Rapid Eye Movement Sleep, Sleep Continuity and Slow Wave Sleep as Predictors of Cognition, Mood, and Subjective Sleep Quality in Healthy Men and Women, Aged 20-84 Years.
Sleep and its sub-states are assumed to be important for brain function across the lifespan but which aspects of sleep associate with various aspects of cognition, mood and self-reported sleep quality has not yet been established in detail. Sleep was quantified by polysomnography, quantitative Electroencephalogram (EEG) analysis and self-report in 206 healthy men and women, aged 20-84 years, without sleep complaints. Waking brain function was quantified by five assessments scheduled across the day covering objectively assessed performance across cognitive domains including sustained attention and arousal, decision and response time, motor and sequence control, working memory, and executive function as well as self-reports of alertness, mood and affect. Controlled for age and sex, self-reported sleep quality was negatively associated with number of awakenings and positively associated with the duration of Rapid Eye Movement (REM) sleep, but no significant associations with Slow Wave Sleep (SWS) measures were observed. Controlling only for age showed that associations between objective and subjective sleep quality were much stronger in women than in men. Analysis of 51 performance measures demonstrated that, after controlling for age and sex, fewer awakenings and more REM sleep were associated significantly with better performance on the Goal Neglect task, which is a test of executive function. Factor analysis of the individual performance measures identified four latent variables labeled Mood/Arousal, Response Time, Accuracy, and Visual Perceptual Sensitivity. Whereas Mood/Arousal improved with age, Response Times became slower, while Accuracy and Visual perceptual sensitivity showed little change with age. After controlling for sex and age, nominally significant association between sleep and factor scores were observed such that Response Times were faster with more SWS, and Accuracy was reduced where individuals woke more often or had less REM sleep. These data identify a positive contribution of SWS to processing speed and in particular highlight the importance of sleep continuity and REM sleep for subjective sleep quality and performance accuracy across the adult lifespan. These findings warrant further investigation of the contribution of sleep continuity and REM sleep to brain function.


Acquired Tracheoesophageal Fistula After Esophageal Atresia Repair
Recurrence of tracheoesophageal fistula is a frequent complication after esophageal atresia repair. Acquired tracheoesophageal fistulas are long new fistulas that are localized at sites that are not typical of the congenital tracheoesophageal fistula. We present four cases to discuss the diagnostic and management challenges concerning various acquired tracheoesophageal fistula localizations. We retrospectively evaluated the medical records of patients admitted with acquired tracheoesophageal fistula in the last 5 years. Among the 16 postoperative tracheoesophageal fistulas, 4 were classified as acquired tracheoesophageal fistula. Patients' admission age ranged from 1 to 8 years. The female to male ratio was 2:2. The presented cases were admitted with recurrent respiratory tract infections, choking, and coughing. The acquired tracheoesophageal fistulas were observed between the esophagus and cervical trachea, between the esophagus and the right bronchus passing through intrathoracic abscess cavity, in the right bronchus, and between the colon conduit and trachea. One of the acquired tracheoesophageal fistulas healed spontaneously, whereas others required surgical ligation. Acquired tracheoesophageal fistula most often occurs secondary to local or diffuse mediastinitis. Acquired tracheoesophageal fistula may appear at unusual sites not typical of congenital tracheoesophageal fistula, such as esophagus-to-right bronchus and conduit to trachea. Therefore, the unusual locations of acquired tracheoesophageal fistula should be borne in mind, and patients evaluated and managed more comprehensively.


Serological Profiling for Malaria Surveillance Using a Standard ELISA Protocol.
The enzyme-linked immunosorbent assay (ELISA) is a reliable and relatively low-cost method for measuring soluble ligands such as antibodies and proteins in biological samples. For analysis of specific antibodies in serum, a capture antigen is immobilized onto a solid polystyrene surface from which it can capture the antibodies. The captured antibodies are subsequently detected using a secondary antibody conjugated to an enzyme. Detection is accomplished by addition of a colorimetric substrate, and the readout is absorbance (optical density). Here, we provide a detailed standardized ELISA protocol for the quantification of antibodies against malaria antigens.


Rapid transition from inhaled iloprost to inhaled treprostinil in patients with pulmonary arterial hypertension.
Inhaled treprostinil is a prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) that may provide a more convenient treatment option for patients receiving inhaled iloprost while maintaining the clinical benefit of inhaled prostacyclin therapy. In this open-label safety study, 73 PAH patients were enrolled with primarily World Health Organization Class II (56%) or III (42%) symptoms. At baseline, most patients (93%) were receiving 5 μg of iloprost per dose but 38% of patients reported a dosing frequency below the labeled rate of 6-9 times daily. Patients initiated inhaled treprostinil at 3 breaths four times daily (qid) at the immediate next scheduled iloprost dose. The primary objective was to assess the safety of rapid transition from iloprost to inhaled treprostinil; clinical status and quality of life were also assessed. Most patients (84%) achieved the target treprostinil dose of 9 breaths qid and remained on study until transition to commercial therapy (89%). The most frequent adverse events (AEs) were cough (74%), headache (44%), and nausea (30%), and five patients prematurely discontinued study drug due to AE (n = 3), disease progression (n = 1), or death (n = 1). At week 12, the time spent on daily treatment activities was reduced compared to baseline, with a mean total savings of 1.4 h per day. Improvements were also observed at week 12 for 6-min walk distance (+16.0; P < 0.001), N-terminal pro-B-type natriuretic peptide (-74 pg/mL; P = 0.001), and the Cambridge Pulmonary Hypertension Outcome Review (all domains P < 0.001). Pulmonary arterial hypertension patients can be safely transitioned from inhaled iloprost to inhaled treprostinil while maintaining clinical status.


Evaluation of the false recent classification rates of multiassay algorithms in estimating HIV type 1 subtype C incidence.
Laboratory cross-sectional assays are useful for the estimation of HIV incidence, but are known to misclassify individuals with long-standing infection as recently infected. The false recent rate (FRR) varies widely across geographic areas; therefore, accurate estimates of HIV incidence require a locally defined FRR. We determined FRR for Botswana, where HIV-1 subtype C infection is predominant, using the BED capture enzyme immunoassay (BED), a Bio-Rad Avidity Index (BAI) assay (a modification of the Bio-Rad HIV1/2+O EIA), and two multiassay algorithms (MAA) that included clinical data. To estimate FRR, stored blood samples from 512 antiretroviral (ARV)-naive HIV-1 subtype C-infected individuals from a prospective cohort in Botswana were tested at 18-24 months postenrollment. The following FRR mean (95% CI) values were obtained: BED 6.05% (4.15-8.48), BAI 5.57% (3.70-8.0), BED-BAI 2.25% (1.13-4.0), and a combination of BED-BAI with CD4 (>200) and viral load (>400) threshold 1.43% (0.58-2.93). The interassay agreement between BED and BAI was 92.8% (95% CI, 90.1-94.5) for recent/long-term classification. Misclassification was associated with viral suppression for BED [adjusted OR (aOR) 10.31; p=0.008], BAI [aOR 9.72; p=0.019], and MAA1 [aOR 16.6; p=0.006]. Employing MAA can reduce FRR to <2%. A local FRR can improve cross-sectional HIV incidence estimates.


Chronic growth faltering amongst a birth cohort of Indian children begins prior to weaning and is highly prevalent at three years of age.
Poor growth of children in developing countries is a major public health problem associated with mortality, morbidity and developmental delay. We describe growth up to three years of age and investigate factors related to stunting (low height-for-age) at three years of age in a birth cohort from an urban slum. 452 children born between March 2002 and August 2003 were followed until their third birthday in three neighbouring slums in Vellore, South India. Field workers visited homes to collect details of morbidity twice a week. Height and weight were measured monthly from one month of age in a study-run clinic. For analysis, standardised z-scores were generated using the 2006 WHO child growth standards. Risk factors for stunting at three years of age were analysed in logistic regression models. A sensitivity analysis was conducted to examine the effect of missing values. At age three years, of 186 boys and 187 girls still under follow-up, 109 (66%, 95% Confidence interval 58-73%) boys and 93 (56%, 95% CI 49-64%) girls were stunted, 14 (8%, 95% CI 4-13%) boys and 12 (7%, 95% CI 3-11%) girls were wasted (low weight-for-height) and 72 (43%, 95% CI 36-51) boys and 66 (39%, 95% CI 31-47%) girls were underweight (low weight-for-age). In total 224/331 (68%) children at three years had at least one growth deficiency (were stunted and/or underweight and/or wasted); even as early as one month of age 186/377 (49%) children had at least one growth deficiency. Factors associated with stunting at three years were birth weight less than 2.5 kg (OR 3.63, 95% CI 1.36-9.70) 'beedi-making' (manual production of cigarettes for a daily wage) in the household (OR 1.74, 95% CI 1.05-2.86), maternal height less than 150 cm (OR 2.02, 95% CI 1.12-3.62), being stunted, wasted or underweight at six months of age (OR 1.75, 95% CI 1.05-2.93) and having at least one older sibling (OR 2.00, 95% CI 1.14-3.51). A high proportion of urban slum dwelling children had poor growth throughout the first three years of life. Interventions are needed urgently during pregnancy, early breastfeeding and weaning in this population.


Improvement/rehabilitation of memory functioning with neurotherapy/QEEG biofeedback.
This article presents a new approach to the remediation of memory deficits by studying the electrophysiological functioning involved in memory and applying biofeedback techniques. A Quantitative EEG (QEEG) activation database was obtained with 59 right-handed subjects during two auditory memory tasks (prose passages and word lists). Memory performance was correlated with the QEEG variables. Clinical cases were administered the same QEEG activation study to determine their deviations from the values that predicted success for the reference group. EEG biofeedback interventions were designed to increase the value (to normal levels) of the specific electrophysiological variable that was related to successful memory function and deviant in the subject. Case examples are presented that indicate the successful use of this intervention style in normal subjects and in subjects with brain injury; improvement cannot be fully explained by spontaneous recovery, given the time postinjury. Five cases (two normal, two subjects with brain injury, and one subject who had stereotactic surgery of the hippocampus for seizure control) are presented. Improvements ranged from 68% to 181% in the group of patients with brain injury, as a result of the interventions.


Recovery and identification of bacterial DNA from illicit drugs.
Bacterial infections, including Bacillus anthracis (anthrax), are a common risk associated with illicit drug use, particularly among injecting drug users. There is, therefore, an urgent need to survey illicit drugs used for injection for the presence of bacteria and provide valuable information to health and forensic authorities. The objectives of this study were to develop a method for the extraction of bacterial DNA from illicit drugs and conduct a metagenomic survey of heroin and methamphetamine seized in the Australian Capital Territory during 2002-2011 for the presence of pathogens. Trends or patterns in drug contamination and their health implications for injecting drug users were also investigated. Methods based on the ChargeSwitch(®)gDNA mini kit (Invitrogen), QIAamp DNA extraction mini kit (QIAGEN) with and without bead-beating, and an organic phenol/chloroform extraction with ethanol precipitation were assessed for the recovery efficiency of both free and cellular bacterial DNA. Bacteria were identified using polymerase chain reaction and electrospray ionization-mass spectrometry (PCR/ESI-MS). An isopropanol pre-wash to remove traces of the drug and diluents, followed by a modified ChargeSwitch(®) method, was found to efficiently lyse cells and extract free and cellular DNA from Gram-positive and Gram-negative bacteria in heroin and methamphetamine which could then be identified by PCR/ESI-MS. Analysis of 12 heroin samples revealed the presence of DNA from species of Comamonas, Weissella, Bacillus, Streptococcus and Arthrobacter. No organisms were detected in the nine methamphetamine samples analysed. This study develops a method to extract and identify Gram-positive and Gram-negative bacteria from illicit drugs and demonstrates the presence of a range of bacterial pathogens in seized drug samples. These results will prove valuable for future work investigating trends or patterns in drug contamination and their health implications for injecting drug users as well as enabling forensic links between seizures to be examined.


Propensity for biofilm formation by clinical isolates from urinary tract infections: developing a multifactorial predictive model to improve antibiotherapy.
A group of biofilm-producing bacteria isolated from patients with urinary tract infections was evaluated, identifying the main factors contributing to biofilm formation. Among the 156 isolates, 58 (37.2%) were biofilm producers. The bacterial species (P<0.001), together with patient's gender (P = 0.022), were the factors with the highest influence for biofilm production. There was also a strong correlation of catheterization with biofilm formation, despite being less significant (P = 0.070) than species or gender. In fact, some of the bacteria isolated were biofilm producers in all cases. With regard to resistance profile among bacterial isolates, β-lactam antibiotics presented the highest number of cases/percentages--ampicillin (32/55.2%), cephalothin (30/51.7%), amoxicillin/clavulanic acid (22/37.9%)--although the carbapenem group still represented a good therapeutic option (2/3.4%). Quinolones (nucleic acid synthesis inhibitors) also showed high resistance percentages. Furthermore, biofilm production clearly increases bacterial resistance. Almost half of the biofilm-producing bacteria showed resistance against at least three different groups of antibiotics. Bacterial resistance is often associated with catheterization. Accordingly, intrinsic (age and gender) and extrinsic (hospital unit, bacterial isolate and catheterization) factors were used to build a predictive model, by evaluating the contribution of each factor to biofilm production. In this way, it is possible to anticipate biofilm occurrence immediately after bacterial identification, allowing selection of a more effective antibiotic (among the susceptibility options suggested by the antibiogram) against biofilm-producing bacteria. This approach reduces the putative bacterial resistance during treatment, and the consequent need to adjust antibiotherapy.


5-ALA fluorescence for intraoperative visualization of spinal ependymal tumors and identification of unexpected residual tumor tissue: experience in 31 patients.
Gross-total resection (GTR) is the treatment of choice in the majority of patients suffering from spinal ependymal tumors. In such tumors, the extent of resection (EOR) is considered the key factor for tumor recurrence and thus patient prognosis. However, incomplete resection is not uncommon and leads to increased risk of tumor recurrence. One important cause of incomplete resection is insufficient intraoperative visualization of tumor tissue as well as residual tumor tissue. Therefore, the authors investigated the value of 5-aminolevulinic acid (5-ALA)-induced fluorescence in a series of spinal ependymal tumors for improved tumor visualization. Adult patients who underwent preoperative 5-ALA administration and surgery for a spinal ependymal tumor were included in this study. For each tumor, a conventional white-light microsurgical resection was performed. Additionally, the fluorescence status (strong, vague, or no fluorescence) and fluorescence homogeneity (homogenous or inhomogeneous) of the spinal ependymal tumors were evaluated during surgery using a modified neurosurgical microscope. In intramedullary tumor cases with assumed GTR, the resection cavity was investigated for potential residual fluorescing foci under white-light microscopy. In cases with residual fluorescing foci, these areas were safely resected and the corresponding samples were histopathologically screened for the presence of tumor tissue. In total, 31 spinal ependymal tumors, including 27 intramedullary tumors and 4 intradural extramedullary tumors, were included in this study. Visible fluorescence was observed in the majority of spinal ependymal tumors (n = 25, 81%). Of those, strong fluorescence was noted in 23 of these cases (92%), whereas vague fluorescence was present in 2 cases (8%). In contrast, no fluorescence was observed in the remaining 6 tumors (19%). Most ependymal tumors demonstrated an inhomogeneous fluorescence effect (17 of 25 cases, 68%). After assumed GTR in intramedullary tumors (n = 15), unexpected residual fluorescing foci within the resection cavity could be detected in 5 tumors (33%). These residual fluorescing foci histopathologically corresponded to residual tumor tissue in all cases. This study indicates that 5-ALA fluorescence makes it possible to visualize the majority of spinal ependymal tumors during surgery. Unexpected residual tumor tissue could be detected with the assistance of 5-ALA fluorescence in approximately one-third of analyzed intramedullary tumors. Thus, 5-ALA fluorescence might be useful to increase the EOR, particularly in intramedullary ependymal tumors, in order to reduce the risk of tumor recurrence.


Distribution and population structure in the naked goby Gobiosoma bosc (Perciformes: Gobiidae) along a salinity gradient in two western Atlantic estuaries.
Many species of fish produce larvae that undergo a prolonged dispersal phase. However, evidence from a number of recent studies on demersal fishes suggests that the dispersal of propagules may not be strongly correlated with gene flow. Instead, other factors like larval behavior and the availability of preferred settlement habitat may be more important to maintaining population structure. We used an ecologically important benthic fish species, Gobiosoma bosc (naked goby), to investigate local and regional scale population structure and gene flow along a salinity gradient (∼3 ppt to ∼18 ppt) in two North Carolina estuaries. G. bosc is an abundant and geographically widespread species that requires complex but patchy microhabitat (e.g. oyster reefs, rubble, woody debris) for reproduction and refuge. We sequenced 155 fish from 10 sites, using a common barcoding gene (COI). We also included recent sequence data from GenBank to determine how North Carolina populations fit into the larger biogeographic understanding of this species. In North Carolina, we found a significant amount of gene flow within and between estuaries. Our analysis also showed high predicted genetic diversity based upon a large number of rare haplotypes found within many of our sampled populations. Moreover, we detected a number of new haplotypes in North Carolina that had not yet been observed in prior work. Sampling along a salinity gradient did not reveal any significant positive or negative correlations between salinity and genetic diversity, nor the proportion of singleton haplotypes, with the exception of a positive correlation between salinity standard deviation and genetic diversity. We also found evidence that an introduced European population of naked gobies may have originated from an Atlantic source population. Altogether, this system offers a compelling way to evaluate whether factors other than dispersal per se mediate recruitment in an estuarine-dependent species of fish with a larval dispersal phase. It also demonstrates the importance of exploring both smaller and larger scale population structure in marine organisms to better understand local and regional patterns of population connectivity and gene flow.


Evaluation of the effects of exposure to organic solvents and hazardous noise among US Air Force Reserve personnel.
Hearing loss affects many workers including those in the military and may be caused by noise, medications, and chemicals. Exposures to some chemicals may lead to an increase in the incidence of hearing loss when combined with hazardous noise. This retrospective study evaluated the risk for hearing loss among Air Force Reserve personnel exposed to occupational noise with and without exposures to toluene, styrene, xylene, benzene, and JP-8 (jet fuel). Risk factors associated with hearing loss were determined using logistic and linear regression. Stratified analysis was used to evaluate potential interaction between solvent and noise exposure. The majority of the subjects were male (94.6%) and 35 years or older on the date of their first study audiogram (66%). Followed for an average of 3.2 years, 9.2% of the study subjects had hearing loss in at least one ear. Increasing age (odds ratio [OR] = 1.03 per year of age) and each year of follow-up time (OR = 1.23) were significantly associated with hearing loss. Low and moderate solvent exposures were not associated with hearing loss. Linear regression demonstrated that hearing loss was significantly associated with age at first study audiogram, length of follow-up time, and exposure to noise. Hearing decreased by 0.04 decibels for every decibel increase in noise level or by almost half a decibel (0.4 dB) for every 10 decibel increase in noise level.


Hedgehog Signaling in Malignant Pleural Mesothelioma.
Malignant pleural mesothelioma (MPM) is a cancer associated with exposure to asbestos fibers, which accumulate in the pleural space, damage tissue and stimulate regeneration. Hedgehog signaling is a pathway important during embryonic mesothelium development and is inactivated in adult mesothelium. The pathway is reactivated in some MPM patients with poor clinical outcome, mainly mediated by the expression of the ligands. Nevertheless, mutations in components of the pathway have been observed in a few cases. Data from different MPM animal models and primary culture suggest that both autocrine and paracrine Hedgehog signaling are important to maintain tumor growth. Drugs inhibiting the pathway at the level of the smoothened receptor (Smo) or glioma-associated protein transcription factors (Gli) have been used mostly in experimental models. For clinical development, biomarkers are necessary for the selection of patients who can benefit from Hedgehog signaling inhibition.


Repeatability and timing of tropical influenza epidemics.
Much of the world experiences influenza in yearly recurring seasons, particularly in temperate areas. These patterns can be considered repeatable if they occur predictably and consistently at the same time of year. In tropical areas, including southeast Asia, timing of influenza epidemics is less consistent, leading to a lack of consensus regarding whether influenza is repeatable. This study aimed to assess repeatability of influenza in Vietnam, with repeatability defined as seasonality that occurs at a consistent time of year with low variation. We developed a mathematical model incorporating parameters to represent periods of increased transmission and then fitted the model to data collected from sentinel hospitals throughout Vietnam as well as four temperate locations. We fitted the model for individual (sub)types of influenza as well as all combined influenza throughout northern, central, and southern Vietnam. Repeatability was evaluated through the variance of the timings of peak transmission. Model fits from Vietnam show high variance (sd = 64-179 days) in peak transmission timing, with peaks occurring at irregular intervals and throughout different times of year. Fits from temperate locations showed regular, annual epidemics in winter months, with low variance in peak timings (sd = 32-57 days). This suggests that influenza patterns are not repeatable or seasonal in Vietnam. Influenza prevention in Vietnam therefore cannot rely on anticipation of regularly occurring outbreaks.


Scaling up of facility-based neonatal care: a district health system experience.
With proportion of neonatal mortality increasing within under-five deaths, innovative approaches and stronger health systems are needed in neonatal care. We present data of a scaled-up neonatal facility in a District Government Headquarters hospital in Southern India. The special care neonatal unit (SCNU) was a community propelled, public private partnership worked out on the principles of private funding of public institutions and effective budgeting of the public health care system. In the first phase the unit was optimized over 3 years with non-governmental organizations (NGO) and government support from a basic nursery to a SCNU. The unit was operational through fixed maintenance budget from government and mobilized funds from NGOs and beneficiaries. Community health workers were motivated for effective utilization. In the second phase the unit's performance was studied and statistically analyzed in two time frames before and 5 years into the upgradation process. Neonatal admissions from the district increased by 14.65%. Hospital stillbirth, early neonatal and perinatal mortality rates showed significant decline (p < 0.05). There was a 48.59% (CI: 25.46-77.80) increase in antenatal referrals from community health centers. Caesarian sections for neonatal parameters that affect obstetric decisions showed percent changes of 163.25 (CI: 31.18-430.45) and 73.4 (CI: 14.15-164.39) for prematurity and low birth weight (LBW), respectively. Significant decline in case fatality rates for LBW, sepsis and birth asphyxia (p < 0.001) were observed. The district perinatal mortality rate showed a decline. Within the purview of financial constraints of the public health system, private funding, public-private cooperation and effective budgeting may become significant. Motivation of health workers and community to effectively utilize public health care services sets an evolutionary process of referral and vertical linkage of health care system.


Discovery of Novel Haloalkane Dehalogenase Inhibitors.
Haloalkane dehalogenases (HLDs) have recently been discovered in a number of bacteria, including symbionts and pathogens of both plants and humans. However, the biological roles of HLDs in these organisms are unclear. The development of efficient HLD inhibitors serving as molecular probes to explore their function would represent an important step toward a better understanding of these interesting enzymes. Here we report the identification of inhibitors for this enzyme family using two different approaches. The first builds on the structures of the enzymes' known substrates and led to the discovery of less potent nonspecific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of an HLD from the human pathogen Mycobacterium tuberculosis H37Rv. The best inhibitor exhibited high specificity for the target structure, with an inhibition constant of 3 μM and a molecular architecture that clearly differs from those of all known HLD substrates. The new inhibitors will be used to study the natural functions of HLDs in bacteria, to probe their mechanisms, and to achieve their stabilization.


Rational design of a live attenuated dengue vaccine: 2'-o-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques.
Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A cost-effective, safe vaccine conferring protection with ideally a single injection could stop dengue transmission. Current vaccine candidates require several booster injections or do not provide protection against all four serotypes. Here we demonstrate that dengue virus mutants lacking 2'-O-methyltransferase activity are highly sensitive to type I IFN inhibition. The mutant viruses are attenuated in mice and rhesus monkeys and elicit a strong adaptive immune response. Monkeys immunized with a single dose of 2'-O-methyltransferase mutant virus showed 100% sero-conversion even when a dose as low as 1,000 plaque forming units was administrated. Animals were fully protected against a homologous challenge. Furthermore, mosquitoes feeding on blood containing the mutant virus were not infected, whereas those feeding on blood containing wild-type virus were infected and thus able to transmit it. These results show the potential of 2'-O-methyltransferase mutant virus as a safe, rationally designed dengue vaccine that restrains itself due to the increased susceptibility to the host's innate immune response.


Spontaneous redistribution of surface immunoglobulin in the motile B lymphocyte.
This paper reports that B cells undergoing translatory motion spontaneously segregate their surface Ig to one portion of their plasma membrane. The spontaneous redistribution of surface Ig was found to be: (a) selective, concanavalin A-dependent on translatory motion and energy metabolism. Abundant B cells undergoing motility were found after cultures in lipopolysaccharide or trypsin, or after brief exposure to cholinergic drugs.


Prevalence of antibodies to Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma hominis in infertile women.
A total of 57 infertile women, who had been referred for in vitro fertilisation or for diagnostic laparoscopy, were tested for the presence of antibodies to Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma hominis. Four were excluded from the study. Of the remaining 53, 33 had laparoscopically obvious tubal disorders, such as adhesions, distal occlusions and strictures, and 20 did not. Antibodies to C trachomatis were found in 7/33 (21.2%) v 0/20, antibodies to N gonorrhoeae in 20/38 (60.6%) v 5/20 (25%), and antibodies to M hominis in 18/24 (75%) women with tubal disorders v 13/19 (68.4%) of those with no disorder. Antibodies to C trachomatis and N gonorrhoeae were significantly (p less than 0.05) more common in women with tubal disorders. The high prevalence of antibodies to N gonorrhoeae in infertile women without tubal disorders suggests that ciliated tubal epithelium is damaged after inflammation without this being laparoscopically visible. Our results confirm the important role of N gonorrhoeae and C trachomatis in the aetiology of infertility after tubal inflammation.


Excitation of capillary waves in strongly absorbing liquids by a modulated laser beam.
Several mechanisms for the excitation of capillary waves and for the development of the average deformation of a liquid surface under the action of a modulated laser beam are considered. The amplitude of the capillary wave in a strongly absorbing solution of the dye LDS 751 in ethylene glycol is experimentally studied as a function of laser intensity. Consecutive changes in the predominant mechanism of the excitation with increasing laser intensity are observed and described. At low laser intensities the mechanism connected with the creation of a surface tension gradient prevails. This mechanism becomes nonlinear with increasing influence of the convective motion. In addition, pressure pulsations of the convective flow start to contribute significantly to the generation process. The resonances of capillary waves in a cylindrical container are also investigated and used for determining the surface tension and viscosity of the liquid.


A randomized controlled trial of stage-matched intervention for smoking cessation in cardiac out-patients.
To examine the effectiveness of a stage-matched smoking cessation counselling intervention for smokers who had cardiac diseases. A total of 1860 Chinese cardiac patients who smoked at least one cigarette in the past 7 days and aged 18 years or above recruited from cardiac out-patient clinics in Hong Kong hospitals were allocated randomly to an intervention group or control group. The intervention group (n = 938) received counselling matched with their stage of readiness to quit by trained counsellors at baseline, 1 week and 1 month. The control group (n = 922) received brief counselling on healthy diet at baseline. The primary outcomes were self-reported 7-day and 30-day point prevalence (PP) of tobacco abstinence at 12 months after baseline. The secondary outcome measures included biochemically validated abstinence at 12-month follow-up, self-reported 7-day and 30-day PP abstinence and reduction of cigarette consumption by 50% at 3 and 6 months. By intention-to-treat analysis, the intervention and control groups showed no significant difference in self-reported 7-day PP abstinence (intervention: 26.5% versus control: 25.5%; P = 0.60) and 30-day PP (intervention: 25.4% versus control: 24.2%; P = 0.55), biochemically validated abstinence (intervention: 6.6% versus control: 4.9%; P = 0.14) and overall quit attempts of least 24 hours (intervention: 40.3% versus control: 34.3%; P = 0.007) at the 12-month follow-up, adjusted for the baseline stage of readiness to quit smoking. An intervention, based on the Stages of Change model, to promote smoking cessation in cardiac patients in China failed to find any long-term benefit.


Cdx2 polymorphism affects the activities of vitamin D receptor in human breast cancer cell lines and human breast carcinomas.
Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D) and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative). These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression.


α- and β-crystallins modulate the head group order of human lens membranes during aging.
To examine the physical properties of human lens cell membranes as a function of age. The environment of the phospholipid head groups in fiber cell membranes from human lenses, aged 22 to 83 years, was assessed with Laurdan and two-photon confocal microscopy. The effect of mild thermal stress on head group order was studied with lens pairs in which one intact lens was incubated at 50 °C. Dihydrosphingomyelin vesicles were preloaded with Laurdan, α-, β-, or γ-crystallin was added, and surface fluidity was determined. The membrane head group environment became more fluid with age as indicated by increased water penetration. Furthermore, these changes could be replicated simply by exposing intact human lenses to mild thermal stress; conditions which decreased the concentration of soluble α- and β-crystallins. Vesicle binding experiments showed that α- and β-, but not γ-, crystallins markedly affected head group order. The physical properties of cell membranes in the lens nucleus change substantially with age, and α- and β-crystallins may modulate this effect. β-Crystallins may therefore play a role in lens cells, and cells of other tissues, apart from being simple structural proteins. Age-dependent loss of these crystallins may affect membrane integrity and contribute to the dysfunction of lenses in older people.


Modulating influence of cytochrome P-450 MspI polymorphism on serum liver function profiles in coke oven workers.
It was reported previously that topside oven workers with heavy exposure to coke oven emissions had increased serum activities of hepatic aminotransferase in one coke oven plant. This study was conducted to investigate the modifying effect of CYP1A1 MspI polymorphism on liver function profiles in coke oven workers. 88 coke oven workers from a large steel company in Taiwan were studied in 1995-6. Exposure was categorised by work area: topside oven workers and sideoven workers. Liver function profiles including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), r-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and total bilirubin (BIL) were examined in the morning after personal exposure measurements. The MspI polymorphism was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Five of 23 (22%) topside oven workers and seven of 65 (11%) sideoven workers had the CYP1A1 MspI homozygous variant genotype. With sideoven workers with the combined wild type and heterozygous variant as the reference group in multiple regression models, it was found that topside oven workers with the combined traits had mean AST and ALT activities that were 21% and 46% higher (95% confidence interval (95% CI) 4% to 42% and 12% to 91%, respectively) than the reference group after adjusting for appropriate confounders. Also, topside oven workers with the homozygous variant trait had mean AST, ALT, and GGT activities that were 59%, 68%, and 157% higher (95% CI 21% to 109%, 6% to 168%, and 39% to 374%, respectively) than the reference group. The prevalence of an abnormal hepatocellular pattern (AST > 37 IU/l or ALT > 39 IU/l) was more common in the topside oven workers with the homozygous variant than in the sideoven workers with the other combined genotypes (adjusted odds ratio 9.9, 95% CI 1.2 to 82.3) after adjusting for appropriate confounders. The CYP1A1 MspI polymorphism may modify the biotransformation of coke oven emissions, which results in hepatocellular damage in coke oven workers.


Histone deacetylase 1 contributes to cell cycle and apoptosis.
Histone deacetylases (HDACs) are generally thought to play important roles in human disease. However, little information is available concerning the specific functions of individual HDACs. We previously reported on transgenic mice that expressed human HDAC1 and experienced steatosis and nuclear pleomorphism in their hepatic tissues. To find out if the over-expression of HDAC1 contributes to the expression of genes related to the cell cycle, apoptosis, and lipid metabolism that eventually contribute to the pathological changes in the livers of the transgenic mice, the expression profiles of the related genes in liver tissues were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The activated human HDAC1 significantly induced the expression levels of mRNA for p53, PPAR-gamma and Bak and reduced the p21 expression level compared with the levels in control littermates. However, the protein levels of p53 and PPAR-gamma were significantly decreased. In conclusion, our results indicate that HDAC1 can regulate gene expression at the mRNA and protein levels independently and that this may be a potential cytopathic factor for hepatic tissue in transgenic mice that over-express HDAC1.


Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance.
The risk of delayed autoimmunity occurring months or years after discontinuation of immunotherapy is frequently asserted in the literature. However, specific cases were rarely described until 2018, when a wave of reports surfaced. With expanding I-O indications in the adjuvant/neoadjuvant curative setting, growing numbers of patients will receive limited courses of immunotherapy before entering routine surveillance. In this context, under-recognition of DIRE could pose a growing clinical hazard. The aim of this study was to characterize DIRE through identification of existing reports of delayed post-treatment irAE in cancer patients treated with immunotherapy. We performed a PubMed literature review from 2008 through 2018 to determine the median data safety reporting window from existing I-O clinical trials, which we then applied to define the DIRE cutoff, and collated all qualifying reports over the same time span. DIRE was defined as new immune-related adverse events (irAE) manifesting ≥90 days after discontinuation of immunotherapy. Median duration of I-O clinical trials data safety reporting was 90 days (82% ≤ 90 days). DIRE cutoff was thus set as ≥90 days post-immunotherapy. We identified 23 qualifying cases; 21 by literature review and 2 from our institution. Median off-treatment interval to DIRE was 6 months (range: 3 to 28). Median cumulative immunotherapy exposure was 4 doses (range: 3 to 42). Involvement included endocrine, neurologic, GI, pulmonary, cardiac, rheumatologic and dermatologic irAE. As immunotherapy indications expand into the curative setting, often with brief exposure and potentially sequenced with multimodality treatments, it will be necessary to recognize an emerging diagnostic complex, which we have termed delayed immune-related events (DIRE). Clinical vigilance has the potential to reduce morbidity from diagnostic delay, as irAE are generally manageable with prompt initiation of treatment - or from misdiagnosis - as misattribution can lead to unnecessary or harmful interventions as we describe. DIRE should therefore figure prominently in the differential diagnosis of patients presenting with illnesses of unclear etiology, irrespective of intervening treatments or interval post-immunotherapy, both of which can confound diagnosis. Increased recognition will rest on delineation of DIRE as a clinical diagnostic entity.


Pneumococcal meningitis in Jamaican children.
To describe the clinical features and outcome of pneumococcal meningitis in Jamaican children. All patients admitted to the Bustamante Hospital for Children, during the period 1995-1999, who had pneumococcus isolated from cerebrospinal fluid (CSF) or pleocytosis in association with a blood culture isolate of pneumococcus were selected. Demographic, clinical and laboratory data were collected. Twenty-five (23%) of 111 patients with pneumococcal infections satisfied criteria for meningitis. The median age was 8 months (range 0.5-60 months). There were 4 (16%) cases of sickle cell disease, 2 (50%) of whom were first diagnosed during the current illness. This represents a 53-fold increased risk of pneumoccocal meningitis in patients with Sickle-cell disease based on population prevalence rates. Oxacillin resistance occurred in 3 (12%) patients, one of whom died. Mortality rate was 12% (3) with all deaths occurring in infants < 1 year. Poor outcome occurred in 36% (9) of the patients. Of the (35%) 8 survivors who had follow-up evaluation, (38%) 3 had documented hearing loss. Meningitis is a common clinical syndrome of invasive pneumococcal disease, occurring in 23% of cases resulting in mortality and high morbidity among Jamaican children. Local seroepidemiological studies are urgently needed to inform national vaccine decisions. As an interim plan, policymakers should consider a risk-based strategy to vaccine prophylaxis that will ensure that high risk groups such as children with sickle cell disease are offered currently available conjugate pneumococcal vaccines.


Proportion of beneficiaries and factors affecting Janani Suraksha Yojana direct cash transfer scheme in Puducherry, India.
Janani Suraksha Yojana (JSY) direct benefit transfer scheme was launched in the year 2013 in India and there is a paucity of information affecting it. The study aimed to assess the proportion of eligible beneficiaries utilizing JSY direct cash benefit transfer in Puducherry and to identify its barriers and facilitating factors. This cross sectional study was conducted from January to March 2015 among 152 eligible JSY beneficiaries residing in rural and urban field practice areas of a tertiary care institution in Puducherry, India. Data were collected using a pretested semi structured questionnaire and presented as proportion or percentages. About 144 beneficiaries participated in the study with a response rate of 94.7%. About 46% (66) of them availed cash transfer benefit. The mean time of receiving the benefit is 95.8 days (interquartile range 60-120 days). Among those who have not received (78), about 49 (62.8%) had not applied and 29 (37.18%) filled applications were rejected due to various reasons. About 77.1% (111) of beneficiaries were informed about JSY scheme through health workers. About 52.1% (75/144) still preferred direct bank transfer through the bank. The reasons for not availing benefits includes not having a bank account (24.3%), followed by not having Aadhaar number (9.7%), 11.8% had no ration card, and 13.8% stayed in their mother house. Majority of the beneficiaries did not receive direct cash transfer benefits in urban area than rural area and there is a need to simplify the procedures to improve the uptake of services to this group.


Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3.
Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis, which internalizes plasma membrane constituents such as G protein-coupled receptors (GPCRs). AP2, a heterotetramer of α, β, μ and σ subunits, links clathrin to vesicle membranes and binds to tyrosine- and dileucine-based motifs of membrane-associated cargo proteins. Here we show that missense mutations of AP2 σ subunit (AP2S1) affecting Arg15, which forms key contacts with dileucine-based motifs of CCV cargo proteins, result in familial hypocalciuric hypercalcemia type 3 (FHH3), an extracellular calcium homeostasis disorder affecting the parathyroids, kidneys and bone. We found AP2S1 mutations in >20% of cases of FHH without mutations in calcium-sensing GPCR (CASR), which cause FHH1. AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular calcium and reduced CaSR endocytosis, probably through loss of interaction with a C-terminal CaSR dileucine-based motif, whose disruption also decreased intracellular signaling. Thus, our results identify a new role for AP2 in extracellular calcium homeostasis.


A Gly-zipper motif mediates homodimerization of the transmembrane domain of the mitochondrial kinase ADCK3.
Interactions between α-helices within the hydrophobic environment of lipid bilayers are integral to the folding and function of transmembrane proteins; however, the major forces that mediate these interactions remain debated, and our ability to predict these interactions is still largely untested. We recently demonstrated that the frequent transmembrane association motif GASright, the GxxxG-containing fold of the glycophorin A dimer, is optimal for the formation of extended networks of Cα-H hydrogen bonds, supporting the hypothesis that these bonds are major contributors to association. We also found that optimization of Cα-H hydrogen bonding and interhelical packing is sufficient to computationally predict the structure of known GASright dimers at near atomic level. Here, we demonstrate that this computational method can be used to characterize the structure of a protein not previously known to dimerize, by predicting and validating the transmembrane dimer of ADCK3, a mitochondrial kinase. ADCK3 is involved in the biosynthesis of the redox active lipid, ubiquinone, and human ADCK3 mutations cause a cerebellar ataxia associated with ubiquinone deficiency, but the biochemical functions of ADCK3 remain largely undefined. Our experimental analyses show that the transmembrane helix of ADCK3 oligomerizes, with an interface based on an extended Gly-zipper motif, as predicted by our models. The data provide strong evidence for the hypothesis that optimization of Cα-H hydrogen bonding is an important factor in the association of transmembrane helices. This work also provides a structural foundation for investigating the role of transmembrane association in regulating the biological activity of ADCK3.


Straightforward protocol for the efficient synthesis of varied N(1)-acylated (aza)indole 2-/3-alkanoic acids and esters: optimization and scale-up.
A library of approximately 40 N(1)-acylated (aza)indole alkanoic esters and acids was prepared employing a microwave-assisted approach. The optimized synthetic route allows for parallel synthesis, variation of the indole substitution pattern and high overall yield. Additionally, the procedure has been scaled up to yield multi-gram amounts of preferred indole compounds, e.g.: 2'-des-methyl indomethacin 2. The reported compounds were designed as biomedical tools for primary and secondary in vitro and in vivo studies at relevant molecular targets.


Global scale-up of the programmatic management of multidrug-resistant tuberculosis.
Worldwide, an estimated 8.6 million people develop tuberculosis (TB) each year resulting in 1.3 million deaths. Although rates of TB are declining in many areas of the world, the emergence of drug-resistant strains of M. tuberculosis threatens to undermine TB control programmes. Multidrug-resistant TB (MDR-TB), strains that are resistant to at least isoniazid and rifampicin, are more difficult to diagnose and treat than other forms of TB and are associated with a higher mortality rate. Unfortunately, most countries with a high burden of MDR-TB detect less than 25% of the estimated MDR-TB cases and among those detected only 82% are treated. Of the estimated 300,000 MDR-TB patients among notified TB cases, only 6% are eventually detected and treated successfully. There are many gaps in the programmatic management of drug-resistant TB (PMDT) that must be closed in order for us to successfully control TB and additional financing will be required. Through these new efforts, we hope to see more rapid scale up of PMDT activities and ultimately control and prevention of drug-resistant TB.


Intellectual ability and cortical development in children and adolescents.
Children who are adept at any one of the three academic 'R's (reading, writing and arithmetic) tend to be good at the others, and grow into adults who are similarly skilled at diverse intellectually demanding activities. Determining the neuroanatomical correlates of this relatively stable individual trait of general intelligence has proved difficult, particularly in the rapidly developing brains of children and adolescents. Here we demonstrate that the trajectory of change in the thickness of the cerebral cortex, rather than cortical thickness itself, is most closely related to level of intelligence. Using a longitudinal design, we find a marked developmental shift from a predominantly negative correlation between intelligence and cortical thickness in early childhood to a positive correlation in late childhood and beyond. Additionally, level of intelligence is associated with the trajectory of cortical development, primarily in frontal regions implicated in the maturation of intelligent activity. More intelligent children demonstrate a particularly plastic cortex, with an initial accelerated and prolonged phase of cortical increase, which yields to equally vigorous cortical thinning by early adolescence. This study indicates that the neuroanatomical expression of intelligence in children is dynamic.


A review of the therapeutic uses of thrombin.
Thrombin is the product of the hemostatic response essential to the conversion of fibrinogen to fibrin. In addition, it is also responsible for the aggregation of blood platelets in the formation of the "platelet plug" as well as the activation of factor VIII, factor V, factor XI, factor XIII and protein C. The action of thrombin is not confined to the hemostatic response as it also has a critical function in the wound healing process by stimulating 'mitogenic' events through interaction with cell surface receptors. In this review, we consider the various biological activities of thrombin as they relate to current therapeutic use. While there has been considerable interest in the development of fibrin sealant products, there has been considerably less interest in documenting the continuing use of thrombin as a therapeutic. The use of thrombin for topical hemostasis and the treatment of pseudoaneurysms will be discussed in detail. It is concluded that the use of thrombin as a drug will not only continue but also will significantly increase. However, the availability of a safe human thrombin preparation will be critical for the continued use of thrombin as a therapeutic.


First Confirmed Report of Cercospora Blight of Asparagus Caused by Cercospora asparagi in Korea.
In September 2011, hundreds of asparagus (Asparagus officinalis L.) showing symptoms of blight with nearly 100% incidence (percentage of plants affected) were found in polyethylene tunnels at an organic farm in Gangneung City of Korea. Lesions on needles and branches of the ferns were small, elliptic to subcircular, pale tan to brown with reddish brown borders, and became gray and cottony due to heavy sporulation under continuous high humidity. Infection caused premature defoliation and weakened plant vigor. The damage purportedly due to this disease has reappeared with confirmation of the causal agent made again in 2012. A cercosporoid fungus was consistently associated with disease symptoms. Stromata were well developed, consisting of brown cells, and were 10 to 30 μm wide. Conidiophores were fasciculate (n = 2 to 12), olivaceous brown, paler upwards, straight to mildly curved, not geniculate in shorter ones, or 1 to 2 times geniculate in longer ones, 40 to 260 μm long, 3.5 to 5.5 μm wide, and 1- to 6-septate. Conidia were hyaline, cylindric to acicular, straight in shorter ones, curved in longer ones, truncate to obconically truncate at the base with darkened hila, guttulate, 2- to 12-septate, and 40 to 220 × 3 to 5 μm. Morphological characteristics of the fungus were consistent with the previous reports of Cercospora asparagi Sacc. (1). Voucher specimens were housed at the Korea University herbarium (KUS). An isolate from KUS-F26046 was deposited in the Korean Agricultural Culture Collection (Accession No. KACC46400). The complete internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced. The resulting sequence of 497 bp was deposited in GenBank (Accession No. JX964995). This showed >99% similarity with sequences of many Cercospora species, indicating their close phylogenetic relationship. For pathogenicity tests, conidial suspensions (105 conidia/ml) were prepared by culturing the fungus on V8 juice agar (2) for 3 weeks. Five plants were inoculated with conidial suspensions and five plants were sprayed with sterile distilled water. The plants were covered with plastic bags to maintain 100% RH for 24 h and then transferred to a greenhouse. Typical symptoms of necrotic lesions appeared on the inoculated plants 6 days after treatment, and were identical to the ones observed in the field. C. asparagi was reisolated from symptomatic tissues, confirming Koch's postulates. No symptoms were observed on control plants. The disease has been reported through the regions of the world where asparagus is grown (3). In Korea, the disease was recorded in 1928 by Japanese workers under Cercosporina asparagicola Speg. (regarded as synonymous with Cercospora asparagi) with brief notes (4). Though one sample of asparagus was sent to the author (KSH) for diagnosis in 2009 summer and determined to be infected with C. asparagi (unpublished data), there has been no additional finding of the disease in Korea for the last 82 years. To our knowledge, this is the first confirmed report of Cercospora blight of asparagus caused by C. asparagi in Korea. References: (1) C. Chupp. A Monograph of the Fungus Genus Cercospora. Ithaca, NY, 1953. (2) C. J. Cooperman and S. F. Jenkins. Phytopathology 76:617, 1986. (3) D. F. Farr and A. Y. Rossman. Fungal Databases. Syst. Mycol. Microbiol. Lab., Online publication, ARS, USDA, Retrieved October 20, 2012. (4) K. Nakata and S. Takimoto. Bull. Agric. Exp. Stat. Korea 15:1, 1928.


Prognostic clinicopathologic factors in cutaneous T-cell lymphoma.
Influence of clinicopathologic data on survival was analyzed in 43 patients with cutaneous T-cell lymphoma. The median age was 66 years; 35 were male and eight female. The extent of the disease, established according to a modification of the TNM system, was as follows: T1, three patients; T2, 15; T3, 14; T4, 11; N0, 15; N1, 28; M0, 38; M1, 5; B0, 37; and B1, six. The first treatment applied after staging was skin-limited therapy in seven patients and different regimens of systemic chemotherapy in 29. Seven patients received no treatment or only topical corticosteroids and tars. Median follow-up was 26 months. Nineteen patients died, with a median survival of 36.3 months. The prognostic value of age, sex, delay of diagnosis and staging, pruritus, number of sites of clinically enlarged lymph nodes, results of staging and TNM classification, erythrocyte sedimentation rate, peripheral blood cell count, liver function tests, serum lactate dehydrogenase levels, protein electrophoresis, presence of epidermotropism, thickness of cutaneous infiltrate, blastic cell percentage, mitotic index, cellular density, cutaneous eosinophilia, and follicular mucinosis was studied. Multivariate analysis (proportional hazard model with covariates) indicated that the major prognostic factors in patients with cutaneous T-cell lymphoma are as follows: (1) in a clinical model, the T category of TNM classification and the serum lactate dehydrogenase value; and (2) in a clinicopathologic model, the T category of TNM classification and the thickness of cutaneous infiltrate (measured in 10(-1) mm from the granular layer to the lower limit of the infiltrate) of the clinically thickest lesion.


Aquaporin expression and freeze tolerance in Candida albicans.
Aquaporins are members of the major intrinsic protein superfamily of integral membrane proteins which enable the transport of water, glycerol, and other solutes across membranes in various organisms. In microorganisms, the physiological role of aquaporins is not yet defined. We found a clear correlation between expression of the Candida albicans aquaporin-encoding gene AQY1 and freeze tolerance. A connection with the function for the aquaporin in the natural environment of C. albicans is, however, not obvious.


Effects of cell volume regulating osmolytes on glycerol 3-phosphate binding to triosephosphate isomerase.
During cell volume regulation, intracellular concentration changes occur in both inorganic and organic osmolytes in order to balance the extracellular osmotic stress and maintain cell volume homeostasis. Generally, salt and urea increase the Km's of enzymes and trimethylamine N-oxide (TMAO) counteracts these effects by decreasing Km's. The hypothesis to account for these effects is that urea and salt shift the native state ensemble of the enzyme toward conformers that are substrate-binding incompetent (BI), while TMAO shifts the ensemble toward binding competent (BC) species. Km's are often complex assemblies of rate constants involving several elementary steps in catalysis, so to better understand osmolyte effects we have focused on a single elementary event, substrate binding. We test the conformational shift hypothesis by evaluating the effects of salt, urea, and TMAO on the mechanism of binding glycerol 3-phosphate, a substrate analogue, to yeast triosephosphate isomerase. Temperature-jump kinetic measurements promote a mechanism consistent with osmolyte-induced shifts in the [BI]/[BC] ratio of enzyme conformers. Importantly, salt significantly affects the binding constant through its effect on the activity coefficients of substrate, enzyme, and enzyme-substrate complex, and it is likely that TMAO and urea affect activity coefficients as well. Results indicate that the conformational shift hypothesis alone does not account for the effects of osmolytes on Km's.


Real-time experimental demonstration of low-cost VCSEL intensity-modulated 11.25 Gb/s optical OFDM signal transmission over 25 km PON systems.
The feasibility of utilising low-cost, un-cooled vertical cavity surface-emitting lasers (VCSELs) as intensity modulators in real-time optical OFDM (OOFDM) transceivers is experimentally explored, for the first time, in terms of achievable signal bit rates, physical mechanisms limiting the transceiver performance and performance robustness. End-to-end real-time transmission of 11.25 Gb/s 64-QAM-encoded OOFDM signals over simple intensity modulation and direct detection, 25 km SSMF PON systems is experimentally demonstrated with a power penalty of 0.5 dB. The low extinction ratio of the VCSEL intensity-modulated OOFDM signal is identified to be the dominant factor determining the maximum obtainable transmission performance. Experimental investigations indicate that, in addition to the enhanced transceiver performance, adaptive power loading can also significantly improve the system performance robustness to variations in VCSEL operating conditions. As a direct result, the aforementioned capacity versus reach performance is still retained over a wide VCSEL bias (driving) current (voltage) range of 4.5 mA to 9 mA (275 mVpp to 320 mVpp). This work is of great value as it demonstrates the possibility of future mass production of cost-effective OOFDM transceivers for PON applications.


Sildenafil Treatment in Heart Failure With Preserved Ejection Fraction: Targeted Metabolomic Profiling in the RELAX Trial.
Phosphodiesterase-5 inhibition with sildenafil compared with a placebo had no effect on the exercise capacity or clinical status of patients with heart failure with preserved ejection fraction (HFpEF) in the PhosphodiesteRasE-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure with Preserved Ejection Fraction (RELAX) clinical trial. Metabolic impairments may explain the neutral results. To test the hypothesis that profiling metabolites in the RELAX trial would clarify the mechanisms of sildenafil effects and identify metabolites associated with clinical outcomes in HFpEF. Paired baseline and 24-week plasma samples of 160 stable outpatient individuals with HFpEF enrolled in the RELAX clinical trial were analyzed using flow injection tandem mass spectrometry (60 metabolites) and conventional assays (5 metabolites). Sildenafil (n = 79) or a placebo (n = 81) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. The primary measure was metabolite level changes between baseline and 24 weeks stratified by treatments. Secondary measures included correlations between metabolite level changes and clinical biomarkers and associations between baseline metabolite levels and the composite clinical score. No metabolites changed between baseline and 24 weeks in the group treated with a placebo; however, 7 metabolites changed in the group treated with sildenafil, including decreased amino acids (alanine and proline; median change [25th-75th], -38.26 [-100.3 to 28.19] and -28.24 [-56.29 to 12.08], respectively; false discovery rate-adjusted P = .01 and .03, respectively), and increased short-chain dicarboxylacylcarnitines glutaryl carnitine, octenedioyl carnitine, and adipoyl carnitine (median change, 6.19 [-3.37 to 14.18], 2.72 [-3 to 12.57], and 10.72 [-11.23 to 29.57], respectively; false discovery rate-adjusted P = .01, .04, and .05, respectively), and 1 long-chain acylcarnitine metabolite (palmitoyl carnitine; median change, 7.83 [-5.64 to 26.99]; false discovery rate-adjusted P = .03). The increases in long-chain acylarnitine metabolites and short-chain dicarboxylacylcarnitines correlated with increases in endothelin-1 and creatinine/cystatin C, respectively. Higher baseline levels of short-chain dicarboxylacylcarnitine metabolite 3-hydroxyisovalerylcarnitine/malonylcarnitine and asparagine/aspartic acid were associated with worse clinical rank scores in both treatment groups (β, -96.60, P = .001 and β, -0.02, P = .01; after renal adjustment, P = .09 and .02, respectively). Our study provides a potential mechanism for the effects of sildenafil that, through adverse effects on mitochondrial function and endoplasmic reticulum stress, could have contributed to the neutral trial results in RELAX. Short-chain dicarboxylacylcarnitine metabolites and asparagine/aspartic acid could serve as biomarkers associated with adverse clinical outcomes in HFpEF.


Alcohol consumption and fatal injuries in Australia before and after major traffic safety initiatives: a time series analysis.
The associations between population-level alcohol consumption and fatal injuries have been examined in a number of previous studies, but few have considered the external impacts of major policy interventions. This study aims to quantify the associations between per capita alcohol consumption and traffic and nontraffic injury mortality rates in Australia before and after major traffic safety initiatives (the introduction of compulsory seat belt legislation [CSBL] and random breath testing [RBT] in 1970s). Using data from 1924 to 2006, gender- and age-specific traffic and nontraffic mortality rates (15 years and above) were analyzed in relation to per capita alcohol consumption using time series analysis. The external effects of policy interventions were measured by inserting a dummy variable in the time series models. Statistically significant associations between per capita alcohol consumption and both types of fatal injuries were found for both males and females. The results suggest that an increase in per capita alcohol consumption of 1 l was accompanied by an increase in traffic mortality of 3.4 among males and 0.5 among females per 100,000 inhabitants and an increase in nontraffic mortality of 3.0 among males and 0.9 among females. The associations between alcohol consumption and fatal injury rates varied across age groups. The introduction of CSBL and RBT was associated with significant reductions in traffic crash mortality in Australia, particularly for males and young people. The magnitude and distribution of the preventive effects from the reduction in population drinking on fatal injuries vary across different gender and age groups, with the strongest preventive impacts on fatal injuries among people aged 15 to 29 and 70 years and above. The mechanisms behind these effects are unclear from this study, but are likely to be due to the strong association between per capita consumption and heavy drinking.


Patient decision-making: medical ethics and mediation.
A review of medical ethics literature relating to the importance of the participation of patients in decision-making introduces the role of rights-based mediation as a voluntary process now being developed innovatively in America. This is discussed in relation to the theory of communicative ethics and moral personhood. References are then made to the work of medical ethics committees and the role of mediation within these. Finally it is suggested that mediation is part of an eirenic ethic already being used informally in good patient care, and that there is a case for developing it further.


Disruption of the Dimer-Dimer Interaction of the Mumps Virus Attachment Protein Head Domain, Aided by an Anion Located at the Interface, Compromises Membrane Fusion Triggering.
Mumps virus (MuV), an enveloped negative-strand RNA virus belonging to the family Paramyxoviridae, enters the host cell through membrane fusion mediated by two viral envelope proteins, an attachment protein hemagglutinin-neuraminidase (MuV-HN) and a fusion (F) protein. However, how the binding of MuV-HN to glycan receptors triggers membrane fusion is not well understood. The crystal structure of the MuV-HN head domain forms a tetramer (dimer of dimers) like other paramyxovirus attachment proteins. In the structure, a sulfate ion (SO42-) was found at the interface between two dimers, which may be replaced by a hydrogen phosphate ion (HPO42-) under physiological conditions. The anion is captured by the side chain of a positively charged arginine residue at position 139 of one monomer each from both dimers. Substitution of alanine or lysine for arginine at this position compromised the fusion support activity of MuV-HN without affecting its cell surface expression, glycan-receptor binding, and interaction with the F protein. Furthermore, the substitution appeared to affect the tetramer formation of the head domain as revealed by blue native-PAGE analysis. These results, together with our previous similar findings with the measles virus attachment protein head domain, suggest that the dimer-dimer interaction within the tetramer may play an important role in triggering membrane fusion during paramyxovirus entry.IMPORTANCE Despite the use of effective live vaccines, mumps outbreaks still occur worldwide. Mumps virus (MuV) infection typically causes flu-like symptoms and parotid gland swelling but sometimes leads to orchitis, oophoritis, and neurological complications, such as meningitis, encephalitis, and deafness. MuV enters the host cell through membrane fusion mediated by two viral proteins, a receptor-binding attachment protein, and a fusion protein, but its detailed mechanism is not fully understood. In this study, we show that the tetramer (dimer of dimers) formation of the MuV attachment protein head domain is supported by an anion located at the interface between two dimers and that the dimer-dimer interaction plays an important role in triggering the activation of the fusion protein and causing membrane fusion. These results not only further our understanding of MuV entry but provide useful information about a possible target for antiviral drugs.


Avalanche dynamics of fiber bundle models.
We present a detailed analytical and numerical study of the avalanche distributions of the continuous damage fiber bundle model (CDFBM). Linearly elastic fibers undergo a series of partial failure events which give rise to a gradual degradation of their stiffness. We show that the model reproduces a wide range of mechanical behaviors. We find that macroscopic hardening and plastic responses are characterized by avalanche distributions, which exhibit an algebraic decay with exponents between 5/2 and 2 different from those observed in mean-field fiber bundle models. We also derive analytically the phase diagram of a family of CDFBM which covers a large variety of potential avalanche size distributions. Our results provide a unified view of the statistics of breaking avalanches in fiber bundle models.


Comparative effectiveness research and evidence-based health policy: experience from four countries.
The discussion about improving the efficiency, quality, and long-term sustainability of the U.S. health care system is increasingly focusing on the need to provide better evidence for decision making through comparative effectiveness research (CER). In recent years, several other countries have established agencies to evaluate health technologies and broader management strategies to inform health care policy decisions. This article reviews experiences from Britain, France, Australia, and Germany. This article draws on the experience of senior technical and administrative staff in setting up and running the CER entities studied. Besides reviewing the agencies' websites, legal framework documents, and informal interviews with key stakeholders, this analysis was informed by a workshop bringing together U.S. and international experts. This article builds a matrix of features identified from the international models studied that offer insights into near-term decisions about the location, design, and function of a U.S.-based CER entity. While each country has developed a CER capacity unique to its health system, elements such as the inclusiveness of relevant stakeholders, transparency in operation, independence of the central government and other interests, and adaptability to a changing environment are prerequisites for these entities' successful operation. While the CER entities evolved separately and have different responsibilities, they have adopted a set of core structural, technical, and procedural principles, including mechanisms for engaging with stakeholders, governance and oversight arrangements, and explicit methodologies for analyzing evidence, to ensure a high-quality product that is relevant to their system.


Low birthweight and premature birth are risk factors for podocytopenia and focal segmental glomerulosclerosis.
Recent reports suggest that low birthweight (LBW) is a risk factor for kidney diseases, including focal segmental glomerulosclerosis (FSGS), although the underlying pathological mechanism remains unknown. Podocyte loss triggers glomerulosclerosis; however, whether FSGS in LBW children is associated with podocytopenia is unclear. We reviewed the birthweights and gestational age of all patients who underwent renal biopsies from 1995 to 2011 at our Institute. Sixteen patients had FSGS, of which 6 (37.5%) had LBW; this LBW rate was significantly higher than the overall LBW rate in Japan (9.7%). The incidence of LBW was also high in patients with minimal change nephrotic syndrome (MCNS; 12.5%). The glomerular cell numbers in biopsy sections were calculated using computer image analysis and compared with FSGS of normal birthweight (NBW-FSGS). Biopsy specimens from age-matched patients with MCNS were also compared. Wilms' tumor-1 (WT1) immunohistochemistry was performed to enumerate the podocytes. All patients in the LBW-FSGS group were also preterm, with an average gestational age of 25.8 weeks. The number of podocytes per glomerulus in the LBW-FSGS patients was 34 and 24% lower as compared to that in the MCNS patients (p < 0.01) and the NBW-FSGS patients (p < 0.05), respectively. Similar results were observed for the WT1-positive glomerular cell number. LBW and premature birth were associated with FSGS development. The possibility that LBW and premature birth may be predisposing factors for severe podocytopenia in children with FSGS warrants further investigation.


Alanylglutamine reduces muscle loss of alanine and glutamine in post-operative anaesthetized dogs.
1. The present study examined the effect of an infusion of the dipeptide alanylglutamine or of the corresponding amino acids alanine and glutamine in equimolar amounts (10 mumol min-1 kg-1) on the canine hindlimb exchange of alanine and glutamine in the post-operative anaesthetized dog. In contrast to glutamine, the dipeptide alanylglutamine is stable in aqueous solution and therefore would be a suitable substrate for parenteral nutrition. 2. The infusion of alanylglutamine increased (a) the arterial concentration of alanylglutamine to a plateau level (120 +/- 9.5 mumol/l, mean +/- SEM) 20 min after start of the infusion, (b) the mean arterial alanine concentration from 761 +/- 42 to a plateau of 1500-1700 mumol/l (P greater than 0.01) and (c) the arterial glutamine concentration from 407 +/- 51 to a plateau of 1050-1500 mumol/l (P greater than 0.01). Alanine and glutamine levels were slightly higher (14% and 26%, respectively, NS) in the group receiving the equimolar amount of alanine and glutamine. 3. Infusion of alanylglutamine for 1 h abolished the net efflux of glutamine (from -0.80 +/- 0.1 to -0.03 +/- 0.2 mumol min-1 kg-1; P greater than 0.05) and invoked a net influx of alanine (from -0.50 +/- 0.19 to +0.27 +/- 0.14 mumol min-1 kg-1; P greater than 0.01). These changes were similar to those achieved when the two amino acids were infused. 4. This study demonstrates that during short-term administration of alanylglutamine or of the corresponding amino acids the nitrogen release from the hindlimb of the anaesthetized post-operative dog via alanine and glutamine is reduced.


Correlates of regular cigarette smoking in a population-based sample of Australian twins.
To investigate the role of measured risk factors and the influence of genetic and environmental factors on regular cigarette smoking. Design Members of monozygotic and dizygotic, including unlike-sex twin pairs (n = 6257) from a young adult cohort from the Australian Twin Registry. Cox proportional hazards models were used to determine whether putative risk factors were significantly associated with regular cigarette smoking. Risk factors were classified into four tiers: tier 1 (parental history, including parental education, alcoholism and cigarette smoking), tier 2 (early home and family influences), tier 3 (early life events, e.g. trauma) and tier 4 (psychiatric symptoms/disorders with onset prior to 14 years), after controlling for gender, zygosity and their interactions. Genetic models were fitted to examine the heritability of smoking behavior before and after controlling for significant covariates from the four tiers. Parental history of cigarette smoking and alcoholism, parental closeness and home environment, as well as incidence of childhood sexual abuse or other trauma, a history of early onset panic attacks and conduct problems were associated with regular cigarette smoking. Important age interactions were found, particularly for family background risk factors. Regular cigarette smoking was moderately heritable, even after accounting for significant covariates. Several measured risk factors are associated with regular smoking. While some of the genetic influences on regular smoking may be shared with these risk factors, a significant proportion of the genetic vulnerability to regular smoking is phenotype-specific.


1987 Volvo award in clinical sciences. A new clinical model for the treatment of low-back pain.
Because there is increasing concern about low-back disability and its current medical management, this analysis attempts to construct a new theoretic framework for treatment. Observations of natural history and epidemiology suggest that low-back pain should be a benign, self-limiting condition, that low back-disability as opposed to pain is a relatively recent Western epidemic, and that the role of medicine in that epidemic must be critically examined. The traditional medical model of disease is contrasted with a biopsychosocial model of illness to analyze success and failure in low-back disorders. Studies of the mathematical relationship between the elements of illness in chronic low-back pain suggest that the biopsychosocial concept can be used as an operational model that explains many clinical observations. This model is used to compare rest and active rehabilitation for low-back pain. Rest is the commonest treatment prescribed after analgesics but is based on a doubtful rationale, and there is little evidence of any lasting benefit. There is, however, little doubt about the harmful effects--especially of prolonged bed rest. Conversely, there is no evidence that activity is harmful and, contrary to common belief, it does not necessarily make the pain worse. Experimental studies clearly show that controlled exercises not only restore function, reduce distress and illness behavior, and promote return to work, but actually reduce pain. Clinical studies confirm the value of active rehabilitation in practice. To achieve the goal of treating patients rather than spines, we must approach low-back disability as an illness rather than low-back pain as a purely physical disease. We must distinguish pain as a purely the symptoms and signs of distress and illness behavior from those of physical disease, and nominal from substantive diagnoses. Management must change from a negative philosophy of rest for pain to more active restoration of function. Only a new model and understanding of illness by physicians and patients alike makes real change possible.


Baseline tumour measurements predict survival in advanced non-small cell lung cancer.
The association between tumour measurements and survival has been studied extensively in early-stage and locally advanced non-small cell lung cancer (NSCLC). We analysed these factors in patients with advanced NSCLC. Data were derived from the E4599 trial of paclitaxel-carboplatin±bevacizumab. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD), response rate, progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. A total of 759 of the 850 patients (89%) in the E4599 trial had measurable diseases and were included in this analysis. The median BSLD was 7.5 cm. BSLD predicted OS (hazard ratio (HR) 1.41; P<0.001) and had a trend towards association with PFS (HR 1.14; P=0.08). The median OS was 12.6 months for patients with BSLD <7.5 cm compared with 9.5 months for BSLD ≥ 7.5 cm. This association persisted in a multivariable model controlling multiple prognostic factors, including the presence and sites of extrathoracic disease (HR 1.24; P=0.01). There was no association between BSLD and response rate. Tumour measurements are associated with survival in the E4599 trial. If validated in other populations, this parameter may provide important prognostic information to patients and clinicians.


Evaluation of rooms with negative pressure ventilation used for respiratory isolation in seven midwestern hospitals.
To determine the number and efficacy of respiratory isolation facilities in St. Louis hospitals and to assess the mechanisms in place for evaluating function of hospital ventilation systems. A prospective multi-hospital surveillance study using direct observation and a standardized questionnaire. Seven hospitals (including university-affiliated large teaching, private community, private teaching, and private nonteaching adult hospitals, and one pediatric teaching hospital) in St. Louis, Missouri. Actual direction of airflow in rooms designated for respiratory isolation was measured using smokesticks. Hospital demographic information, respiratory isolation policies, and frequency of ventilation tests were provided by infection control personnel. One hundred twenty-one (3.4%) of 3,574 hospital rooms were designed to have negative pressure ventilation suitable for respiratory isolation. The percentage of isolation rooms in each institution ranged from 0.4% (92 of 486) to 93% (39 of 42). Only three (43%) of seven hospitals had intensive care respiratory isolation rooms, and none had isolation rooms in the emergency department. No hospital had tested routinely the efficacy of the negative pressure ventilation, and two (28%) of seven had tested airflow for the first time in the past year. We tested 115 (95%) of 121 isolation rooms. With the doors closed, 52 (45%) of 115 designated negative pressure rooms actually had positive airflow to the corridor. The number of negative pressure rooms and the presence or absence of anterooms did not predict correct direction of airflow. There was a significant difference among hospitals in the percentage of designated isolation rooms that had truly negative pressure (P < 0.0001). Hospital age, size, and type correlated with correct direction of airflow (P < 0.0001). In the hospitals studied, only a small number of rooms were designated for respiratory isolation, and the performance of these was not tested routinely. High-risk areas including intensive care units and emergency rooms were not equipped to provide respiratory isolation. The direction of airflow in respiratory isolation rooms was not always correct and should be evaluated frequently.


Posttraumatic stress disorder after motor vehicle accidents: 3-year follow-up of a prospective longitudinal study.
The paper presents a 3-year follow-up of a prospective longitudinal study of posttraumatic stress disorder (PTSD) after motor vehicle accidents (J. Abnormal Psychol., 107 (1998) 508). Participants were 546 patients who had been assessed when attending an emergency clinic shortly after a motor vehicle accident, and at 3 months and 1 year afterwards. The prevalence of posttraumatic stress disorder PTSD at 3 years was 11%. Maintaining psychological factors, i.e. negative interpretation of intrusions, rumination, thought suppression and anger cognitions, were important in predicting the persistence of PTSD at 3 years, as were persistent health and financial problems after the accident. Other predictors were female sex, hospital admission for injuries, perceived threat and dissociation during the accident, and litigation.


The PI3K-PDK1 connection: more than just a road to PKB.
Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that have been implicated in the regulation of cell growth, proliferation, survival, differentiation and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase Akt or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and phosphorylation by 3'-phosphoinositide-dependent kinase-1 (PDK1). Here we review the mechanism by which PKB is activated and the downstream actions of this multifunctional kinase. We also discuss the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, the mechanisms by which this activity of PDK1 could be regulated and the possibility that some of the currently postulated PKB substrates targets might in fact be phosphorylated by PDK1-regulated kinases other than PKB.


Agreement between electronic medical record-based and self-administered pain numeric rating scale: clinical and research implications.
Pain screening may improve the quality of care by identifying patients in need of further assessment and management. Many health care systems use the numeric rating scale (NRS) for pain screening, and record the score in the patients' electronic medical record (EMR). Determine the level of agreement between EMR and patient survey NRS, and whether discrepancies vary by demographic and clinical characteristics. We linked survey data from a sample of veterans receiving care in 8 Veterans Affairs medical facilities, to EMR data including an NRS collected on the day of the survey to compare responses to the NRS question from these 2 sources. We assessed correlation, agreement on clinical cut-points (eg, severe), and, using the survey as the gold standard, whether patient characteristics were associated with a discrepancy on moderate-severe pain. A total of 1643 participants had a survey and EMR NRS score on the same day. The correlation was 0.56 (95% confidence interval, 0.52-0.59), but the mean EMR score was significantly lower than the survey score (1.72 vs. 2.79; P<0.0001). Agreement was moderate (κ=0.35). Characteristics associated with an increased odds of a discrepancy included: diabetes [adjusted odds ratio (AOR)=1.48], posttraumatic stress disorder (AOR=1.59), major depressive disorder (AOR=1.81), other race versus white (AOR=2.29), and facility in which care was received. The underestimation of pain using EMR data, especially clinically actionable levels of pain, has important clinical and research implications. Improving the quality of pain care may require better screening.


Evolutionary origins of leadership and followership.
Drawing upon evolutionary logic, leadership is reconceptualized in terms of the outcome of strategic interactions among individuals who are following different, yet complementary, decision rules to solve recurrent coordination problems. This article uses the vast psychological literature on leadership as a database to test several evolutionary hypotheses about the origins of leadership and followership in humans. As expected, leadership correlates with initiative taking, trait measures of intelligence, specific task competencies, and several indicators of generosity. The review finds no link between leadership and dominance. The evolutionary analysis accounts for reliable age, health, and sex differences in leadership emergence. In general, evolutionary theory provides a useful, integrative framework for studying leader-follower relationships and generates various novel research hypotheses.


Atomic force microscopy characterization of cellulose nanocrystals.
Cellulose nanocrystals (CNCs) are gaining interest as a "green" nanomaterial with superior mechanical and chemical properties for high-performance nanocomposite materials; however, there is a lack of accurate material property characterization of individual CNCs. Here, a detailed study of the topography, elastic and adhesive properties of individual wood-derived CNCs is performed using atomic force microscopy (AFM). AFM experiments involving high-resolution dynamic mode imaging and jump-mode measurements were performed on individual CNCs under ambient conditions with 30% relative humidity (RH) and under a N(2) atmosphere with 0.1% RH. A procedure was also developed to calculate the CNC transverse elastic modulus (E(T)) by comparing the experimental force-distance curves measured on the CNCs with 3D finite element calculations of tip indentation on the CNC. The E(T) of an isolated CNC was estimated to be between 18 and 50 GPa at 0.1% RH; however, the associated crystallographic orientation of the CNC could not be determined. CNC properties were reasonably uniform along the entire CNC length, despite variations along the axis of 3-8 nm in CNC height. The range of RH used in this study was found to have a minimal effect on the CNC geometry, confirming the resistance of the cellulose crystals to water penetration. CNC flexibility was also investigated by using the AFM tip as a nanomanipulator.


Finger-to-Heart (F2H): Authentication for Wireless Implantable Medical Devices.
Any proposal to provide security for implantable medical devices (IMDs), such as cardiac pacemakers and defibrillators, has to achieve a trade-off between security and accessibility for doctors to gain access to an IMD, especially in an emergency scenario. In this paper, we propose a finger-to-heart (F2H) IMD authentication scheme to address this trade-off between security and accessibility. This scheme utilizes a patient's fingerprint to perform authentication for gaining access to the IMD. Doctors can gain access to the IMD and perform emergency treatment by scanning the patient's finger tip instead of asking the patient for passwords/security tokens, thereby, achieving the necessary trade-off. In the scheme, an improved minutia-cylinder-code-based fingerprint authentication algorithm is proposed for the IMD by reducing the length of each feature vector and the number of query feature vectors. Experimental results show that the improved fingerprint authentication algorithm significantly reduces both the size of messages in transmission and computational overheads in the device, and thus, can be utilized to secure the IMD. Compared to existing electrocardiogram signal-based security schemes, the F2H scheme does not require the IMD to capture or process biometric traits in every access attempt since a fingerprint template is generated and stored in the IMD beforehand. As a result, the scarce resources in the IMD are conserved, making the scheme sustainable as well as energy efficient.


The enhancement of beneficial effects following audio feedback by cognitive preparation in the treatment of social anxiety: a single-session experiment.
According to cognitive models, negatively biased processing of the publicly observable self is an important aspect of social phobia; if this is true, effective methods for producing corrective feedback concerning the public self should be strived for. Video feedback is proven effective, but since one's voice represents another aspect of the self, audio feedback should produce equivalent results. This is the first study to assess the enhancement of audio feedback by cognitive preparation in a single-session randomized controlled experiment. Forty socially anxious participants were asked to give a speech, then to listen to and evaluate a taped recording of their performance. Half of the sample was given cognitive preparation prior to the audio feedback and the remainder received audio feedback only. Cognitive preparation involved asking participants to (1) predict in detail what they would hear on the audiotape, (2) form an image of themselves giving the speech and (3) listen to the audio recording as though they were listening to a stranger. To assess generalization effects all participants were asked to give a second speech. Audio feedback with cognitive preparation was shown to produce less negative ratings after the first speech, and effects generalized to the evaluation of the second speech. More positive speech evaluations were associated with corresponding reductions of state anxiety. Social anxiety as indexed by the Implicit Association Test was reduced in participants given cognitive preparation. Small sample size; analogue study. Audio feedback with cognitive preparation may be utilized as a treatment intervention for social phobia.


Benzodiazepines and related drugs for insomnia in palliative care.
Insomnia, a subjective complaint of poor sleep and associated impairment in daytime function, is a common problem. Currently, benzodiazepines are the most used pharmacological treatment for this complaint. They are considered helpful for occasional short-term use up to four weeks but longer term use is not advised due to potential problems regarding tolerance, dosing escalation, psychological addiction and physical dependence. There is no consensus on their utility in patients with progressive incurable conditions who may require assistance with sleep for many weeks as their condition deteriorates. To assess the effectiveness and safety of benzodiazepines or benzodiazepine receptor agonists such as Zolpidem, Zopiclone and Zaleplon for insomnia in palliative care. Several electronic databases were searched including Cochrane PaPaS Group specialized register, Cochrane Library Issue 4, 2001, MEDLINE, EMBASE, BNI plus, CINAHL, BIOLOGICAL ABSTRACTS, PSYCINFO, CANCERLIT, HEALTHSTAR, WEB OF SCIENCE, SIGLE, Dissertation Abstracts, ZETOC and the MetaRegister of ongoing trials. These were searched from 1960 to 2001 or as much of this range as possible. Additional articles were sought by handsearching reference lists in standard textbooks and reviews in the field and by contacting academic centres in palliative care and pharmaceutical companies. There were no language restrictions. Studies considered for inclusion were randomized controlled trials of adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition. (For example, cancers, AIDS, Motor Neurone Disease, Multiple Sclerosis, Parkinson's Disease, Chronic Obstructive Pulmonary Disease). There had to be an explicit complaint of insomnia in study participants, diagnosed by any of the three main classification systems (DSM-IV (APA 1994), ICSD (AASD 1990) or ICD (WHO 1992)), or as described in the study if it involved a subjective complaint of poor sleep. Studies had to compare a benzodiazepine or Zolpidem or Zopiclone or Zaleplon with placebo or active control for the treatment of insomnia. Any duration of therapy were considered. Abstracts were independently inspected by both reviewers, full papers were obtained where necessary. Where there was uncertainty advice was sought by a third (PW). Data extraction and quality assessments were undertaken independently by both reviewers. No randomized controlled trials were identified meeting the a priori inclusion criteria. Thirty-seven studies were considered but all were excluded from the review. Despite a comprehensive search no evidence from randomized controlled trials was identified. It was not possible to draw any conclusions regarding the use of benzodiazepines in palliative care.