Patient-specific vaccine therapy for non-Hodgkin lymphoma.
Follicular non-Hodgkin lymphoma (NHL) is an indolent, or slow-growing, malignant disease of the lymphoid tissue, which usually responds to initial therapy. However, the disease is characterized by multiple relapses and remissions, eventually causing death. Several effective therapies are available, but improvement of overall survival in patients with follicular NHL has not been demonstrated. Stimulation of the immune system to recognize malignant lymphoma cells as foreign has been demonstrated as a viable treatment option for patients with follicular NHL. Patient-specific vaccine therapy is a new form of active immunotherapy being studied for NHL. Clinical trials have shown a benefit for patients receiving this type of therapy. This article will provide a foundation for nurses caring for patients receiving patient-specific vaccine therapy.


Memory deficits and memory surfeits: differential cognitive consequences of tokenism for tokens and observers.
Historically, women and minority group members have been underrepresented in the professions and in better paying, high-status jobs. Even when they have been admitted to such positions, these underrepresented persons often have been the only member of their social category: a token. Previous field and laboratory research has shown that "tokens" attract disproportionate attention and are either evaluated unfairly or evaluated on the basis of their normal reactions to differential treatment by majority group members. We tested the possibilities of whether tokens might suffer more cognitive deficits than would nontokens, and whether they do so even when they are treated no differently. College students were led to believe that they were sharing their views on everyday topics with three other students (actually videotaped confederates), who were either all of the student's own sex or all of the opposite sex. In a later memory test, token participants remembered fewer of the opinions that they and the three other students had expressed than did nontokens. Observers, in contrast, remembered more of what token subjects said than what the three other students said. Theoretical and public policy implications are discussed.


Advanced Theory of Mind in patients at early stage of Parkinson's disease.
Advanced Theory of Mind (ToM) refers to the sophisticated ability to infer other people's thoughts, intentions, or emotions in social situations. With appropriate advanced ToM, one can behave well in social interactions and can understand the intention of others' behavior. Prefrontal cortex plays a vital role in this ability, as shown in functional brain imaging and lesion studies. Considering the primary neuropathology of Parkinson's disease (PD) involving the frontal lobe system, patients with PD are expected to exhibit deficits in advanced ToM. However, few studies on this issue have been explored, and whether advanced ToM is independent of executive functions remains uncertain. Thirty-nine early non-demented PD patients and 40 normal control subjects were included. Both groups were matched in age, level of education, and verbal intelligence quotient. Each participant received advanced ToM, executive functions, and verbal intelligence quotient tests. We discovered that the performance of the PD patients on the Cartoon ToM task was significantly poorer than that of their normal counterparts. Correlation analysis revealed that performance scores of advanced ToM in PD patients were significantly associated with their executive functions scores; however, this is not the case for normal controls. We conclude that dysfunction of advanced ToM develops in early PD patients, who require more cognitive abilities than their normal counterparts to generate advanced ToM. Our findings might be helpful in developing educational and medical care programs for PD patients in the future.


Anatabine ameliorates experimental autoimmune thyroiditis.
Tobacco smoking favorably influences the course of Hashimoto thyroiditis, possibly through the antiinflammatory proprieties of nicotine. In this study we tested anatabine, another tobacco alkaloid, in a model of experimental autoimmune thyroiditis. Experimental autoimmune thyroiditis was induced by different doses of thyroglobulin, to produce a disease of low, moderate, or high severity, in 88 CBA/J female mice: 43 drank anatabine supplemented water and 45 regular water. Mice were bled after immunization and killed to assess thyroid histopathology, thyroglobulin antibodies, T(4), and thyroid RNA expression of 84 inflammatory genes. We also stimulated in vitro a macrophage cell line with interferon-γ or lipopolysaccharide plus or minus anatabine to quantitate inducible nitric oxide synthase and cyclooxygenase 2 protein expression. Anatabine reduced the incidence and severity of thyroiditis in the moderate disease category: only 13 of 21 mice (62%) developed thyroid infiltrates when drinking anatabine as compared with 22 of 23 (96%) controls (relative risk 0.59, P = 0.0174). The median thyroiditis severity was 0.5 and 2.0 in anatabine and controls, respectively (P = 0.0007 by Wilcoxon rank sum test). Anatabine also reduced the antibody response to thyroglobulin on d 14 (P = 0.029) and d 21 (P = 0.045) after immunization and improved the recovery of thyroid function on d 21 (P = 0.049). In the thyroid transcriptome, anatabine restored expression of IL-18 and IL-1 receptor type 2 to preimmunization levels. Finally, anatabine suppressed in a dose-dependent manner macrophage production of inducible nitric oxide synthase and cyclooxygenase 2. Anatabine ameliorates disease in a model of autoimmune thyroiditis, making the delineation of its mechanisms of action and potential clinical utility worthwhile.


Sensing the ortho Positions in C6Cl6 and C6H4Cl2 from Cl2- Formation upon Molecular Reduction.
The geometrical effect of chlorine atom positions in polyatomic molecules after capturing a low-energy electron is shown to be a prevalent mechanism yielding Cl2-. In this work, we investigated hexachlorobenzene reduction in electron transfer experiments to determine the role of chlorine atom positions around the aromatic ring, and compared our results with those using ortho-, meta- and para-dichlorobenzene molecules. This was achieved by combining gas-phase experiments to determine the reaction threshold by means of mass spectrometry together with quantum chemical calculations. We also observed that Cl2- formation can only occur in 1,2-C6H4Cl2, where the two closest C-Cl bonds are cleaved while the chlorine atoms are brought together within the ring framework due to excess energy dissipation. These results show that a strong coupling between electronic and C-Cl bending motion is responsible for a positional isomeric effect, where molecular recognition is a determining factor in chlorine anion formation.


A Danish adaptation of the quality in psychiatric care-forensic in-patient questionnaire: psychometric properties and factor structure.
The aims of this study were to adapt and evaluate the psychometric properties and factor structure of the Danish version of the Quality in Psychiatric Care-Forensic In-Patient (QPC-FIP) questionnaire. A sample of 139 inpatients from 25 wards in Denmark who received care during 5 weeks in March and April 2012 participated in the study by completing the QPC-FIP instrument. Confirmatory factor analysis revealed that the factor structure of the Danish version was equivalent to that of the original Swedish QPC-FIP. The results indicate that the concept of quality of care expressed in the QPC-FIP is equivalent among forensic inpatients in nationally different healthcare systems and cultural contexts. The Danish version of QPC-FIP is a reliable and valid measurement instrument recommended for use in evaluating quality of care in forensic inpatient care.


Between two worlds: Exploring esports betting in relation to problem gambling, gaming, and mental health problems.
Esports betting is an emerging gambling activity where individuals place bets on an organized video gaming competition. It represents only one of several gambling activities commonly endorsed by adolescents. To date, limited research has explored the relationship between esports betting and mental health among adolescents and its convergence with both problem gambling (PG) and problem video gaming (PVG). The present study examined the relation between esports betting, PG and PVG, and both externalizing and internalizing problems among adolescents while accounting for adolescents' video gaming intensity (i.e., how often they play 2 h or more in a day) and engagement in other gambling activities. Data was collected from 6,810 adolescents in Wood County, Ohio schools. A subset of 1,348 adolescents (M age = 14.67 years, SD = 1.73, 64% male) who had gambled and played video games during the past year were included in the analyses. Approximately 20% (n = 263) of the included sample had bet on esports during the past year. Esports betting was positively correlated with other forms of gambling, both PG and PVG, and externalizing behaviors. Mediation analyses revealed esports betting was associated to both internalizing and externalizing problems through PVG and not PG. Esports betting may be particularly appealing to adolescents who are enthusiastic video gamers. As such, regulators must be vigilant to ensure codes of best practices are applied to esports betting operators specifically for underaged individuals.


Differential trans activation associated with the muscle regulatory factors MyoD1, myogenin, and MRF4.
Expression of the mammalian muscle regulatory factors MyoD1, myogenin, and MRF4 will convert C3H10T1/2 fibroblasts to stable muscle cell lineages. Recent studies have shown that MyoD1 and myogenin also trans-activate expression of a number of cotransfected contractile protein genes, suggesting that these muscle regulatory factors are involved in controlling terminal differentiation events. The extent and specificity of trans activation by the muscle regulatory factors, however, have not been compared directly. In this study, we found that MyoD1, myogenin, and MRF4 exhibited different trans-activation capacities. In contrast to MyoD1 and myogenin, MRF4 was inefficient in trans-activating most of the genes tested, although conversion of C3H10T1/2 fibroblasts to a myogenic lineage was observed at similar frequencies with all three factors. Addition of basic fibroblast growth factor to cells expressing exogenous muscle regulatory factors inhibited the transcriptional activation of cotransfected genes, demonstrating that MyoD1, myogenin, or MRF4 proteins alone are not sufficient to produce a terminally differentiated phenotype. In all cases, trans activation was dependent on signal transduction pathways that are regulated by fibroblast growth factor. Our observations, coupled with previous studies showing differences in the temporal expression and protein structure of MyoD1, myogenin, and MRF4, suggest that the individual members of the muscle regulatory factor family have distinct biological roles in controlling skeletal muscle development.


[1H-NMR studies of the ACTH-like immunoregulatory peptides].
A comparative study of the conformational and dynamics properties of the ACTH-like linear peptides, sequences of which correspond to amino acid residues 11-20 of the heavy chain of human immunoglobulin G1 Eu, residues 78-85 of human pro-interleukin-1 alpha and site 10-18 of human ACTH, was performed in aqueous solution and dimethylsulfoxide by 1H-NMR spectroscopy at 400 MHz. The peptides were shown to possess an unordered unfolded flexible conformation in aqueous solution. The revealed structural and dynamic features of the peptides are discussed together with biological activity of this class of compounds.


Adherence to ventilator-associated pneumonia bundle and incidence of ventilator-associated pneumonia in the surgical intensive care unit.
To examine the impact of adherence to a ventilator-associated pneumonia (VAP) bundle on the incidence of VAP in our surgical intensive care units (SICUs). Prospectively collected data were retrospectively examined from our Infection Control Committee surveillance database of SICU patients over a 38-month period. Cost of VAP was estimated at $30,000 per patient stay. Two SICUs at a tertiary care academic level I trauma center. Ventilated patients admitted to a SICU. The Institute for Healthcare Improvement VAP bundle was instituted at the beginning of the study and included head-of-bed elevation, extubation assessment, sedation break, peptic ulcer prophylaxis, and deep vein thrombosis prophylaxis. A daily checklist was considered compliant if all 5 items were performed for each patient. Patients were assessed for VAP. Staff were assessed for compliance with the VAP bundle. Prior to initiation of the bundle, VAP was seen at a rate of 10.2 cases/1000 ventilator days. Compliance with the VAP bundle increased over the study period from 53% and 63% to 91% and 81% in each respective SICU. The rate of VAP decreased to 3.4 cases/1000 ventilator days. A cost savings of $1.08 million was estimated. Initiation of the VAP bundle is associated with a significantly reduced incidence of VAP in patients in the SICU and with cost savings. Initiation of a VAP bundle protocol is an effective method for VAP reduction when compliance is maintained.


Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins.
Calnexin and calreticulin interact specifically with newly synthesized glycoproteins in the endoplasmic reticulum (ER) and function as molecular chaperones. The carbohydrate-specific interactions between ER components and glycoproteins synthesized in isolated canine pancreatic microsomes were analyzed using a cross-linking approach. A carbohydrate-dependent interaction between newly synthesized glycoproteins, the thiol-dependent reductase ERp57, and either calnexin or calreticulin was identified. The interaction between ERp57 and the newly synthesized glycoproteins required trimming of the N-linked oligosaccharide side chain. Thus, it is likely that ERp57 functions as part of the glycoprotein-specific quality control machinery operating in the lumen of the ER.


Association Between State Indoor Tanning Legislation and Google Search Trends Data in the United States From 2006 to 2019: Time-Series Analysis.
Exposure to ultraviolet radiation from the sun or indoor tanning is the cause of most skin cancers. Although indoor tanning has decreased in recent years, it remains most common among adolescents and young adults, whose skin is particularly vulnerable to long-term damage. US states have adopted several types of legislation to attempt to minimize indoor tanning among minors: a ban on indoor tanning among all minors, a partial minor ban by age (eg, <14 years), or the requirement of parental consent or accompaniment for tanning. Currently, only 6 US states have no indoor tanning legislation for minors. This study investigated whether internet searches (as an indicator of interest) related to indoor tanning varied across US states by the type of indoor tanning legislation, using data from Google Trends from 2006 to 2019. We conducted a time-series analysis of Google Trends data on indoor tanning from 2006 to 2019 by US state. Time-series linear regression models were generated to assess the Google Trends data over time by the type of indoor tanning legislation. We found that indoor tanning search rates decreased significantly for all 50 states and the District of Columbia over time (P<.01). The searches peaked in 2012 when indoor tanning received marked attention (eg, indoor tanning was banned for all minors by the first state-California). The reduction in search rates was more marked for states with a complete ban among minors compared to those with less restrictive types of legislation. Our findings are consistent with those of other studies on the association between indoor tanning regulations and attitudinal and behavioral trends related to indoor tanning. The main limitation of the study is that raw search data were not available for more precise analysis. With changes in interest and norms, indoor tanning and skin cancer risk among young people may change. Future studies should continue to determine the impact of such public health policies in order to inform policy efforts and minimize risks to public health.


Morphological changes in the subthalamic nucleus of people with mild-to-moderate Parkinson's disease: a 7T MRI study.
This project investigated whether structural changes are present in the subthalamic nucleus (STN) of people with mild-to-moderate severity of Parkinson's disease (PD). Within-subject measures of STN volume and fractional anisotropy (FA) were derived from high-resolution 7Tesla magnetic resonance imaging (MRI) for 29 subjects with mild-to-moderate PD (median disease duration = 2.3±1.9 years) and 18 healthy matched controls. Manual segmentation of the STN was performed on 0.4 mm in-plane resolution images. FA maps were generated and FA values were averaged over the left and right STN separately for each subject. Motor sign severity was assessed using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Linear effects models showed that STN volume was significantly smaller in the PD subjects compared to controls (p = 0.01). Further, after controlling for differences in STN volumes within or between groups, the PD group had lower FA values in the STN compared to controls (corrected p ≤ 0.008). These findings demonstrate that morphological changes occur in the STN, which likely impact the function of the hyperdirect and indirect pathways of the basal ganglia and movement control.


Medication management activities performed by informal caregivers of older adults.
Medication management is commonly performed by informal caregivers, yet they are often unprepared and ill-equipped to manage complex medication regimens for their older adult care recipients. In order to develop interventions that will enhance the caregiver's ability to safely and confidently manage medications, it is critical to first understand caregiver challenges and unmet needs related to medication management. To explore how informal caregivers manage medications for their older adult care recipients by identifying the activities involved in medication management and the tools or strategies used to facilitate these activities. Four focus groups with caregivers of older adults were conducted with 5-9 caregivers per group. Participants were asked to describe the medication management activities performed and the tools or strategies used to facilitate these activities. Focus groups were recorded, transcribed verbatim, and analyzed for themes using an inductive approach. Caregivers were commonly involved in 2 types of activities: direct activities requiring physical handling of medications such as obtaining medications, preparing pill boxes, and assisting with medication administration; and indirect activities that were more complex and required more of a cognitive effort by the caregiver, such as organizing and tracking medications, gathering information, and making treatment decisions. They utilized a variety of tools and strategies to support these medication management activities; however, these approaches often needed to be modified or personalized to meet the specific needs of their caregiving situation. Informal caregivers play a vital role in ensuring safe and appropriate medication use by older adults. Medication management is complex and involves many activities that are supported through the use of a variety of tools and strategies that have been adapted and individualized to each specific caregiving scenario. Caregivers should be an important component of interventions that aim to improve medication use among older adults.


The roots of flight nursing: Lauretta M. Schimmoler and the Aerial Nurse Corps of America.
In any history of flight nursing or aeromedical evacuation, one usually sees reference to Lauretta Schimmoler and the Aerial Nurse Corps of America. A pioneer aviatrix with the foresight to see that one day there would be a need for military evacuation of wounded troops by air, Schimmoler spent nearly 15 years developing a paramilitary nursing organization that proved that such a thing could be successfully accomplished. This paper will survey the career of this remarkable woman, examine the structure and function of her organization, and discuss why it never gained official recognition by the military or the Red Cross.


An invertebrate hyperglycemic model for the identification of anti-diabetic drugs.
The number of individuals diagnosed with type 2 diabetes mellitus, which is caused by insulin resistance and/or abnormal insulin secretion, is increasing worldwide, creating a strong demand for the development of more effective anti-diabetic drugs. However, animal-based screening for anti-diabetic compounds requires sacrifice of a large number of diabetic animals, which presents issues in terms of animal welfare. Here, we established a method for evaluating the anti-diabetic effects of compounds using an invertebrate animal, the silkworm, Bombyx mori. Sugar levels in silkworm hemolymph increased immediately after feeding silkworms a high glucose-containing diet, resulting in impaired growth. Human insulin and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator, decreased the hemolymph sugar levels of the hyperglycemic silkworms and restored growth. Treatment of the isolated fat body with human insulin in an in vitro culture system increased total sugar in the fat body and stimulated Akt phosphorylation. These responses were inhibited by wortmannin, an inhibitor of phosphoinositide 3 kinase. Moreover, AICAR stimulated AMPK phosphorylation in the silkworm fat body. Administration of aminoguanidine, a Maillard reaction inhibitor, repressed the accumulation of Maillard reaction products (advanced glycation end-products; AGEs) in the hyperglycemic silkworms and restored growth, suggesting that the growth defect of hyperglycemic silkworms is caused by AGE accumulation in the hemolymph. Furthermore, we identified galactose as a hypoglycemic compound in jiou, an herbal medicine for diabetes, by monitoring its hypoglycemic activity in hyperglycemic silkworms. These results suggest that the hyperglycemic silkworm model is useful for identifying anti-diabetic drugs that show therapeutic effects in mammals.


Food ingredients as anti-obesity agents: a review.
Overweight and obesity have a major impact on global health; their prevalence has rapidly increased in all industrialized countries in the past few decades and diabetes and hypertension are their direct consequences. Pharmacotherapy provides reinforcement for obesity treatment, but should be an adjunctive support to diet, exercise, and lifestyle modification. At present, only orlistat and sibutramine have been approved by the US Food and Drug Administration for long-term use, but sibutramine was withdrawn for sale by the European Medicines Agency. The development of functional foods for the prevention and/or treatment of obesity suppose an opportunity for the food market and involve the knowledge of the mechanisms of appetite and energy expenditure as well as the metabolic sensation of satiety. Strategies for weight control management affect gut hormones as potential targets for the appetite metabolic regulation, stimulation of energy expenditure (thermogenesis), and modifications in the metabolic activity of the gut microbiota. Functional foods for obesity may also include bioactive fatty acids, phenolic compounds, soybean, plant sterols, dietary calcium, and dietary fiber. This review intends to offer an overview of the present situation of the anti-obesity agents currently used in dietary therapy as well as some functional food ingredients with potentially anti-obesity effects.


Pleuropulmonary blastoma: a report from the TREP (Tumori Rari in Età Pediatrica) Project.
Pleuropulmonary blastoma (PPB) is a rare, aggressive mesenchymal tumor of childhood. The Italian Tumori Rari in Età Pediatrica (TREP) Registry was the first in Europe dedicated to prospective data collection on rare pediatric tumors. We analyzed data from an Italian series of patients with PPB, focusing on the role of the TREP Project. We considered patients aged 0-14 with histologically confirmed diagnosis, registered in population-based cancer registries (before 2000) or the TREP Registry (2000 to 2014), and analyzed data on clinical characteristics, treatment, and outcome. Event-free survival (EFS) and overall survival (OS) were estimated. Relevant prognostic factors were identified performing a univariate analysis. Thirty-seven cases were included (7 type I, 13 type II, 17 type III). The average diagnosis rate rose from 1.10 to 1.73 cases/year after the TREP Project started. All patients underwent surgery, 33 received chemotherapy, and 9 had radiotherapy. The median follow-up was 8.7 years. For type I, II, and III, respectively, the 5-year OS was 85.7% (33.4-97.9), 52.7% (23.4-75.5), and 57.8% (31.1-77.3); the 5-year EFS was 85.7% (33.4-97.9), 52.7% (23.4-75.5), and 52.9% (27.6-73.0). Favorable prognostic factors for EFS were Intergroup Rhabdomyosarcoma Study (IRS) stage I (p = 0.03) and T1 tumor (p = 0.05). A total of 78.3% of patients who had chemotherapy after 2000 received a standardized treatment. The TREP Registry showed an excellent capacity for registering cases of PPB. Patients received homogeneous treatment after the TREP Project started. Long-term outcomes were excellent for type I and unsatisfactory for type II and III. Tumor invasiveness and IRS stage were of prognostic value.


Uncoupling learning from initial recall: the relationship between speed and memory deficits in old age.
Nettelbeck & Rabbitt (1992) found that measures of speed of performance with low knowledge requirements (four-choice reaction time, inspection time and coding-substitution) accounted substantially for age-related changes among 104 persons aged from 54 to 85 years in a number of more complex cognitive measures reflecting general fluid ability. However, the numbers of words recalled from a list after either a single brief viewing of each word, or following a cumulative learning procedure across four trials, provided an exception to this general trend, leading to the conclusion that some aspects of memory may be independent of mental speed. A follow-up of 82 of the same people 18-20 months later was designed to partition performance in a similar cumulative learning procedure into an initial first recall component and a subsequent learning component. This was accomplished by fitting individual cumulative learning data with a hyperbolic power function which met the theoretical requirement of defining separate initial recall and learning parameters. These parameters were found to be independent and it was concluded that learning involved rehearsal, whereas first recall did not. The hyperbolic power function provided a good account for 92 per cent of individual cases. Analyses which combined Nettelbeck & Rabbitt's (1992) data with new measures confirmed the reliability of these authors' results. Furthermore, it was found that first recall, but not learning, was mediated by processing speed. Learning was relatively unaffected by age-related slowing in mental speed, suggesting that Nettelbeck & Rabbitt's results were the consequence of a strong rehearsal component in their memory tasks. Thus, while mental slowing is clearly one important aspect of cognitive decline during old age, it does not constitute a sufficient explanation for changes in all areas of cognitive functioning. Specifically, age-decline in rate of learning with rehearsal appeared to be independent of slowing in speed of information processing.


Surgical assessment clinic - One stop emergency out-patient clinic for rapid assessment, reduced admissions and improved acute surgical service: A quality improvement study.
There is increasing pressure on emergency services within the NHS requiring efficient, rapid assessment and management of patients. A subsequent reduction in hospital admissions reduces overall costs with an aim to improve quality of care. At the Royal Shrewsbury Hospital we run a one stop emergency surgical clinic. With strict criteria for admission to this clinic we have established a care pathway for those patients requiring urgent surgical review but not necessarily hospital admission. We reviewed our initial referral pathway to the emergency surgical assessment clinic. New guidelines were distributed to the local Care Coordination Centre (CCC) through which GP referrals to the clinic were made. A re-audit carried out 6 weeks later assessed change in clinical practice. With the introduction of guidelines for referral we significantly increased the percentage of appropriate referrals to the one stop emergency surgical clinic (42.9%-79.4%, p = 0.000017). The majority (75.8%) of appropriate referrals can be successfully managed on an urgent outpatient basis. Appropriate referrals unsuitable for discharge from clinic had genuine reasons for admission such as abnormal results on assessment, or a need for surgery. 97.8% of referrals not deemed appropriate for the clinic were admitted for inpatient management. By providing suitable guidance for referring practitioners we have optimised our clinic use significantly and improved our acute ambulatory surgical care. We have reduced admissions, provided rapid treatment and have established a service that helps address the ever increasing demand on acute services within the NHS.


[Kinetics of procalcitonin in infections caused by multidrug-resistant bacteria].
Procalcitonin guidance stimulates a reduction in the duration of antibiotic treatment in critically ill patients with a presumed bacterial infection, but its role in infections caused by multidrug-resistant bacteria has not been sufficiently explored. In this retrospective observational study, we analyzed procalcitonin curves of 32 patients with culture-confirmed ventilation-associated pneumonia (VAP) and catheter-related bloodstream infections (CRBSI) occurred during the period 11/1/2016 to 7/1/2019. Sixteen infections were caused by multidrug-resistant bacteria (10 CRBSI and 6 VAP) and other 16 by sensitive bacteria (10 CRBSI and 6 VAP). CRBSI generated by multidrug-resistant bacteria elicited significantly higher procalcitonin levels than CRBSI infections caused by sensitive bacteria (39 ± 30 υg/l vs. 10.7 ± 11 υg/l, p = 0.02). Patients with VAP caused by sensitive and multidrug-resistant bacteria elicited similar procalcitonin levels. The time to a decrease in procalcitonin level to less than 80% of the peak value or less than 0.5 υg/l upon effective antibiotic treatment was 7.2 ± 2.9 days in multidrug-resistant bacteria vs. 5 ± 1.8 days in sensitive bacteria (p = 0.03). In multidrug-resistant bacteria, the inflammatory response measured by procalcitonin is stronger and longer, even with an effective antibiotic treatment. However, the decline occurs before the conventional antibiotic scheme is completed. The potential application of antibiotic protocols guided by procalcitonin to these groups of patients grants further studies aimed to reduce exposure to antibiotics in critical multidrug-resistant infections.


Photodynamic therapy as an alternative antimicrobial modality for oral infections.
Infections of the mouth are mostly local in nature, but if left untreated, may lead to potentially life-threatening conditions. Mouth infections, such as caries, pulpitis, periodontal disease, and oral mucosal infections, such as mouth ulcers, are readily accessible and thus well suited to photodynamic therapy (PDT). Many organisms, which may cause infections in the oral cavity, have been found to be susceptible to PDT to varying degrees. Several photosensitizers have been shown to be effective against target organisms without inducing damage to the host tissues. The use of appropriate photosensitizers and light doses can eradicate virtually all organisms in the region, but in the oral cavity where there is a balance of native microflora, this would potentially be a problem leading to the overgrowth of opportunistic organisms. This may be overcome using a photosensitizer linked to an antibody recognizing the target organisms. At present, treatment of infections with PDT appears best for localized and superficial infections. Treatment of deeply seated infections, such as abscesses, may also be possible with improvements in the delivery of the sensitizer and light. PDT has the potential to become established as an alternative antimicrobial approach for oral infections and deserves further evaluation.


Induction of apoptosis by Antrodia camphorata in human premyelocytic leukemia HL-60 cells.
Antrodia camphorata (A. camphorata) is well known in Taiwan as a traditional Chinese medicine, and it has been shown to exhibit antioxidant effects. In this study, the ability of A. camphorata to induce apoptosis was studied in cultured human premyelocytic leukemia HL-60 cells. Treatment of the HL-60 cells with a variety of concentrations of the fermented culture broth of A. camphorata (25-150 microg/ml) resulted in dose- and time-dependent sequences of events marked by apoptosis, as shown by loss of cell viability, chromatin condensation, and internucleosomal DNA fragmentation. Furthermore, apoptosis in the HL-60 cells was accompanied by the release of cytochrome c, activation of caspase-3, and specific proteolytic cleavage of poly (ADP-ribose) polymerase (PARP). This increase in A. camphorata-induced apoptosis was also associated with a reduction in the levels of Bcl-2, a potent cell-death inhibitor, and an increase in those of the Bax protein, which heterodimerizes with and thereby inhibits Bcl-2. The data suggest that A. camphorata exerts antiproliferative action and growth inhibition on HL-60 cells through apoptosis induction and that it may have anticancer properties valuable for application in drug products.


Structural determinants of adenophostin A activity at inositol trisphosphate receptors.
Adenophostin A is the most potent known agonist of inositol 1,4,5-trisphosphate (InsP(3)) receptors. Ca(2+) release from permeabilized hepatocytes was 9.9 +/- 1.6-fold more sensitive to adenophostin A (EC(50), 14.7 +/- 2.4 nM) than to InsP(3) (145 +/- 10 nM), consistent with the greater affinity of adenophostin A for hepatic InsP(3) receptors (K(d) = 0.48 +/- 0.06 and 3.09 +/- 0.33 nM, respectively). Here, we systematically modify the structures of the glucose, ribose, and adenine moieties of adenophostin A and use Ca(2+) release and binding assays to define their contributions to high-affinity binding. Progressive trimming of the adenine of adenophostin A reduced potency, but it fell below that of InsP(3) only after complete removal of the adenine. Even after substantial modifications of the adenine (to uracil or even unrelated aromatic rings, retaining the beta-orientation), the analogs were more potent than InsP(3). The only analog with an alpha-ribosyl linkage had massively decreased potency. The 2'-phosphate on the ribose ring of adenophostin A was essential and optimally active when present on a five-membered ring in a position stereochemically equivalent to its location in adenophostin A. Xylo-adenophostin, where xylose replaces the glucose ring of adenophostin A, was only slightly less potent than adenophostin A, whereas manno-adenophostin (mannose replacing glucose) had similar potency to InsP(3). These results are consistent with the relatively minor role of the 3-hydroxyl of InsP(3) (the equivalent is absent from xylo-adenophostin) and greater role of the equatorial 6-hydroxyl (the equivalent is axial in manno-adenophostin). This is the first comprehensive analysis of all the key structural elements of adenophostin A, and it provides a working model for the design of related high-affinity ligands of InsP(3) receptors.


Myeloperoxidase Controls Bone Turnover by Suppressing Osteoclast Differentiation Through Modulating Reactive Oxygen Species Level.
Myeloperoxidase (MPO) is a heme peroxidase that plays an important role in innate immunity for host defense against invading microorganisms by catalyzing hydrogen peroxide (H2 O2 )-mediated reactions. Although many reports indicate MPO exerts beneficial or detrimental effects on a variety of inflammatory diseases, little is known with regard to its functional role in bone homeostasis in vivo. Here, our work demonstrates that MPO was transcriptionally downregulated in response to osteoclastogenic stimuli and that exogenous alteration of MPO expression negatively regulated osteoclast (OC) differentiation in vitro. Genetic ablation of Mpo resulted in osteoporotic phenotypes and potentiated bone-resorptive capacity in mice. Mechanistically, accumulation of intracellular H2 O2 and reactive oxygen species (ROS) were observed in MPO deficiency, and MPO overexpression suppressed ROS production in mouse OC precursors. Moreover, a ROS scavenger Tempol inhibited the effect of MPO deficiency on OC formation and function as well as on receptor activator of nuclear factor-κB ligand (RANKL)-initiated transduction signal activation including NF-κB, mitogen-activated protein kinases (MAPKs), and Akt, indicating the increased ROS caused by MPO deficiency contributes to osteoclastogenesis. Taken together, our data demonstrate that MPO has a protective role in bone turnover by limiting osteoclastogenesis and bone resorption physiologically through modulating intracellular H2 O2 level. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Uptake of HDL-cholesterol contributes to lipid accumulation in clear cell renal cell carcinoma.
Clear cell renal cell carcinoma (ccRCC), which accounts for the majority of kidney cancer, is known to accumulate excess cholesterol. However, the mechanism and functional significance of the lipid accumulation for development of the cancer remains obscure. In this study, we analyzed 42 primary ccRCC samples, and determined that cholesterol levels of ~ 70% of the tumors were at least two-fold higher than that of benign kidney tissues. Compared to tumors without cholesterol accumulation, those containing excess cholesterol expressed higher levels of scavenger receptor BI (SR-B1), a receptor for uptake of HDL-associated cholesterol, but not genes involved in cholesterol synthesis and uptake of LDL-associated cholesterol. To further determine the roles of sterol accumulation for cancer development, we implanted ccRCC from patients into mouse kidneys using a mouse ccRCC xenograft model. Feeding mice with probucol, a compound lowing HDL-cholesterol, markedly reduced levels of cholesterol in tumors containing excess cholesterol. This treatment, however, did not affect growth of these tumors. Our study suggests that cholesterol overaccumulation in ccRCC is the consequence of increased uptake of HDL-cholesterol as a result of SR-B1 overexpression, but the lipid accumulation by itself may not play a significant role in progression of the cancer.


Detection of cancer cells in the cerebrospinal fluid: current methods and future directions.
The spread of cancer into the central nervous system is a serious problem leading to neurological symptoms and rapid mortality. The current tools available for detecting the spread of cancer into the cerebrospinal fluid (CSF) are cytology, neurologic examination, and neuroimaging. All three of these methods can be applied in concert to reach a diagnosis, but they all suffer from a lack of sensitivity, leading to delays in treatment in many cases. An overview of research tools in the field of CSF cancer detection reveals a variety of promising technologies that can be used to answer questions about the biology of metastatic cancer and to develop more powerful clinical detection methods. Methods currently under investigation include new immunocytochemistry methods and flow cytometry for the in vitro detection of cells. Additionally, polymerase chain reaction, fluorescence in situ hybridization, capillary electrophoresis with laser-induced fluorescence, and mass spectrometry using matrix-assisted laser absorption-deionization time-of-flight and surface-enhanced laser desorption/ionization time-of-flight techniques are being tested for in vitro assessment of the non-cellular biomarkers in CSF. For in vivo detection of cancer in the CSF, research techniques include certain quantum dot platforms as well as magnetic iron oxide nanoparticles. As systemic therapies for cancer improve, the CNS is becoming a more common site of disease recurrence. This increases the importance of effective detection methods in the CSF, since early intervention can maximize therapeutic benefit. Furthermore, many cell-based detection methods can be combined with therapeutic agents to serve multiple medical functions through a common targeting system.


Vascular smooth muscle sensitivity to varying oxygen tensions, Bay K 8644 and nifedipine.
With the suggestion that while high oxygen levels may alter the response beyond the receptor, with wrong information about excitation-contraction coupling; it was observed that levels of oxygen affect both the calcium channel blockers and facilitators with net reduction of influx or utilisation of external calcium. In this our study, using rat tail artery activated by noradrenaline and potassium chloride in the presence of Bay K. 8644 and nifedipine at different oxygen levels, we showed that desensitisation of the responses of the vascular smooth muscle occurred. It was evident that the underlying basis of vascular responses observed with different oxygen levels was apparently due to shifting of the control curves. Hence, drugs which modify calcium channels functions may in vitro, be altered qualitatively and quantitatively by hyperoxic conditions, in receptor or voltage sensitive calcium channels, since oxygen appears to exert facilitatory effects on calcium channels.


The control of Azorhizobium caulinodans nifA expression by oxygen, ammonia and by the HF-I-like protein, NrfA.
The control of Azorhizobium caulinodans nifA expression in response to oxygen and ammonia involves FixLJ, FixK, NtrBC, NtrXY and the HF-I-like protein NrfA. The regulation is thus complex and possibly involves post-transcriptional regulation by NrfA. The coding region of nifA was determined using a translational lacZ fusion and by site-directed mutagenesis to identify which of four in frame AUG codons was used. The major NifA protein is translated from the second AUG codon and is predicted to consist of 613 amino acids. Primer extension analysis showed a major transcript starting 34 bp downstream from the anaerobox in wild-type, nifA, rpoN, ntrC and nrfA strains, but not in a fixK mutant. FixK- and oxygen-dependent transcription of nifA was confirmed by the analysis of four transcriptional nifA-lacZ fusions with fusion junctions at positions +1, +47, +110 and +181 with respect to the start site. Regulation by ammonia was independent of FixK and RpoN, NtrC being only partially required. Thus, there may be another type of nitrogen control that does not involve NtrC in A. caulinodans. NrfA is not required for the initiation of nifA transcription but, most probably, has an effect on nifA mRNA stability and/or translation. NrfA also restores the defect in rpoS translation to an Escherichia coli hfq mutant, indicating that HF-I and NrfA have similar activities in both A. caulinodans and E. coli.


Human pontine glioma cells can induce murine tumors.
Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9 months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy (1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or (2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprising human cells. Of note, direct injection of cells obtained postmortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.


Proteomic profiling of developing cotton fibers from wild and domesticated Gossypium barbadense.
Pima cotton (Gossypium barbadense) is widely cultivated because of its long, strong seed trichomes ('fibers') used for premium textiles. These agronomically advanced fibers were derived following domestication and thousands of years of human-mediated crop improvement. To gain an insight into fiber development and evolution, we conducted comparative proteomic and transcriptomic profiling of developing fiber from an elite cultivar and a wild accession. Analyses using isobaric tag for relative and absolute quantification (iTRAQ) LC-MS/MS technology identified 1317 proteins in fiber. Of these, 205 were differentially expressed across developmental stages, and 190 showed differential expression between wild and cultivated forms, 14.4% of the proteome sampled. Human selection may have shifted the timing of developmental modules, such that some occur earlier in domesticated than in wild cotton. A novel approach was used to detect possible biased expression of homoeologous copies of proteins. Results indicate a significant partitioning of duplicate gene expression at the protein level, but an approximately equal degree of bias for each of the two constituent genomes of allopolyploid cotton. Our results demonstrate the power of complementary transcriptomic and proteomic approaches for the study of the domestication process. They also provide a rich database for mining for functional analyses of cotton improvement or evolution.


Role of commensal relationships on the spatial structure of a surface-attached microbial consortium.
A flow cell-grown model consortium consisting of two organisms, Burkholderia sp. LB400 and Pseudomonas sp. B13(FR1), was studied. These bacteria have the potential to interact metabolically because Pseudomonas sp. B13(FR1) can metabolize chlorobenzoate produced by Burkholderia sp. LB400 when grown on chlorobiphenyl. The expected metabolic interactions in the consortium were demonstrated by high performance liquid chromatography (HPLC) analysis. The spatial structure of the consortium was studied by fluorescent in situ rRNA hybridization and scanning confocal laser microscopy. When the consortium was fed with medium containing a low concentration of chlorobiphenyl, microcolonies consisting of associated Burkholderia sp. LB400 and Pseudomonas sp. B13(FR1) bacteria were formed, and separate Pseudomonas sp. B13(FR1) microcolonies were evidently not formed. When the consortium was fed citrate, which can be metabolized by both species, the two species formed separate microcolonies. The structure development In the consortium was studied online using a gfp-tagged Pseudomonas sp. B13(FR1) derivative. After a shift In carbon source from citrate to a low concentration of chlorobiphenyl, movement of the Pseudomonas sp. B13(FR1) bacteria led to a change in the spatial structure of the consortium from the unassociated form towards the associated form within a few days. Experiments Involving a gfp-based Pseudomonas sp. B13(FR1) growth activity reporter strain Indicated that chlorobenzoate supporting growth of Pseudomonas sp. B13(FR1) is located close to the Burkholderia sp. LB400 microcolonies in chlorobiphenyl-grown consortia.


Impact of COVID-19 on inpatient referral of acute heart failure: a single-centre experience from the south-west of the UK.
Healthcare services worldwide have been significantly impacted by the COVID-19 pandemic. Recent reports have shown a decline in hospitalization for emergency cardiac conditions. The impact of the COVID-19 pandemic on hospitalization and particularly mortality due to acute heart failure has not been thoroughly described. In this single-centre observational study, we examined referrals to the acute heart failure team over a period of 16 weeks (7 January to 27 April 2020) spanning the ongoing COVID-19 pandemic; 283 patients referred to our acute heart failure services over the study period were included on the basis of typical symptoms, raised BNP, and echocardiogram. There was a substantial but statistically non-significant drop in referrals with 164 referred in the 8 weeks before the first UK death due to COVID-19 on 2 March 2020 (BC), compared with 119 referred after (AC) in the subsequent 8 weeks, representing a 27% reduction overall (P = 0.06). The 30 day case fatality rate was increased from 11% in the BC group compared with 21% in the AC group (risk ratio = 1.9, 95% confidence interval 1.09-3.3). Age, gender, length of stay, left ventricular ejection fraction, and N-terminal pro-brain natriuretic peptide were similar between the groups. Admission creatinine, age, and AC cohort status were found to be univariable predictors of mortality. On multivariate Cox regression analysis, only age (hazard ratio 1.04, P = 0.03) and AC cohort status (hazard ratio 2.1, P = 0.017) remained significant predictors of mortality. On sensitivity analysis, this increased mortality was driven by COVID-19 positive status. There was a reduction in referral of patients with acute heart failure with significant increase in mortality in the 8 weeks following the first reported UK death due to COVID-19. The observation of increased mortality does not appear related to a change in population in terms of demographics, left ventricular ejection fraction, or N-terminal pro-brain natriuretic peptide. The observed increased mortality appears to be related to the coexistence of COVID19 infection with acute heart failure. The study highlights the need for widespread preventative and shielding measures particularly in this group of patients especially in the light of the second wave. Longer follow-up with inclusion of data from other centres and community heart failure services will be needed.


Whole-grain intake and insulin sensitivity: the Insulin Resistance Atherosclerosis Study.
Increased intake of whole-grain foods has been related to a reduced risk of developing diabetes and heart disease. One underlying pathway for this relation may be increased insulin sensitivity. We assessed the relation between dietary intake of whole grain-containing foods and insulin sensitivity (S(I)). We evaluated data from the Insulin Resistance Atherosclerosis Study (IRAS Exam I, 1992-1994). Usual dietary intakes in 978 middle-aged adults with normal (67%) or impaired (33%) glucose tolerance were ascertained by using an interviewer-administered, validated food-frequency questionnaire. Whole-grain intake (servings per day) was derived from dark breads and high-fiber and cooked cereals. S(I) was assessed by minimal model analyses of the frequently sampled intravenous-glucose-tolerance test. Fasting insulin was measured by using a radioimmunoassay. We modeled the relation of whole-grain intake to log(S(I) + 1) and to log(insulin) by using multivariable linear regression. On average, IRAS participants consumed 0.8 servings of whole grains/d. Whole-grain intake was significantly associated with S(I) (beta = 0.082, P = 0.0005) and insulin (beta = -0.0646, P = 0.019) after adjustment for demographics, total energy intake and expenditure, smoking, and family history of diabetes. The addition of body mass index and waist circumference attenuated but did not explain the association with S(I). The addition of fiber and magnesium resulted in a nonsignificant association that is consistent with the hypothesis that these constituents account for some of the effect of whole grains on S(I). Higher intakes of whole grains were associated with increases in insulin sensitivity.


Bone-resorbing agents promote and interferon-gamma inhibits bone cell collagenase production.
Parathyroid hormone, prostaglandin E2, 1 alpha,25-dihydroxyvitamin D3, interleukin-1, tumor necrosis factor alpha, and epidermal growth factor, all known stimulators of bone resorption, markedly enhanced collagenase secretion by rat fetus osteoblastlike cells in primary culture as judged by enzyme-linked immunosorbent assay. Untreated cells contained no immunostainable or extractable collagenase. Collagenase was detected in the treated cells and media only after 1-3 h of treatment, and there was no increment in collagenase activity when cells were treated in the presence of actinomycin D or cycloheximide. Cells secreted collagenase in a latent form and also elaborated collagenase inhibitor; chromatographic separation of collagenase from collagenase inhibitor and subsequent activation of the collagenase with trypsin yielded the active species in stimulated but not in unstimulated cells. The ability of individual prostanoids, among seven tested, to promote collagenase production correlated positively with their reported capacity to promote bone resorption. Interferon-gamma (IFN-gamma), a known resorption inhibitor, blocked the increment in collagenase production caused by all agents tested. These results indicate a close linkage between stimulation of bone resorption and collagenase production by osteoblastlike cells. Various resorption stimulators, including some not previously tested for effects on collagenase, augment the de novo synthesis and secretion of collagenase and act by an IFN-gamma-inhibitable mechanism.


Parental support buffers the association of depressive symptoms with cortisol and C-reactive protein during adolescence.
Social experiences can affect the relationship between depression and physical health. The current study examined how social support from parents and friends may moderate the association of depressive symptoms with hypothalamic-pituitary-adrenal (HPA) axis activity and C-reactive protein among adolescents (N=316, Mage=16.40, SD=.74; 57% female) from diverse ethnic backgrounds (23.1% Asian, 29.1% European, 41.8% Latino, and 6.0% other backgrounds). Results indicated that parent support, but not friend support, moderated the link between depressive symptoms and both total daily cortisol output (a measure HPA activity) and C-reactive protein (a marker of inflammation). These patterns did not differ by ethnicity. Overall, the study highlights the continued, and perhaps accumulated, importance of parents during adolescence despite increasing needs for autonomy from and exploration outside of the family unit.


Acetylcholine and caffeine activate Cl- and suppress K+ conductances in human bronchial smooth muscle.
The conductance changes underlying agonist-evoked depolarization in human airway smooth muscle (ASM) were examined using single ASM cells liberated enzymatically from noncarcinomatous bronchi and studied using patch-clamp techniques. Step commands to potentials at or more positive than the resting membrane potential evoked outward current, which was predominantly delayed rectifier K+ current with some Ca(2+)-dependent K+ current Caffeine (5 mM) evoked depolarization and contraction lasting several minutes. During voltage clamp at -60 mV, caffeine evoked inward current with a latency of approximately equal to 1 s, mean amplitude of 320 +/- 65 pA, and a duration of approximately equal to 5 s (even though agonist application exceeded this duration). With the use of the perforated-path configuration, these responses could be evoked repeatedly at 4-min intervals for up to 30 min; rupture of the membrane and dialysis of the cytosol, however, abrogated the responses to caffeine. The current was outwardly rectifying with mean reversal potential (Vrev) of -31 +/- 4 mV. When K+ conductances were blocked by Ca+, the current-voltage (I-V) relationship was linear (i.e., an outwardly-rectifying component was eliminated) and Vrev was displaced in the positive direction to +2 +/- 1 mV. Changes in the CL- equilibrium potential were accompanied by a displacement of Vrev in a manner predicted by the Nernst equation for a Cl- current. The effects of caffeine were mimicked by acetylcholine; in addition, acetylcholine and caffeine each occluded the response to the other agonist. Spasmogens also caused a prolonged suppression of K+ currents (both Ca(2+)--dependent and delayed rectifier). We conclude that, in human ASM, acetylcholine and caffeine cause a transient activation of Ca(2+)--dependent Cl- current (due to release of internal Ca2+) and prolonged suppression of K+ currents, leading to depolarization and contraction.


Household characteristics for older adults and study background from SAGE Ghana Wave 1.
Globally, the population aged 60 years and older is projected to reach 22% by 2050. In sub-Saharan Africa, this figure is projected to exceed 8%, while in Ghana, the older adult population will reach 12% by 2050. The living arrangements and household characteristics are fundamental determinants of the health and well-being of this population, data sources about which are increasingly available. The World Health Organization's Study on global AGEing and adult health (SAGE) Wave 1 was conducted in China, Ghana, India, Russian Federation, Mexico, and South Africa between 2007 and 2010. SAGE Ghana Wave 1 was implemented in 2007/08 using face-to-face interviews in a nationally representative sample of persons aged 50-plus, along with a smaller cohort aged 18-49 years for comparison purposes. Household information included a household roster including questions about health insurance coverage for all household members, household and sociodemographic characteristics, status of the dwelling, and economic situation. Re-interviews were done in a random 10% of the sample and proxy interviews done where necessary. Verbal autopsies were conducted for deaths occurring in older adult household members in the 24 months prior to interview. The total household population was 27,270 from 5,178 households. The overall household response rate was 86% and household cooperation rate was 98%. Thirty-four percent of household members were under 15 years of age while 8.3% were aged 65-plus years. Households with more than 11 members were more common in rural areas (57.2%) and in the highest income quintile (30.6%). Household members with no formal education formed 24.7% of the sample, with Northern and Upper East regions reaching more than 50%. Only 26.8% of the household members had insurance coverage. Households with hard floors ranged from 25.7% in Upper West to 97.7% in Ashanti region. Overall, 84.9% of the households had access to improved sources of drinking water, with the lowest at 29.6% in the Volta region. The overall rate of access to improved sanitation was just 14.9%. The findings show significant regional differences, with the three Northern Regions having worse education, income, and sanitation levels, compared to Southern and Central Regions of the country. Household characteristics and intra-household dynamics have been shown to influence health and health-seeking behaviors across a number of contexts and countries, and play a fundamental role in the well-being of older Ghanaians. SAGE Ghana is part of a multi-country study using standardized questionnaires and tested methodologies to provide household level data required to inform policy on the growing population of older adults in Ghana. With the good response rates and measures instituted to assure quality of data, this article demonstrates the high quality data and research methods of SAGE.


[Gender differences in premature mortality and avoidable deaths].
This paper aims to describe and to analyse disparities between men and women for "premature" mortality rates (deaths before 65 year-old). The study is particularly focused on "avoidable" causes of death. These types of deaths are greatly related to risk behaviours such as alcohol abuse, tobacco abuse or dangerous driving. Taking account of these indicators ("premature" and "avoidable" mortality) enables to study health status discrepancies by gender and to characterize specific public health issues in France including high rates of "premature" mortality and risk behaviours. The analysis is based on exhaustive mortality data from 1980 to 1999 supplied by the Centre for epidemiology of medical causes of death (CepiDc-INSERM). Specific causes of death closely related to risk behaviours are classified as "avoidable": lung and upper airways cancers, cirrhosis, alcoholic psychosis, traffic accidents, aids and suicide. The contribution of these categories in the global male overmortality was assessed according to different demographic and geographic characteristics. Within "premature" mortality, males experience greater burden of "avoidable" mortality (sex-ratio: 4 versus 2). The gender differences are mainly due to injuries and suicides in the younger age groups and to tobacco and alcohol-related cancers (lung and upper airways) in the 45-64 years age group. The recent decline in "premature" mortality sex-ratio is explained by an increase of these two cancers for females. Among european countries, the French male overmortality is especially marked and mainly attributable to "avoidable" causes of death. "Avoidable" and "premature" mortality provide useful tools for the follow-up of health status in France particularly because of high risk behaviours and prevention inadequacy. Reducing gender discrepancies will depend mainly on public health policies in terms of primary prevention.


Blacklists and Whitelists To Tackle Predatory Publishing: a Cross-Sectional Comparison and Thematic Analysis.
We aimed to develop an in-depth understanding of quality criteria for scholarly journals by analyzing journals and publishers indexed in blacklists of predatory journals and whitelists of legitimate journals and the lists' inclusion criteria. To quantify content overlaps between blacklists and whitelists, we employed the Jaro-Winkler string metric. To identify topics addressed by the lists' inclusion criteria and to derive their concepts, we conducted qualitative coding. We included two blacklists (Beall's and Cabells Scholarly Analytics') and two whitelists (the Directory of Open Access Journals' and Cabells Scholarly Analytics'). The number of journals per list ranged from 1,404 to 12,357, and the number of publishers ranged from 473 to 5,638. Seventy-two journals and 42 publishers were included in both a blacklist and a whitelist. Seven themes were identified in the inclusion criteria: (i) peer review; (ii) editorial services; (iii) policy; (iv) business practices; (v) publishing, archiving, and access; (vi) website; and (vii) indexing and metrics. Business practices accounted for almost half of the blacklists' criteria, whereas whitelists gave more emphasis to criteria related to policy. Criteria could be allocated to four concepts: (i) transparency, (ii) ethics, (iii) professional standards, and (iv) peer review and other services. Whitelists gave most weight to transparency. Blacklists focused on ethics and professional standards. Whitelist criteria were easier to verify than those used in blacklists. Both types gave little emphasis to quality of peer review. Overall, the results show that there is overlap of journals and publishers between blacklists and whitelists. Lists differ in their criteria for quality and the weight given to different dimensions of quality. Aspects that are central but difficult to verify receive little attention.IMPORTANCE Predatory journals are spurious scientific outlets that charge fees for editorial and publishing services that they do not provide. Their lack of quality assurance of published articles increases the risk that unreliable research is published and thus jeopardizes the integrity and credibility of research as a whole. There is increasing awareness of the risks associated with predatory publishing, but efforts to address this situation are hampered by the lack of a clear definition of predatory outlets. Blacklists of predatory journals and whitelists of legitimate journals have been developed but not comprehensively examined. By systematically analyzing these lists, this study provides insights into their utility and delineates the different notions of quality and legitimacy in scholarly publishing used. This study contributes to a better understanding of the relevant concepts and provides a starting point for the development of a robust definition of predatory journals.


Right Heart Clot-in-Transit: Endovascular Therapies.
Right heart thrombus is a challenging high mortality disease typically seen in the setting of pulmonary embolism. Traditional treatments have included anticoagulation, thrombolysis, and surgical embolectomy. Advances in recognition and treatment of clot-in-transit have led to the development of endovascular therapies increasingly becoming the preferred method of treatment due to rapid debulking and lower morbidity. Novel endovascular devices are large bore aspiration thrombectomy systems which mitigate the use of concomitant thrombolytics. The article reviews the disease process, relevant literature, and current endovascular devices and strategies for the treatment of right heart thrombus and clot-in-transit.


The Role of Executive Function in the Effectiveness of Multi-Component Interventions Targeting Physical Activity Behavior in Office Workers.
A knowledge gap remains in understanding how to improve the intervention effectiveness in office workers targeting physically active (PA) behavior. We aim to identify the modifying effect of executive function (EF) on the intervention effectiveness targeting PA-behaviors, and to verify whether the observed effect varies by Job Demand Control (JDC) categories. This workplace-based intervention study included 245 participants who were randomized into a control group and two intervention arms-promoting physical activity (iPA) group or reducing sedentary behavior (iSED) group. The interventions were conducted through counselling-based cognitive behavioral therapy and team activities over 6 months. PA-behaviors were measured by an accelerometer. EF was assessed by the Trail Making Test-B, Stroop, and n-back test. The JDC categories were measured by the demand control questionnaire. Higher EF level at baseline was significantly associated with the intervention effect on increased sleep time (β-coefficient: 3.33, p = 0.003) and decreased sedentary time (-2.76, p = 0.049) in the iSED-group. Participants with active jobs (high job demands, high control) presented significantly increased light-intensity PA in the iSED-group in comparison to the control group. Among participants with a high level of EF and active jobs, relative to the control group, the iPA-group showed a substantial increase in light-intensity PA (1.58, p = 0.036) and the iSED-group showed a tendency of reducing sedentary behavior (-5.35, p = 0.054). The findings suggest that office workers with a high EF and active jobs may benefit most from an intervention study targeting PA-behaviors.


Quantitating Changes in Jitter and Spike Number Using Concentric Needle Electrodes in Amyotrophic Lateral Sclerosis Patients.
Single-fiber electromyography (SFEMG) has been suggested as a quantitative method for supporting chronic partial denervation in amyotrophic lateral sclerosis (ALS) by the revised EI Escorial criteria. Although concentric needle (CN) electrodes have been used to assess jitter in myasthenia gravis patients and healthy controls, there are few reports using CN electrodes to assess motor unit instability and denervation in neurogenic diseases. The aim of this study was to determine whether quantitative changes in jitter and spike number using CN electrodes could be used for ALS studies. Twenty-seven healthy controls and 23 ALS patients were studied using both CN and single-fiber needle (SFN) electrodes on the extensor digitorum communis muscle with an SFEMG program. The SFN-jitter and SFN-fiber density data were measured using SFN electrodes. The CN-jitter and spike number were measured using CN electrodes. The mean CN-jitter was significantly increased in ALS patients (47.3 ± 17.0 μs) than in healthy controls (27.4 ± 3.3 μs) (P < 0.001). Besides, the mean spike number was significantly increased in ALS patients (2.5 ± 0.5) than in healthy controls (1.7 ± 0.3) (P < 0.001). The sensitivity and specificity in the diagnosis of ALS were 82.6% and 92.6% for CN-jitter (cut-off value: 32 μs), and 91.3% and 96.3% for the spike number (cut-off value: 2.0), respectively. There was no significant difference between the SFN-jitter and CN-jitter in ALS patients; meanwhile, there was no significant difference between the SFN-jitter and CN-jitter in healthy controls. CN-jitter and spike number could be used to quantitatively evaluate changes due to denervation-reinnervation in ALS.


[Dynamics of changes in the rat thymus gland as affected by intratracheal administration of 238Pu].
A study was made of the effect of intratracheal administration of 238Pu nitrate on rat thymus. Incorporation of an acutely effective dose of the radionuclide (740 kBq X kg-1) induced damages to all thymus structures. The optimal blastomogenic 238Pu amount (92.5 kBq X kg-1) administered during the chronic period of the disease caused complex changes of atrophic, hyper- and neoplastic nature the lymphoid component of the thymus being primarily damaged.


[Effects of 5-HT on activity of arcuate neurons of rat hypothalamic slices].
Extracellular recordings were made from 176 spontaneous discharging units in the arcuate nucleus of rat hypothalamic slices. Depending on the patterns of discharge, the units were divided into three types; slow irregular (76%), fast continuous (26.5%) and phasic units (6.3%). The effect of 5-HT on the different types of units were observed. The results indicated that most of neurons were inhibited by 5-HT, and only a small portion of the cells showed excitation and a few of the slow irregular units showed "excitation after inhibition". With 5-HT 10(-6) mol/L we found that 12 units inhibited by 5-HT could not be reversed by CHD, while the 4 inhibited units could be partly or completely reversed by MSG. 4 of the 7 neurons inhibited by 5-HT were partly blocked by Pindobind-5-HT1A but not for the remaining 3 neurons. The results suggest that the inhibitory effect of 5-HT on arcuate neurons may be mediated by 5-HT1 receptor, while some by 5-HT1A receptor.


Lack of intramembranous particle clusters in collecting ducts of mice with nephrogenic diabetes insipidus.
We suggested previously, on the basis of indirect evidence, that in two strains of mice with nephrogenic defects of urinary concentration the deficiency arose from an inadequate rise in water permeability of the collecting duct system. In this study we tested the question further by assuming that the frequency of intramembranous particle (IMP) clusters seen by freeze-fracture can be used as a morphological marker of vasopressin-induced water permeability. Three genotypes of mice were studied: 1) DI +/+ Severe, with florid, vasopressin-resistant diabetes insipidus; 2) DI +/+ Nonsevere, with an intermediate deficiency of urinary concentration; and 3) normal, VII +/+ mice. In addition, we examined a group of DI +/+ Severe mice that had been injected with exogenous 1-desamino-8-D-arginine vasopressin (DDAVP) subcutaneously for 3 days. Since the results in this group did not differ from those in untreated DI +/+ Severe mice, all data for this genotype were combined. IMP clusters within luminal membranes of inner medullary collecting duct principal cells were quantified by freeze-fracture electron microscopy. Urinary osmolality and percentage of cells showing clusters were, respectively: 203 +/- 43 mosmol/kg H2O and 0% in DI +/+ Severe mice; 1,133 +/- 86 and 33 +/- 4 in DI +/+ Nonsevere mice; and 2,234 +/- 190 and 52 +/- 5 in VII +/+ animals. With the exception of one animal, there was no overlap of the data, which were significantly different from one another for each variable. We conclude that in DI +/+ Severe mice, both endogenous and exogenous vasopressin are unable to increase the water permeability of medullary collecting ducts.(ABSTRACT TRUNCATED AT 250 WORDS)


A meta-analysis of randomized control trials of home-based secondary prevention programs for coronary artery disease.
A variety of different types of secondary prevention programs for coronary heart disease (CHD) exist. Home-based programs have become more common and may be more accessible or preferable to some patients. This review compared the benefits and costs of home-based programs with usual care and cardiac rehabilitation. A meta-analysis following a systematic search of 19 databases, existing reviews, and references was designed. Studies evaluated home-based interventions that addressed more than one main CHD risk factor using a randomized trial with a usual care or cardiac rehabilitation comparison group with data extractable for CHD patients only and reported in English as a full article or thesis. Thirty-nine articles reporting 36 trials were reviewed. Compared with usual care, home-based interventions significantly improved quality of life [weighted mean difference: 0.23; 95% confidence interval (95% CI): 0.02-0.45], systolic blood pressure (weighted mean difference: -4.36 mmHg; 95% CI: -6.50 to -2.22), smoking cessation (difference in proportion: 14%; 95% CI: 0.02-0.26), total cholesterol (standardized mean difference: -0.33; 95% CI: -0.57 to -0.08), and depression (standardized mean difference: -0.33; 95% CI: -0.59 to -0.07). Effect sizes were small to moderate and trials were of low-to-moderate quality. Comparisons with cardiac rehabilitation could not be made because of the small number of trials and high levels of heterogeneity. Home-based secondary prevention programs for CHD are an effective and relatively low-cost complement to hospital-based cardiac rehabilitation and should be considered for stable patients less likely to access or adhere to hospital-based services.


A positively selected FBN1 missense variant reduces height in Peruvian individuals.
On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.


Pulmonary surfactant: no mere paint on the alveolar wall.
The gas-liquid interface within the alveolus is completely lined with a complex mixture of lipids and unique proteins termed pulmonary surfactant, which both reduces surface tension and permits it to vary directly with the radius of curvature. In this way it minimizes the work of breathing and permits alveoli of different sizes to exist in equilibrium. However, surfactant does far more in that it also controls fluid balance in the lung and appears to play a key role in host defence. Either a deficiency in surfactant or an aberrant surfactant results in atelectasis and oedema. The surfactant system is very dynamic: alveolar surfactant phosphatidylcholine, the principal component, having a half life of only a few hours, with as much as 85% being recycled. Although distortion of the alveolar type II cell is now accepted as the principal stimulus for release, much remains to be discovered of modulating factors and intracellular signalling in the control of surfactant homeostasis. Likewise, many questions remain concerning the control of synthesis of the surfactant phospholipids, neutral lipids and proteins and their assembly into the tubular myelin form of alveolar surfactant, the refining of the monolayer with breathing, the control of re-uptake of different components into the type II cells and the roles of the proteins.


Mutational analysis of simian virus 40 T antigen: isolation and characterization of mutants with deletions in the T-antigen gene.
A series of mutants of simian virus 40 has been constructed with deletions in the coding sequence for large T antigen. Nucleotide sequence analysis indicates that 4 mutants have in-phase and 11 have out-of-phase deletions. Mutant DNAs were assayed for the following activities: the ability to form plaques, the ability to produce T antigen as scored by indirect immunofluorescence, viral DNA replication, and morphological transformation of rat cells. Two viable mutants were found, and these had deletions confined to the carboxyl terminus of T antigen. Only those mutants coding for polypeptides greater than 40% of the length of wildtype T antigen produced detectable nuclear fluorescence. The two viable mutants with deletions in the carboxyl terminus of the protein retained the ability both to replicate their DNA, although at a reduced level, and to transform nonpermissive cells. Mutants with sequence changes that result in the loss of more than 117 amino acids from the carboxyl terminus were not viable and were also defective in the DNA replication and transformation functions of T antigen, although several produced detectable nuclear fluorescence. These functions were also sensitive to the removal of amino acids near the amino terminus and in the middle of the protein.


Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors.
Papillary renal cell carcinoma is the second most common carcinoma of the renal tubules and has been characterized genetically. Its morphologic features are incompletely characterized. It has been suggested that the presence of cytokeratin 7 is specific for papillary renal cell carcinoma. Collecting duct carcinoma might have papillary architecture, and it has been suggested that reaction with the Ulex europaeus lectin is specific for it. Sections from 105 papillary renal cell carcinomas larger than 12 mm in diameter from 100 patients were studied, and immunohistochemical reactions were performed on 91. The tumors formed two morphologic groups. Type 1 (67 tumors) consisted of papillae and tubular structures covered by small cells with pale cytoplasm and characterized by small oval nuclei with inconspicuous nucleoli, frequent glomeruloid papillae, papillary edema, foamy macrophages in papillary cores, and psammoma bodies. Type 2 (38 tumors) consisted of papillae covered by large cells with abundant eosinophilic cytoplasm and characterized by pseudostratification and large spherical nuclei with prominent nucleoli, glomeruloid papillae, psammoma bodies, edematous papillae, and foamy macrophages in papillary cores are uncommon. Type 2 tumors were larger, more common in patients younger than age 40, and more frequently Stages 3 or 4 than were Type 1 tumors. Pseudocapsules were common in both and often were infiltrated by carcinoma. Sarcomatoid foci were found in five tumors. Eleven were stage T1, 54 T2, 23 T3, and 12 T4. Reaction for cytokeratin 7 was strong or moderate in 48 of 61 Type 1 tumors, and reaction was null in 24 of 30 Type 2 tumors. No tumor reacted with U. europaeus lectin.


Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study.
To determine whether use of cannabis in adolescence increases the risk for psychotic outcomes by affecting the incidence and persistence of subclinical expression of psychosis in the general population (that is, expression of psychosis below the level required for a clinical diagnosis). Analysis of data from a prospective population based cohort study in Germany (early developmental stages of psychopathology study). Population based cohort study in Germany. 1923 individuals from the general population, aged 14-24 at baseline. Incidence and persistence of subthreshold psychotic symptoms after use of cannabis in adolescence. Cannabis use and psychotic symptoms were assessed at three time points (baseline, T2 (3.5 years), T3 (8.4 years)) over a 10 year follow-up period with the Munich version of the composite international diagnostic interview (M-CIDI). In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021). Furthermore, continued use of cannabis increased the risk of persistent psychotic symptoms over the period from T2 to T3 (2.2, 1.2 to 4.2; P=0.016). The incidence rate of psychotic symptoms over the period from baseline to T2 was 31% (152) in exposed individuals versus 20% (284) in non-exposed individuals; over the period from T2 to T3 these rates were 14% (108) and 8% (49), respectively. Cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder by impacting on the persistence of symptoms.


Role of echocardiography in patients with intravascular hemolysis due to suspected continuous-flow LVAD thrombosis.
This study sought to characterize the echocardiographic findings of patients presenting with intravascular hemolysis (IVH) due to suspected continuous-flow left ventricular assist device (LVAD) pump thrombosis. LVAD patients who develop pump thrombosis often present with IVH. Echocardiography may be able to detect device dysfunction in this setting. Continuous-flow LVAD patients presenting with IVH due to suspected pump thrombosis were identified. Patients underwent echocardiography with cannula Doppler flow velocity interrogation. Findings were compared with baseline and follow-up studies, and with 49 stable LVAD control patients. Of 145 patients, 14 (10%) had IVH due to suspected pump thrombosis. The mean age was 55 ± 15 years, 93% were men, and 50% received LVAD as destination therapy. Mean duration between implantation and IVH was 231 ± 218 days. Eleven (79%) patients presented with hemoglobinuria, 9 (64%) with jaundice, and 5 (36%) with acute heart failure. Reduced cannula diastolic flow velocity and increased systolic/diastolic (S/D) flow velocity ratio were the only echocardiographic parameters significantly different from controls (outflow cannula 0.3 ± 0.2 m/s vs. 0.8 ± 0.3 m/s, p = 0.03, and 5.9 ± 2.8 vs. 1.7 ± 0.7, p < 0.01, respectively), and were worse for IVH patients with acute heart failure compared with those without (outflow cannula 0.2 ± 0.1 m/s vs. 0.5 ± 0.2 m/s, p = 0.04, and 7.2 ± 3.3 vs. 5.3 ± 2.0, p = 0.02, respectively). Outflow cannula diastolic flow velocity and S/D flow velocity ratio changed significantly from baseline (p = 0.01 and p < 0.01, respectively) in IVH patients, whereas systolic flow velocity did not change (p = 0.59). Odds ratios for outflow cannula diastolic flow velocity and S/D flow velocity ratio for predicting IVH were 0.60 (95% confidence interval [CI]: 0.51 to 0.73), p = 0.02, and 2.45 (95% CI: 2.37 to 2.52) p < 0.01, respectively. Corresponding inflow cannula values were similarly significant. Pump thrombosis was confirmed in 7 (50%) patients after LVAD retrieval. Reduced cannula diastolic flow velocity and increased S/D flow velocity ratio identified continuous-flow LVAD dysfunction in patients with IVH due to suspected pump thrombosis better than other echocardiographic parameters.


Potential biomarkers of temporomandibular joint disorders.
The purpose of this study was to identify protein markers present in subjects with temporomandibular joint disorders (TMDs) and clicking compared with the levels in controls. This was a pilot case-control study, and we report the preliminary results. Samples of joint aspirate collected from patients with TMDs and controls who had undergone surgery for a problem other than TMDs were analyzed using isobaric tags for relative and absolute quantitation (iTRAQ) and biotin-labeled-based protein arrays. The data obtained from these techniques were used to identify the proteins of interest, which were then quantitated using enzyme-linked immunosorbent assay (ELISA). The patient samples studied included joint aspirate collected clinically from the controls and patients and included samples from both the right and the left sides of each patient with a TMD. The 8 TMJ aspirate samples from 6 subjects included 5 aspirate samples from 4 patients and 3 from 2 controls. The greatest standardized protein concentration of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 (EG-VEGF/PK1) and D6 was found in both joints of the controls compared with the levels from the joints of the patients. With 1 exception, the standardized protein concentration was significantly lower in the patients than in the controls. The lower levels of EG-VEGF/PK1 and D6 in the patients compared with the controls suggest that these cytokines might be possible biomarkers for TMDs. In the present pilot study, greater levels of EG-VEGF/PK1 and D6 were found in the controls than in the patients with TMDs. Proteomic analysis of the proteins present in the diseased joints compared with those in the controls might help to identify proteins present when pain or degeneration of the joint occurs. The proteomic information might be useful in the development of future therapies.


Hepatitis C infection and outcomes in the Scottish haemophilia population.
Patients with bleeding disorders previously frequently became infected with hepatitis C virus. We identified the number of patients infected in Scotland and assessed several aspects of the outcomes of HCV infection and its treatment comparing these with cohorts infected for other reasons. We calculated the number of individuals infected in Scotland (cohort A) starting with the total number of patients treated in Scottish haemophilia centres registered on the UKHCDO database between 1970 and 1989. Cases were then removed or added based on additional information from centre records. A second cohort B, consisted of 255 patients from cohort A and 47 patients HCV infected outside Scotland, but with follow-up data from Scottish centres around their HCV infection. We estimate that 455 patients with bleeding disorders became infected by coagulation factor provided by NHS Scotland. In 302 individuals with documented HCV infection, rates of natural clearance (17.4%), genotype spread (64% genotype 1) and responses to antiviral therapy (14.5% with monotherapy; 38.8% with combination therapy) were similar to those in other cohorts. Thirty-four liver biopsies were performed without adverse event and liver transplantation has been performed in 11 patients, seven for liver failure, four for hepatocellular carcinoma. Around 455 patients with bleeding disorders became HCV infected in Scotland before 1989. The natural history of HCV infection and responses to treatment are similar to those in other HCV-infected cohorts. Liver transplantation has been used successfully for the treatment of end-stage liver failure and hepatocellular carcinoma.


The Effectiveness and Cost-Effectiveness of Hepatitis C Screening for Migrants in the EU/EEA: A Systematic Review.
Chronic hepatitis C (HCV) is a public health priority in the European Union/European Economic Area (EU/EEA) and is a leading cause of chronic liver disease and liver cancer. Migrants account for a disproportionate number of HCV cases in the EU/EEA (mean 14% of cases and >50% of cases in some countries). We conducted two systematic reviews (SR) to estimate the effectiveness and cost-effectiveness of HCV screening for migrants living in the EU/EEA. We found that screening tests for HCV are highly sensitive and specific. Clinical trials report direct acting antiviral (DAA) therapies are well-tolerated in a wide range of populations and cure almost all cases (>95%) and lead to an 85% lower risk of developing hepatocellular carcinoma and an 80% lower risk of all-cause mortality. At 2015 costs, DAA based regimens were only moderately cost-effective and as a result less than 30% of people with HCV had been screened and less 5% of all HCV cases had been treated in the EU/EEA in 2015. Migrants face additional barriers in linkage to care and treatment due to several patient, practitioner, and health system barriers. Although decreasing HCV costs have made treatment more accessible in the EU/EEA, HCV elimination will only be possible in the region if health systems include and treat migrants for HCV.


Dengue and dengue vectors in the WHO European region: past, present, and scenarios for the future.
After 55 years of absence, dengue has re-emerged in the WHO European region both as locally transmitted sporadic cases and as an outbreak in Madeira, driven by the introduction of people infected with the virus and the invasion of the vector mosquito species Aedes aegypti and Aedes albopictus. Models predict a further spread of A albopictus, particularly under climate change conditions. Dengue transmission models suggest a low risk in Europe, but these models too rarely include transmission by A albopictus (the main established vector). Further information gaps exist with regard to the Caucasus and central Asian countries of the WHO European region. Many European countries have implemented surveillance and control measures for invasive mosquitoes, but only a few include surveillance for dengue. As long as no dengue-specific prophylaxis or therapeutics are available, integrated vector management is the most sustainable control option. The rapid elimination of newly introduced A aegypti populations should be targeted in the European region, particularly in southern Europe and the Caucasus, where the species was present for decades until the 1950s.


Glutathione S-transferase M1 and P1 genotype, passive smoking, and peak expiratory flow in asthma.
Our purpose with this work was to assess the contribution of glutathione S-transferase gene variants to asthma susceptibility and pulmonary function in relation to tobacco smoke exposure in the home. Young individuals with asthma (age: 3-21 years; n = 504) were recruited through primary and secondary care throughout Tayside, Scotland (BREATHE Study). Spirometry was obtained on 407 individuals. Binary logistic regression and general linear modeling were used to explore phenotypic characteristics by genotype and tobacco smoke exposure status in younger children (3-12 years; n = 384) and teenagers and young adults (13-21 years; n = 120). Three- to 12-year-olds with asthma, null for the GSTM1 gene or homozygous for the GSTP1Val105 allele, were overrepresented in the group exposed to environmental tobacco smoke. No differences in lung function values could be detected in this group. In contrast, 13- to 21-year-olds with the GSTM1-null genotype or homozygous for the GSTP1Val105 allele from smoking households were more likely to have a substantially lower percentage of predicted peak expiratory flow rates than those from nonsmoking households (83% vs 98%). Three- to 12-year-olds who are null for GSTM1 or homozygous for the GSTP1Val105 allele are more susceptible to asthma associated with environmental tobacco smoke exposure than those with more intact glutathione S-transferase status. In the 13- to 21-year-olds, GSTM1-null status interacts with environmental tobacco smoke exposure to substantially reduce peak expiratory flow rate. The environmental tobacco smoke effect in GSTM1-null children with asthma could be cumulative over time, resulting in detrimental effects on peak expiratory flow rate in 13- to 21-year-olds with asthma.


Comparison of antihypertensive efficacy of carvedilol and nebivolol in mild-to-moderate primary hypertension: a randomized trial.
The aim of the present study is to compare the antihypertensive effects of carvedilol and nebivolol in mild-to-moderate hypertensive patients. It is a prospective; placebo-controlled, cross-over, double-blind, randomized, single-center clinical trial. Patients (n=20) who were first diagnosed with mild to moderate systemic hypertension according to mean ambulatory blood pressure measurements > 130/85 mmHg and no previous antihypertensive therapy were prospectively enrolled into the study. After 10 days of placebo run-in period, they were randomized within the same group as cross-over design to one month carvedilol 25 mg and one month nebivolol 5 mg regimen given once daily in the morning. The primary outcome variables were systolic and diastolic blood pressures determined by 24-hour ambulatory blood pressure measurements. Mutlivariate analysis of variance for repeated measurements with 3x2 factorial design was used for statistical analysis of results. The study group consisted of 6 women and 14 men whose mean age was 42.9±12.8 years (range 19-63 years). Mean heart rate was significantly decreased after commencing both carvedilol (70.2±5.2 bpm) and nebivolol (64.9±3.9 bpm) treatments compared to placebo (78.8±5.2 bpm) (p<0.05). Both carvedilol (133.8±9/86.6±8.6 mmHg) and nebivolol (134±8.7/85.6±7.4 mmHg) significantly decreased mean systolic and diastolic blood pressures compared to placebo (143.9±8.9/94.4±9.2 mmHg), respectively (p<0.05). However, there was no significant difference in decreasing either systolic or diastolic blood pressure between nebivolol and carvedilol therapies (p>0.05). No side effects were recorded during both carvedilol and nebivolol treatments. Although both carvedilol and nebivolol effectively decreased blood pressure compared to placebo, they showed similar efficacy for lowering blood pressure.


Both resting and activated B lymphocytes expressing engineered peptide-Ig molecules serve as highly efficient tolerogenic vehicles in immunocompetent adult recipients.
To test the potential for genetically transferring foreign sequences into autologous cells for specific modulation of immunity, we have generated transgenic mice that express an engineered peptide-IgG construct in the peripheral B cell compartment. B cells from these mice express and can be stimulated to secrete a murine IgG1 chain grafted with residues 12-26 from bacteriophage A cI repressor protein in-frame at the heavy chain N terminus. As expected, 12-26-IgG transgenic mice are profoundly tolerant to the peptide at both the T and B cell levels. Importantly, the injection of transgenic whole spleen, purified B cells, or even bone marrow cells into normal, immunocompetent adults results in profound peptide-specific T cell tolerance, as well as partial B cell tolerance. Injection of LPS-activated peptide-Ig-expressing B cells was uniquely effective at diminishing an ongoing humoral immune response typical of both Th1 and Th2 help. Since fixed transgenic B cells were tolerogenic, this suggests that secretion of the fusion protein is not required for tolerogenicity. These results show that an engineered self Ig, as well as B lymphocytes expressing epitopes from such a fusion protein, can regulate both cellular and humoral immune responses. Moreover, these studies provide the basis for expressing foreign epitopes on engineered IgG for the induction of gene-transferred tolerogenesis in autoimmune states.


Breast cancer detection using targeted plasma metabolomics.
Breast cancer (BC) is a major cause of human morbidity and mortality, especially among women. Despite the important role of metabolism in the molecular pathogenesis of cancer, robust metabolic markers to enable enhanced screening and disease monitoring of BC are still critically needed. In this study, a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolic profiling approach is presented for the identification of metabolic marker candidates that could enable highly sensitive and specific detection of all-stage as well as early-stage BC. In this targeted approach, 105 metabolites from >35 metabolic pathways of potential biological relevance were reliably detected in 201 plasma samples taken from two groups of subjects (102 BC patients and 99 healthy controls). The results of our general linear model and partial least squares-discriminant analysis (PLS-DA) informed the construction of a novel 6-metabolite panel of potential biomarkers. A receiver operating characteristic (ROC) curve generated based on an improved PLS-DA model showed relatively high sensitivity (0.80), specificity (0.75), and area under the receiver-operating characteristic curve (AUROC = 0.89). Similar classification performance of the model was observed for detection of early-stage BC (AUROC = 0.87, sensitivity: 0.86, specificity: 0.75). Bioinformatics analyses revealed significant disturbances in arginine/proline metabolism, tryptophan metabolism, and fatty acid biosynthesis. Our univariate and multivariate results indicate the effectiveness of this metabolomics approach for all-stage as well as early-stage BC diagnosis; our bioinformatics results indicate affected pathways related to tumor growth, metastasis, and immune escape mechanisms. Future studies should validate these results using more samples from different locations.