancy and protein malnutrition during pregnancy and lactation on the development and growth of the offspring's femur.
To evaluate the effects of physical training of mother rats during pregnancy associated with a low-protein diet offered during pregnancy and lactation on the development and growth of the femur of their offspring. Forty 90-day old male Wistar rats were divided into four groups: pups of sedentary nourished mothers, pups of sedentary malnourished mothers, pups of trained nourished mothers, and pups of trained malnourished mothers; all groups included 10 rats. Physical training on a treadmill for 8 weeks, 5 weeks before conception and 3 weeks in the gestational period for mother rats of pups of trained nourished mothers and pups of trained malnourished mothers. Induction of low-protein diet to the mother rats during pregnancy and lactation for the groups of pups of sedentary malnourished mothers and trained malnourished mothers. After the pups were sacrificed, on the 90th day of life, we analyzed weight, length, and femoral bone mineral content. Decreased body weight, femur weight, and femur length (p < 0.05) were observed for the groups of pups of sedentary malnourished mothers and trained malnourished mothers in comparison with to the groups of pups of sedentary nourished mothers and trained nourished mothers, respectively. There was no difference in bone mineral content of the femur in either of the groups. Mild physical training on the treadmill during pregnancy does not interfere with bone development and growth of the offspring. However, protein malnutrition during this period and during lactation promotes permanent damage to the bone structure of the offspring.


Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity?
Lesions obtained early in the course of multiple sclerosis (MS) have been studied immunocytochemically, and compared with the early stages of the experimental lesion induced in rats by the intraspinal injection of lipopolysaccharide. Large hemispheric or double hemispheric sections were examined from patients who had died in the course of acute or early relapsing multiple sclerosis. In MS patients exhibiting hypoxia-like lesions [Pattern III; Lucchinetti et al. Ann Neurol (2000) 47: 707-17], focal areas in the white matter showed mild oedema, microglial activation and mild axonal injury in the absence of overt demyelination. In such lesions T-cell infiltration was mild and restricted to the perivascular space. Myeloperoxidase and the inducible form of nitric oxide synthase were expressed primarily by microglia, and the activated form of these cells was associated with extracellular deposition of precipitated fibrin. In addition, these lesions showed up-regulation of proteins involved in tissue preconditioning. When active demyelination started, lesions were associated with massive T-cell infiltration and microglia and macrophages expressed all activation markers studied. Similar tissue alterations were found in rats in the pre-demyelinating stage of lesions induced by the focal injection of bacterial lipopolysaccharide into the spinal white matter. We suggest that the areas of microglial activation represent an early stage of tissue injury, which precedes the formation of hypoxia-like demyelinated plaques. The findings indicate that mechanisms associated with innate immunity may play a role in the formation of hypoxia-like demyelinating lesions in MS.


Muscle activity pattern dependent pain development and alleviation.
Muscle activity is for decades considered to provide health benefits irrespectively of the muscle activity pattern performed and whether it is during e.g. sports, transportation, or occupational work tasks. Accordingly, the international recommendations for public health-promoting physical activity do not distinguish between occupational and leisure time physical activity. However, in this body of literature, attention has not been paid to the extensive documentation on occupational physical activity imposing a risk of impairment of health - in particular musculoskeletal health in terms of muscle pain. Focusing on muscle activity patterns and musculoskeletal health it is pertinent to elucidate the more specific aspects regarding exposure profiles and body regional pain. Static sustained muscle contraction for prolonged periods often occurs in the neck/shoulder area during occupational tasks and may underlie muscle pain development in spite of rather low relative muscle load. Causal mechanisms include a stereotype recruitment of low threshold motor units (activating type 1 muscle fibers) characterized by a lack of temporal as well as spatial variation in recruitment. In contrast during physical activities at leisure and sport the motor recruitment patterns are more dynamic including regularly relatively high muscle forces - also activating type 2 muscles fibers - as well as periods of full relaxation even of the type 1 muscle fibers. Such activity is unrelated to muscle pain development if adequate recovery is granted. However, delayed muscle soreness may develop following intensive eccentric muscle activity (e.g. down-hill skiing) with peak pain levels in thigh muscles 1-2 days after the exercise bout and a total recovery within 1 week. This acute pain profile is in contrast to the chronic muscle pain profile related to repetitive monotonous work tasks. The painful muscles show adverse functional, morphological, hormonal, as well as metabolic characteristics. Of note is that intensive muscle strength training actually may rehabilitate painful muscles, which has recently been repeatedly proven in randomized controlled trials. With training the maximal muscle activation and strength can be shown to recover, and consequently allow for decreased relative muscle load during occupational repetitive work tasks. Exercise training induces adaptation of metabolic and stress-related mRNA and protein responses in the painful muscles, which is in contrast to the responses evoked during repetitive work tasks per se.


Comparative role of 20% cord blood serum and 20% autologous serum in dry eye associated with Hansen's disease: a tear proteomic study.
To compare the role of topically applied serum therapy with preservative-free artificial tear (AT) drops in patients with moderate to severe dry eye in Hansen's disease along with change in tear protein profile. 144 consecutive patients were randomly divided into three groups. After a baseline examination of clinical parameters, each of the patients received designated modality of topical therapy six times a day for 6 weeks. Post-treatment documentation of clinical parameters was done at 6 weeks, and then at 12 weeks after discontinuation of topical therapy. Analysis of three tear proteins using gel electrophoresis (sodium dodecyl sulfate polyacrylamide gel electrophoresis) was done at baseline, at the first and second post-treatment visits. In the cord blood serum (CBS) group, except for McMonnies score and staining score, all other clinical parameters showed continued improvement in the first and second post-treatment analyses. In the autologous serum (ALS) group, all the clinical parameters except Schirmer's I showed significant improvement in the first post-treatment analysis .This was sustained at a significant level in the second analysis except for tear film break-up time (TBUT) and conjunctival impression cytology grading. In the AT group, all the parameters improved at a non-significant level except for TBUT in the first analysis. In the next analysis, apart from McMonnies score and TBUT, other clinical parameters did not improve. In the ALS and CBS groups, tear lysozyme, lactoferrin levels improved in both post-treatment measurements (statistically insignificant).Total tear protein continued to increase at statistically significant levels in the first and second post-treatment analyses in the CBS group and at a statistically insignificant level in the ALS group. In the AT group, the three tear proteins continued to decrease in both the analyses. In moderate to severe dry eye in Hansen's disease, serum therapy in comparison with AT drops, improves clinical parameters and causes betterment in tear protein profile. CTRI/2013/07/003802.


Influenza virion-derived viral ribonucleoproteins synthesize both mRNA and cRNA in vitro.
The mechanisms regulating the synthesis of mRNA, cRNA, and viral genomic RNA (vRNA) by the influenza A virus RNA-dependent RNA polymerase are not fully understood. Early results suggested that the RNA polymerase "switched" from a transcriptase to a replicase during the viral life cycle in response to the expression of viral proteins. However, recently an alternative model suggesting that replication of influenza virus is regulated by stabilization of the replicative intermediates was proposed. According to this model, the virion-associated polymerase is capable of synthesizing both mRNA and cRNA. We now demonstrate that virion-derived viral ribonucleoproteins (vvRNPs) synthesize both mRNA and cRNA in vitro in the absence of non-virion-associated RNA polymerase or nucleoproteins. The authenticity of the in vitro-transcribed mRNA and cRNA was confirmed by terminal sequence analysis. The addition of non-virion-associated polymerase or NP had no effect on vvRNP activity. De novo synthesis of cRNA was found to be more sensitive than the capped primer-dependent synthesis of mRNA to the concentration of ATP, CTP, and GTP. We conclude that vvRNPs intrinsically possess both transcriptase and replicase activities and that there is no switch in the synthesis of mRNA to cRNA during the influenza virus life cycle.


Cell-free, de novo synthesis of poliovirus.
Cell-free translation of poliovirus RNA in an extract of uninfected human (HeLa) cells yielded viral proteins through proteolysis of the polyprotein. In the extract, newly synthesized proteins catalyzed poliovirus-specific RNA synthesis, and formed infectious poliovirus de novo. Newly formed virions were neutralized by type-specific antiserum, and infection of human cells with them was prevented by poliovirus receptor-specific antibodies. Poliovirus synthesis was increased nearly 70-fold when nucleoside triphosphates were added, but it was abolished in the presence of inhibitors of translation or viral genome replication. The ability to conduct cell-free synthesis of poliovirus will aid in the study of picornavirus proliferation and in the search for the control of picornaviral disease.


Imagine a world without cancer.
Since the "War on Cancer" was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type. Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patient's own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy. Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer.


Brief workshops to teach drug and alcohol first aid: A pilot evaluation study.
Health and community service workers frequently encounter people with alcohol and other drug (AOD) problems in the course of their work, yet few have had training on how to respond effectively. A Drug and Alcohol First Aid workshop was developed by Lyndon, a non-government organisation treatment provider, and delivered to community and health sector workers and the general public. It presented evidence-based information regarding AOD use and harm reduction and treatment options. A pilot evaluation of the workshop was conducted to assess changes in participants' knowledge about AOD, methods of responding to use and attitudes towards individuals who use AOD, over a 3 month period. A self-report evaluation survey was developed and administered to workshop participants at three time points: before (T1), immediately after (T2) and 3 months after the workshop (T3). Paired samples t-tests examined changes in knowledge, role adequacy, motivation and personal views. A total of 142 participants completed the T1 survey, 184 completed the T2 survey and 98 completed the T3 survey. Between T1 and T2, there were significant increases in scores for knowledge and role adequacy, indicating significant improvements in these areas. No significant differences were found for motivation and personal views. At T3, knowledge and role adequacy scores remained significantly higher than at baseline. Drug and Alcohol First Aid appears to be a viable initiative to improve AOD-related knowledge and role adequacy. However, alternative strategies may be required to shift negative attitudes towards individuals who use AOD. [Kostadinov VR, Roche AM, McEntee A, Allan JM, Meumann NR, McLaughlin LL. Brief workshops to teach drug and alcohol first aid: A pilot evaluation study. Drug Alcohol Rev 2018;37:23-27].


Chemosuppressive field trials in Thailand. II. The suppression of Plasmodium falciparum and Plasmodium vivax parasitemias by a diformyldapsone-pyrimethamine combination.
In an area of Thailand where chloroquine-resistant falciparum malaria is known to exist, a chemosuppressive field trial was undertaken to test the efficacy of the preparation diformyldapsone (DFD) combined with pyrimethamine (Py) in suppressing falciparum and vivax parasitemias. Six hundred and fifty-nine Thai villagers were randomly assigned to one of five treatment groups: DFD-Py; dapsone (DDS)-Py; DFD alone; Py alone; and placebo. Five hundred and ninety-three study subjects completed the 26-week trial. The combination DFD-Py given weekly was shown to be an effective chemosuppressive against both falciparum and vivax parasitmias, causing a more than fourfold reduction in falciparum and an approximately threefold reduction in vivax parasitemias; however, this combination was not more efficacious than DDS-Py for the chemosuppression of falciparum malaria. DFD alone was only moderately effective, while there was no difference in chemosuppression between Py alone and placebo.


Variables associated with alcohol, drug, and daily smoking cessation in patients with severe mental illnesses.
Co-occurrence of substance use disorders and severe mental illnesses (SMIs) is a major U.S. public health issue, although the role of tobacco is usually neglected. This study explored variables associated with alcohol, drug, and smoking cessation in a naturalistic setting. Logistic regression was used to study variables associated with cessation of alcohol and drug use disorder and daily smoking in 560 SMI inpatients and outpatients from central Kentucky facilities. Patients with a lifetime history of alcohol or drug use disorder were considered to be in cessation if they had not suffered from abuse or dependence during the last year. Alcohol and drug use disorder diagnoses were determined using the Clinician Rating of Alcohol and Drug Use Disorder. Patients were recruited from July 2000 to March 2003. The cessation rates for alcohol and drug use disorders were, respectively, 44% (95% CI = 39% to 49%) and 46% (CI = 40% to 51%); these were higher than the daily cigarette smoking cessation rate of 10% (CI = 7% to 13%). Drug use disorders (p < or = .02), outpatient status (p < .001), and having a medical complication of obesity (diabetes mellitus, hypertension, or hyperlipidemia; p < .001) were significantly associated with alcohol cessation. Alcohol use disorder (p < .001), starting treatment with psychiatric medications after 33 years of age (p < .001), taking these medications for 14 years or more (p = .02), schizophrenia diagnosis (p < .001), outpatient status (p = .03), and obesity (p = .04) were significantly associated with drug cessation. Cessation of daily smoking was associated with hypertension (p = .02), late start of treatment with psychiatric medications (> 33 years old; p = .01), and lack of lifetime drug abuse (p < .001). These results are limited by the cross-sectional and naturalistic design but suggest that public health experts, researchers, and clinicians need to mindfully address smoking cessation in patients with SMIs. Clinicians may want to consider that medical illnesses may motivate patients with SMIs to stop substance abuse and that patients with SMIs who abuse both alcohol and drugs rarely stop abusing just one of them.


Genomic variation in the vomeronasal receptor gene repertoires of inbred mice.
Vomeronasal receptors (VRs), expressed in sensory neurons of the vomeronasal organ, are thought to bind pheromones and mediate innate behaviours. The mouse reference genome has over 360 functional VRs arranged in highly homologous clusters, but the vast majority are of unknown function. Differences in these receptors within and between closely related species of mice are likely to underpin a range of behavioural responses. To investigate these differences, we interrogated the VR gene repertoire from 17 inbred strains of mice using massively parallel sequencing. Approximately half of the 6222 VR genes that we investigated could be successfully resolved, and those that were unambiguously mapped resulted in an extremely accurate dataset. Collectively VRs have over twice the coding sequence variation of the genome average; but we identify striking non-random distribution of these variants within and between genes, clusters, clades and functional classes of VRs. We show that functional VR gene repertoires differ considerably between different Mus subspecies and species, suggesting these receptors may play a role in mediating behavioural adaptations. Finally, we provide evidence that widely-used, highly inbred laboratory-derived strains have a greatly reduced, but not entirely redundant capacity for differential pheromone-mediated behaviours. Together our results suggest that the unusually variable VR repertoires of mice have a significant role in encoding differences in olfactory-mediated responses and behaviours. Our dataset has expanded over nine fold the known number of mouse VR alleles, and will enable mechanistic analyses into the genetics of innate behavioural differences in mice.


Neurodevelopmental outcome in very low birthweight infants with pathological umbilical artery flow.
To assess neurodevelopmental outcome during toddlerhood in very low birthweight (VLBW) infants with absent or reverse end-diastolic flow (AREDF) in the umbilical artery (UA) during pregnancy. Retrospective cohort study with matched control group. Tertiary perinatal centre. We compared longitudinally collected data on neonatal and neurodevelopmental outcomes among 41 infants born in our institution from 1997 to 2010 with birth weight <1500 g and UA AREDF and 41 infants with prenatally normal UA Doppler parameters matched for gestational age, birth weight, sex and year of birth. We evaluated neurodevelopmental outcome at a median (range) corrected age of 23.3 (10.1-29.6) months using the Bayley scales of infant development, 2nd edition (BSID-II), and neurological examination. The mental development index in UA AREDF children (median (range) 84 (49-116)) was significantly lower than in controls (median (range) 91 (62-140)), including after adjustment for confounders. Intergroup differences in psychomotor development index (PDI; BSID-II) and the rate of cerebral palsy or minor neuromotor dysfunction were non-significant. VLBW infants with UA AREDF have a higher risk of poorer mental development during toddlerhood than controls matched for gestational age, birth weight, sex and year of birth. UA AREDF may be considered a prenatal predictor of poorer mental development in this population. Long-term follow-up studies with larger cohorts are needed to better evaluate the impact of this prenatal factor on later neurodevelopment.


Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms.
Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI. We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis. Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.


Emergence of clinical isolates of Escherichia coli producing TEM-1 derivatives or an OXA-1 beta-lactamase conferring resistance to beta-lactamase inhibitors.
Sixteen Escherichia coli clinical isolates which were resistant to ampicillin and amoxicillin-clavulanate but susceptible to cephalothin were studied. Eight strains showed the presence of a beta-lactamase which comigrates with reference OXA-1 enzyme. The eight other strains produced different TEM-1 derivatives which had in common a higher Km for penicillins and a higher 50% inhibitory concentration for the beta-lactamase inhibitors. By oligotyping and sequencing of PCR products, it was shown that Ser (AGC) (TEM-30; also called TRI-1) in three strains and Cys (TGC) (TEM-31; also called TRI-2) in one strain were substituted for Arg-241 (CGC), that Leu (CTG) (TEM-33) and Val (GTG) (TEM-34) in one strain each were substituted for Met-67 (ATG), and that in other mutants the two latter substitutions occurred together with the substitution of Asp (GAT) (TEM-35 and TEM-36) for Asn-272 (AAT). Therefore, different sets of amino acid substitutions of TEM-1 can be found in clinical isolates and lead to resistance to beta-lactamase inhibitors.


Modulation of insulin activities by leptin.
Leptin mediates its effects on food intake through the hypothalamic form of its receptor OB-R. Variants of OB-R are found in other tissues, but their function is unknown. Here, an OB-R variant was found in human hepatic cells. Exposure of these cells to leptin, at concentrations comparable with those present in obese individuals, caused attenuation of several insulin-induced activities, including tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, and down-regulation of gluconeogenesis. In contrast, leptin increased the activity of IRS-1-associated phosphatidylinositol 3-kinase. These in vitro studies raise the possibility that leptin modulates insulin activities in obese individuals.


Exercise therapy for human immunodeficiency virus/AIDS patients: Guidelines for clinical exercise therapists.
Human immunodeficiency virus (HIV) has infected > 60 million people since its discovery and 30 million people have died since the pandemic began. Antiretroviral therapy has transformed HIV infection from an acute to a chronic disease, increasing life expectancy but also adding to the potential side effects associated with drug therapy and the comorbidity accompanying longevity. Exercise can play a valuable role in the management of HIV/AIDS patients by addressing various symptoms and improving their quality of life, but the optimum mode, intensity, frequency, and duration of exercise that take the different clinical stages of the disease into consideration are inadequately known. Searches of Medline, Embase, Science Citation Index, CINAHL database, HealthSTAR, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Physiotherapy Evidence Database (PEDro), and SPORTDiscus were conducted between 2000 and January 2014. Searches of published and unpublished abstracts were conducted, as well as a hand search of reference lists and tables of contents of relevant journals and books. Identified studies were reviewed for methodological quality. A total of 33 studies met the inclusion criteria. Most studies failed to indicate the optimum type (mode), intensity, frequency, and duration of aerobic and progressive resistive exercise prescribed to HIV-infected individuals in relation to the different clinical stages of the disease. The purpose of this review is to provide evidence-based recommendations after revision of exercise guidelines for HIV patients, by highlighting practical guidelines that clinical exercise therapists should consider when prescribing exercise for patients in different stages of the disease.


Molecular aspects of soybean cultivar-specific nodulation by Sinorhizobium fredii USDA257.
Sinorhizobium fredii USDA257 forms nitrogen-fixing nodules in association with the primitive soybean cultivar 'Peking' but fails to initiate nodules on many advanced soybean cultivars, including 'McCall'. This distinction is controlled by a set of nodulation genes termed nolXWBTUV. Inactivation of any of these genes enables USDA257 to nodulate McCall and many other improved soybean cultivars. Mutation in the nolXWBTUV locus also alters the Nod factor structure resulting in the production of a novel molecule with glucose incorporated into the chitin backbone. Some of the genes located in the nolXWBTUV locus reveal sequence homologies to known components of the type III secretion system (TTSS) of plant and animal pathogenic bacteria. Recent studies have demonstrated the presence of a complete TTSS in USDA257 and few other symbiotic bacteria. The TTSS cluster of USDA257 contains 27 open reading frames out of which 10 code for the structural components of the TTSS. USDA257, when grown in presence of flavonoids, secrete several proteins called Nops (Nodulation Outer Proteins) into the extracellular environment. Genes located in the TTSS of USDA257 encode some of the extracellular proteins, such as NopX, NopB, and NopL. These type III secreted proteins appear to play an important role in regulating nodulation in a host-dependent manner. Failure to elaborate the Nops results in a drastic phenotypic effect on soybean nodulation, indicating that these proteins may play a pivotal role in soybean cultivar specificity. The secretion of Nops appears to be facilitated by novel filamentous appendages (pili) that are produced by USDA257 upon induction by flavonoids. Biochemical studies have demonstrated the close association of several Nops with the purified pili. However, it remains to be seen if the filamentous appendages can function as conduits for delivery of Nops into the host cell. This review examines the current state of our knowledge on the molecular aspects of soybean cultivar-specific nodulation by USDA257.


Recognizing Atypical Parkinsonisms: "Red Flags" and Therapeutic Approaches.
The overlap of signs and symptoms between Parkinson's disease and the atypical parkinsonian syndromes, such as progressive supranuclear palsy, multiple system atrophy, corticobasal syndrome and dementia with Lewy bodies, can render clinical diagnoses challenging. The continued evolution of diagnostic criteria to reflect the increasingly recognized heterogeneous presentations of these diseases further complicates timely recognition and diagnosis. In this review, we provide a diagnostic approach to the classic atypical parkinsonian syndromes, with an emphasis on the key clinical and pathological features of each and the recognition of "red flags" in the setting of recent advances in diagnosis and treatment.


Low intraspecific diversity in a polynucleobacter subcluster population numerically dominating bacterioplankton of a freshwater pond.
Cultivation-dependent and -independent methods were combined to investigate the microdiversity of a Polynucleobacter subcluster population (Betaproteobacteria) numerically dominating the bacterioplankton of a small, humic freshwater pond. Complete coverage of the population by cultivation allowed the analysis of microdiversity beyond the phylogenetic resolution of ribosomal markers. Fluorescent in situ hybridization with two probes specific for the narrow subcluster C (PnecC bacteria) of the Polynucleobacter cluster revealed that this population contributed up to 60% to the total number of bacterioplankton cells. Microdiversity was investigated for a date at which the highest relative numbers of PnecC were observed. A clone library of fragments of the ribosomal operon (16S rRNA genes, complete 16S-23S internal transcribed spacer 1 [ITS1], partial 23S rRNA genes) amplified with universal bacterial primers was constructed. The library was stepwise screened for fragments from PnecC bacteria and for different ITS genotypes of PnecC bacteria. The isolated PnecC strains were characterized by sequencing of the 16S rRNA genes and the ITS1. Both the clone library and the established culture collection contained only the same three ITS genotypes, and one of them contributed 46% to the entire number of clones. Genomic fingerprinting of the isolates with several methods always resulted in the detection of only one fingerprint per ITS genotype. We conclude that a Polynucleobacter population with an extremely low intraspecific diversity and an uneven structure numerically dominated the bacterioplankton community in the investigated habitat. This low intraspecific diversity is in strong contrast to the high intraspecific diversities found in marine bacterial populations.


Commissioning, implementation and delivery of an interface secondary fracture prevention service within the NHS: Lessons learnt from the Oxfordshire Fracture Prevention Service.
To provide a case history of the service model, commissioning, implementation and delivery of an interface secondary fracture prevention service. Fracture Prevention has been identified as key to reducing the burden on the NHS from an ageing population. The need to have a systematic process for identifying, assessing and ensuring treatment adherence is vital. Delivering the service to identify patients at risk and initiate treatment is important as is the use of a database for patient tracking and the need to ensure that patients remain on treatment to ensure maximum fracture prevention benefit, and cost savings are seen. The process for implementing a Fracture Prevention service can be challenging but identifying the components and working closely with local commissioners can provide the evidence and release the resource required. The key components of a Fracture Prevention Service should include robust case-finding, assessment, treatment initiation, patient education and monitoring.


Induction of autoimmunity in a transgenic model of B cell receptor peripheral tolerance: changes in coreceptors and B cell receptor-induced tyrosine-phosphoproteins.
Abrogation of peripheral tolerance in transgenic mice that express a uniform B-cell receptor may create a powerful tool to examine the molecular mechanisms that underlie the autoimmune response in B cells. Here we report that processes that induce a systemic lupus erythematosus-like syndrome in normal mice, namely chronic graft vs host reaction, trigger systemic autoimmunity in a well-established transgenic mice model of B cell receptor peripheral tolerance. The induction of graft vs host reaction in mice that carry both a rearranged B cell Ag receptors specific for hen egg lysozyme and expressing chronically circulating hen egg lysozyme Ag resulted in induction of high and sustained levels of circulating anti-hen egg lysozyme autoantibodies and glomerulonephritis with proteinuria. This was associated with marked changes in expression of cell-surface proteins, such as CD23 and complement receptor 2. B cells from the graft vs host-induced mice could proliferate in vitro in response to self-Ag, and upon stimulation with anti-IgD demonstrated rapid phosphotyrosine phosphorylation of specific proteins, which could not be induced in the anergic double transgenic B cells. Conversely, loss of tolerance was not associated with a higher induction in the level of Syk kinase phosphorylation following stimulation with anti-IgD. Taken collectively, these data establish that 1) processes that induce a systemic lupus erythematosus-like syndrome in normal mice can abrogate peripheral tolerance in transgenic mice expressing self-tolerized B cells, and that 2) loss of tolerance in this model is associated with marked changes in surface expression of B cell coreceptors as well as with selective changes in IgD-induced signaling by discrete tyrosine-phosphoproteins, but not Syk kinase.


Translating evidence-based guidelines into practice: a survey of practices of commissioners and managers of the English stop smoking services.
The English National Health Service's (NHS) Stop Smoking Services (SSSs) constitute one of the most highly developed behavioural support programmes in the world. However, there is significant variation in success rates across the approximately 150 services, some of which may be due to variation in practice. This study aimed to assess these differences in practice. Two online surveys were administered. All commissioners (people who purchase services for the NHS) and managers (those who run the services) of NHS SSSs in England were invited to participate. Items included details of current practices and services provided, what informed the commissioning of SSSs, what targets were included within service specifications and whether the types of treatment model to be delivered were specified. Both surveys had a response rate of 35%, with 50 commissioners and 58 managers participating. There were no significant differences between the characteristics of the Primary Care Trusts (PCTs) from which commissioners and managers responded to this survey and those PCTs from which there was no response. Managers reported that the treatment model most frequently offered by SSSs was one-to-one (98%). A total of 16% of managers reported that some approved medications were not available as first-line treatments. Just over one third (38%) of commissioners reported consulting national guidelines or best evidence to inform local commissioning. Almost one third (30%) of commissioners reported that they specified the types of stop smoking interventions to be delivered by the providers. A substantial part of commissioning of Stop Smoking Services in England appears to take place without adequate consultation of evidence-based guidelines or specification of the service to be provided. This may account for at least some of the variation in success rates.


Anatomy of the first septal perforating artery: a study with implications for ablation therapy for hypertrophic cardiomyopathy.
To determine the variability in the size and distribution of the first septal perforating artery (FSPA). In this pilot study, 10 fresh autopsy hearts from patients who did not have hypertrophic cardiomyopathy (HCM) or clinical evidence of coronary artery disease were evaluated for the variability in the size of the FSPA. The size of the FSPA was also measured during coronary angiography in 8 patients with HCM who were undergoing alcohol septal ablation. Of the 10 autopsy hearts, 2 had a large FSPA (> or = 1.0 mm in maximal diameter) with prominent septal myocardial distribution, 2 had a medium-sized FSPA (0.5-0.9 mm), 2 had a small FSPA (0.1-0.4 mm), 3 had a tiny FSPA (< 0.1 mm), and 1 had an indiscernible ostium. In 2 patients the FSPA supplied the right ventricular free wall. In 4 patients the basal ventricular septum was incompletely supplied by the FSPA. Of the 8 patients with HCM, the FSPA was larger than 2 mm in diameter in 2 patients, 1 to 2 mm in 4, and smaller than 1 mm in 2. The distance between the left anterior descending coronary artery ostium and the origin of the FSPA ranged between 13.1 and 37.4 mm, indicating a large variation in the size and distribution of the FSPA. Variability in the size and distribution of the FSPA in patients without HCM was substantial. Areas of the heart other than the basal septum were supplied in some patients by the FSPA. In other patients the FSPA did not supply the entire basal septum. Similar findings were noted in patients with HCM. A detailed evaluation of the distribution of the FSPA may be necessary in all patients with HCM who are undergoing alcohol septal ablation.


Clinical variables responsible for early and late diagnosis of foreign body aspiration in pediatrics age group.
Incidence of foreign body aspiration has been noticed predominantly in age group ranging from 12 months-3 years. Foreign body in the trachea is a medical emergency as presentation is in respiratory distress. Obstruction of only one main or distal bronchus, leads to severe cough, choking sensation and breathlessness. Without early intervention, it can lead to collapse, consolidation and pneumonia of the affected lung. We retrospectively analyzed 37 pediatric case records who presented from January 2014-December 2018 with foreign body aspiration. Our primary aim was to assess the parameters responsible for early and late diagnosis of foreign body aspiration. We concluded with a diagnostic algorithm for management of foreign body aspiration on the basis of this outcome. Around 32.5% came with a history of aspiration, 43% were referred from the primary centers with a suspicion for the same and the rest came to our tertiary care hospital directly. Those who presented within a week came with complaints of wet cough, wheeze and tachypnea. Furthermore, those who came in after a week had a dry cough and fever as their main complaint. Majority of ingested foreign bodies was a vegetative type (80%) as compared to the non -vegetative. Unlike adults, foreign body aspiration in children is most commonly diagnosed on history, suspicion and clinical findings. Chest x ray has been the primary investigation of choice but in the majority of the cases it was normal with subtle changes. Early diagnosis is the key to avoid complication.


Detection of Atherosclerosis by Small RNA-Sequencing Analysis of Extracellular Vesicle Enriched Serum Samples.
Atherosclerosis can occur throughout the arterial vascular system and lead to various diseases. Early diagnosis of atherosclerotic processes and of individual disease patterns would be more likely to be successful if targeted therapies were available. For this, it is important to find reliable biomarkers that are easily accessible and with little inconvenience for patients. There are many cell culture, animal model or tissue studies that found biomarkers at the microRNA (miRNA) and mRNA level describing atherosclerotic processes. However, little is known about their potential as circulating and liquid biopsy markers in patients. In this study, we examined serum-derived miRNA - profiles from 129 patients and 28 volunteers to identify potential biomarkers. The patients had four different atherosclerotic manifestations: abdominal aneurysm (n = 35), coronary heart disease (n = 34), carotid artery stenosis (n = 24) and peripheral arterial disease (n = 36). The samples were processed with an extracellular vesicle enrichment protocol, total-RNA extraction and small RNA-sequencing were performed. A differential expression analysis was performed bioinformatically to find potentially regulated miRNA biomarkers. Resulting miRNA candidates served as a starting point for an overrepresentation analysis in which relevant target mRNAs were identified. The Gene Ontology database revealed relevant biological functions in relation to atherosclerotic processes. In patients, expression of specific miRNAs changed significantly compared to healthy volunteers; 27 differentially expressed miRNAs were identified. We were able to detect a group-specific miRNA fingerprint: miR-122-5p, miR-2110 and miR-483-5p for abdominal aortic aneurysm, miR-370-3p and miR-409-3p for coronary heart disease, miR-335-3p, miR-381-3p, miR493-5p and miR654-3p for carotid artery stenosis, miR-199a-5p, miR-215-5p, miR-3168, miR-582-3p and miR-769-5p for peripheral arterial disease. The results of the study show that some of the identified miRNAs have already been associated with atherosclerosis in previous studies. Overrepresentation analysis on this data detected biological processes that are clearly relevant for atherosclerosis, its development and progression showing the potential of these miRNAs as biomarker candidates. In a next step, the relevance of these findings on the mRNA level is to be investigated and substantiated.


Site of deep brain stimulation and jaw velocity in Parkinson disease.
While deep brain stimulation (DBS) has proven to be an effective treatment for many symptoms of Parkinson disease (PD), a deterioration of axial symptoms frequently occurs, particularly for speech and swallowing. These unfavorable effects of DBS may depend on the site of stimulation. The authors made quantitative measures of jaw velocity to compare the relative effectiveness of DBS in the globus pallidus internus (GPi) or the subthalamic nucleus (STN). This was a randomized, double-blind, and longitudinal study, with matched healthy controls. The peak velocities of self-scaled and externally scaled jaw movements were studied in 27 patients with PD before and after 6 months of bilateral DBS in the GPi or the STN. A mixed-effects model was used to identify differences in jaw velocity before DBS surgery (baseline) while off and on levodopa therapy, and after 6 months of DBS (postoperative) during 4 treatment conditions (off- and on-levodopa states with and without DBS). Self-scaled jaw velocity was impaired by the DBS procedure in the STN; velocity was significantly decreased across all postoperative conditions compared with either the off- or on-levodopa baseline conditions. In contrast, the postoperative velocity in the GPi group was generally faster than the baseline off-levodopa state. Turning the DBS off and on had no effect on jaw velocity in either group. Unlike baseline, levodopa therapy postoperatively no longer increased jaw velocity in either group, and this lack of effect was not related to postoperative changes in dose. The externally scaled jaw velocity was little affected by PD, but DBS still slightly affected performance, with the STN group significantly slower than the GPi group for most conditions. The authors' results suggest that either the electrode implant in STN or the subsequent period of continuous STN stimulation negatively affected voluntary jaw velocity, including the loss of the preoperative levodopa-induced improvement. While the GPi group showed some improvement in voluntary jaw velocity postoperatively, their performance during the combination of DBS and levodopa was not different from their best medical management presurgery. The results have implications for DBS target selection, particularly for those patients with oromotor dysfunctions.


[Differences in the success rates of inpatient therapy for alcohol and illegal drug abusers. A Replication Study].
Irrespective of the type of psychotherapy used, the abstinence-oriented treatment of drug abusers is less successful than that for alcohol abusers. If, on the other hand, the two groups are parallelized in such a way that the patients are identical with respect to the five characteristics of gender, age, schooling, work situation and partner situation, then there is no difference between the success rates of the drug and alcohol abusers. The aim of this study is to determine whether this result can be replicated in another therapeutic institution. Retrospective field study of 320 abusers of illegal drugs and 320 alcohol abusers who were treated with behaviour therapy. By combining the binary characteristics gender, work situation and age, the drug-dependent patients were divided into 23=8 groups, and the same number of alcohol abusers were randomly selected for each group. The scheduled period of inpatient treatment was 90 days for the alcohol abusers and 120 days for the drug abusers. Every week the patients had one session of individual psychotherapy and four to five group therapy sessions. According to the indications, the certified behaviour therapists implemented the following interventions including behaviour analysis, relapse prevention, cognitive therapy, self-management and behavioural family therapy. Comparison of the success rates was carried out using the Chi2 test, and changes in the psychological findings were tested with one-way variance analysis. There was no difference between drug and alcohol abusers with respect to the rate of therapy termination according to plan (around 80%). A total of 48% of the drug abusers and 41 % of the alcohol abusers who could be followed up had been continuously abstinent at the one-year catamnesis without a single relapse. There were also no differences between the two groups when it was assumed that the patients who could not be followed up had relapsed. In the case of both the drug and alcohol abusers the abstinence rate was highest in over-29-year-old employed men (57.6%; 48.4%). The abstinence rate was lowest in employed female drug abusers (27.8%) and young, unemployed female drug abusers (0%, n=11). What appears to influence the abstinence rate after inpatient treatment is not only the type of substance consumed but also sociodemographic characteristics. In addition to individually tailored therapy, our results confirm the importance of a highly differentiated presentation of the outcomes of therapy in the specialist literature. An average rate of abstinence (e.g. 30%) is insufficient to evaluate an intervention unless information is also provided about the patients for which the intervention is suitable and those for which it is not. In accordance with the Reproducibility Project, we consider replication studies essential in psychotherapy, even though in practice the considerable methodical requirements can only be partially fulfilled.


SUGAR: graphical user interface-based data refiner for high-throughput DNA sequencing.
Next-generation sequencers (NGSs) have become one of the main tools for current biology. To obtain useful insights from the NGS data, it is essential to control low-quality portions of the data affected by technical errors such as air bubbles in sequencing fluidics. We develop a software SUGAR (subtile-based GUI-assisted refiner) which can handle ultra-high-throughput data with user-friendly graphical user interface (GUI) and interactive analysis capability. The SUGAR generates high-resolution quality heatmaps of the flowcell, enabling users to find possible signals of technical errors during the sequencing. The sequencing data generated from the error-affected regions of a flowcell can be selectively removed by automated analysis or GUI-assisted operations implemented in the SUGAR. The automated data-cleaning function based on sequence read quality (Phred) scores was applied to a public whole human genome sequencing data and we proved the overall mapping quality was improved. The detailed data evaluation and cleaning enabled by SUGAR would reduce technical problems in sequence read mapping, improving subsequent variant analysis that require high-quality sequence data and mapping results. Therefore, the software will be especially useful to control the quality of variant calls to the low population cells, e.g., cancers, in a sample with technical errors of sequencing procedures.


A study of the mechanism by which some amphiphilic drugs affect human erythrocyte acetylcholinesterase activity.
The effects of the local anaesthetics procaine, tetracaine and lidocaine and of the antidepressant imipramine on human erythrocyte acetylcholinesterase were investigated. All four amphiphilic drugs inhibited enzymic activity, the IC50 (the concentration causing 50% inhibition) being about 0.40 mM for procaine, 0.05 mM for tetracaine, 0.70 mM for imipramine and 7.0 mM for lidocaine. Procaine and tetracaine inhibited acetylcholinesterase activity competitively at concentrations at which they did not perturb the physical state of the membrane lipid environment, as assessed by steady-state fluorescence polarization, whereas lidocaine and imipramine displayed mixed inhibition kinetics at concentrations at which they induced an enhancement of membrane fluidity. The question was addressed as to whether membrane integrity is a prerequisite for imipramine and lidocaine action. Membrane solubilization by 1% Triton X-100 and a decrease, by dilution, in the detergent concentration to 0.05% [which is above the Triton X-100 critical micelle concentration (c.m.c.)] did not substantially affect the inhibitory potency of the two amphiphilic drugs at their IC50; in the presence of increasing detergent concentrations the inhibitory potency of imipramine was gradually decreased, but not abolished, whereas the inhibitory effect of lidocaine was only slightly diminished, even at 1% Triton X-100. It is suggested that neither competitive nor mixed inhibition kinetics arise from conformational changes of the protein driven by a modification of the physical state of the lipid environment, but from a direct interaction of the amphiphilic drugs with acetylcholinesterase. In particular, the partial loss of the inhibitory potency of imipramine and lidocaine that is observed upon increasing Triton X-100 concentration well above its c.m.c. could be explained in terms of amphiphile partition in detergent micelles and, in turn, of a decreased effective concentration of the two inhibitors in the aqueous phase.


Quantitative analysis of solid-state processes studied with isothermal microcalorimetry.
Quantitative analysis of solid-state processes from isothermal microcalorimetric data is straightforward if data for the total process have been recorded and problematic (in the more likely case) when they have not. Data are usually plotted as a function of fraction reacted (α); for calorimetric data, this requires knowledge of the total heat change (Q) upon completion of the process. Determination of Q is difficult in cases where the process is fast (initial data missing) or slow (final data missing). Here we introduce several mathematical methods that allow the direct calculation of Q by selection of data points when only partial data are present, based on analysis with the Pérez-Maqueda model. All methods in addition allow direct determination of the reaction mechanism descriptors m and n and from this the rate constant, k. The validity of the methods is tested with the use of simulated calorimetric data, and we introduce a graphical method for generating solid-state power-time data. The methods are then applied to the crystallization of indomethacin from a glass. All methods correctly recovered the total reaction enthalpy (16.6 J) and suggested that the crystallization followed an Avrami model. The rate constants for crystallization were determined to be 3.98 × 10(-6), 4.13 × 10(-6), and 3.98 × 10(-6) s(-1) with methods 1, 2, and 3, respectively.


Studies on the persistence of basic amines in the rabbit lung.
We have investigated the time-course of the pulmonary deposition of imipramine (IMIP) following a single iv injection into rabbits. A pool of IMIP and its demethylated metabolites, which exhibited considerable persistence (half-life of decay = 4 hr), was formed in the lung. This pool, now called the slowly effluxable pool (SEP), appears to be synonymous with the noneffluxable pool (NEP), which we have previously shown to be formed with IMIP in the isolated perfused lung (PL). Furthermore, this pool appears to be responsible for the pulmonary persistence of IMIP, inasmuch as 24 hr after an iv injection it contributes greater than 90% of the total lung concentration. Chlorphentermine and methadone formed SEP's in the IPL of comparable size to that formed with IMIP, whereas phentermine formed a considerably smaller SEP. These results suggest that the degree of hydrophobicity of the amine is an important determinant of the size of the SEP formed. This further supported by the lack of an SEP with the relatively polar amines, 5-hydroxytryptamine and amphetamine. The 10-fold difference in the size of the SEP for compounds known to induce pulmonary phospholipidosis (chlorphentermine and IMIP) and known not to induce lipidosis (phentermine and amphetamine) may suggest a possible involvement of the SEP in the onset of phospholipidosis; this possibility is discussed.


A human reproductive approach to the study of infertility in chimpanzees: An experience at Leon's Zoological Park, Mexico.
Great apes are mammals close to humans in their genetic, behavioral, social and evolutionary characteristics and new genomic information is revolutionizing our understanding of evolution in primates. However, all these species are endangered. While there are many global programs to protect these species, the International Union for Conservation of Nature (IUCN) projects that in a near future the wild populations will decrease significantly. Nowadays, the relevance of captive populations of great apes is becoming critical for research and understanding of pathophysiology of diseases. In this report, the evaluation of infertility in a group of captive chimpanzees maintained at Leon's Zoological Park using a human infertility protocol is described. Our results suggested that infertility in this group was due to low hormonal levels and sperm alterations in the male characterized by hormonal assessment and a sperm sample obtained by electroejaculation and cryopreserved using human protocols. In the females, it was demonstrated that it is possible to follow the follicular cycle using non-invasive methods based on morphological changes in genitalia, detection of blood in urine and measurement of hormones in saliva samples; concluding that fertility in females was normal. Also, we demonstrate that human artificial insemination procedures may be applied. Our human approach was successful in finding the infertility cause in this group of captive chimpanzees. In countries with limited resources, collaboration of zoos with human infertility clinics can be beneficial for research and management of reproductive aspects of great apes.