Caregiver burden and quality of life 2 years after attendance at a memory clinic.
We aimed to describe (1) the burden and health-related quality of life (HRQL) of informal caregivers of new patients attending a memory assessment service (MAS), (2) changes in these outcomes over 2 years, and (3) satisfaction with services. Informal caregivers of patients attending one of 73 MASs throughout England completed questionnaires at the patient's first appointment, and 6 and 12 months later. Participants from 30 of these MASs were also followed up at 24 months. Questionnaires covered caregivers' sociodemographic characteristics, Zarit Burden Interview, EQ-5D-3L, and satisfaction with services. We used multivariable linear regression to assess relationships between burden, HRQL, and caregiver and patient characteristics. Of 1020 caregivers at baseline, 569 were followed up at 6 months, 452 at 12 months, and 187 at 24 months. There was a small increase in caregiver burden over 2 years (effect size 0.30 SD). These changes were not associated with most caregiver or patient characteristics, except socio-economic deprivation, which was associated with larger increases in burden at 2 years. Caregivers' HRQL was weakly associated with burden and showed a small reduction over time (0.2 SD). Most caregivers were satisfied with services, but caregivers who were not satisfied with the services they received reported greater increases in burden. Increases in caregiver burden and reductions in HRQL appear to be small over the first 2 years after attending a MAS. However, the longer term impact on caregivers and those they care for needs investigating, as do strategies to reduce their burden.


Cold tolerance of C4 photosynthesis in Miscanthus x giganteus: adaptation in amounts and sequence of C4 photosynthetic enzymes.
Field-grown Miscanthus x giganteus maintains high photosynthetic quantum yields and biomass productivity in cool temperate climates. It is related to maize (Zea mays) and uses the same NADP-malic enzyme C(4) pathway. This study tests the hypothesis that M. x giganteus, in contrast to maize, forms photosynthetically competent leaves at low temperatures with altered amounts of pyruvate orthophosphate dikinase (PPDK) and Rubisco or altered properties of PPDK. Both species were grown at 25 degrees C/20 degrees C or 14 degrees C/11 degrees C (day/night), and leaf photosynthesis was measured from 5 degrees C to 38 degrees C. Protein and steady-state transcript levels for Rubisco, PPDK, and phosphoenolpyruvate carboxylase were assessed and the sequence of C(4)-PPDK from M. x giganteus was compared with other C(4) species. Low temperature growth had no effect on photosynthesis in M. x giganteus, but decreased rates by 80% at all measurement temperatures in maize. Amounts and expression of phosphoenolpyruvate carboxylase were affected little by growth temperature in either species. However, PPDK and Rubisco large subunit decreased >50% and >30%, respectively, in cold-grown maize, whereas these levels remained unaffected by temperature in M. x giganteus. Differences in protein content in maize were not explained by differences in steady-state transcript levels. Several different M. x giganteus C(4)-PPDK cDNA sequences were found, but putative translated protein sequences did not show conservation of amino acids contributing to cold stability in Flaveria brownii C(4)-PPDK. The maintenance of PPDK and Rubisco large subunit amounts in M. x giganteus is consistent with the hypothesis that these proteins are critical to maintaining high rates of C(4) photosynthesis at low temperature.


Comprehensive Metaproteomic Analyses of Urine in the Presence and Absence of Neutrophil-Associated Inflammation in the Urinary Tract.
Inflammation in the urinary tract results in a urinary proteome characterized by a high dynamic range of protein concentrations and high variability in protein content. This proteome encompasses plasma proteins not resorbed by renal tubular uptake, renal secretion products, proteins of immune cells and erythrocytes derived from trans-urothelial migration and vascular leakage, respectively, and exfoliating urothelial and squamous epithelial cells. We examined how such proteins partition into soluble urine (SU) and urinary pellet (UP) fractions by analyzing 33 urine specimens 12 of which were associated with a urinary tract infection (UTI). Using mass spectrometry-based metaproteomic approaches, we identified 5,327 non-redundant human proteins, 2,638 and 4,379 of which were associated with SU and UP fractions, respectively, and 1,206 non-redundant protein orthology groups derived from pathogenic and commensal organisms of the urogenital tract. Differences between the SU and UP proteomes were influenced by local inflammation, supported by respective comparisons with 12 healthy control urine proteomes. Clustering analyses showed that SU and UP fractions had proteomic signatures discerning UTIs, vascular injury, and epithelial cell exfoliation from the control group to varying degrees. Cases of UTI revealed clusters of proteins produced by activated neutrophils. Network analysis supported the central role of neutrophil effector proteins in the defense against invading pathogens associated with subsequent coagulation and wound repair processes. Our study expands the existing knowledge of the urinary proteome under perturbed conditions, and should be useful as reference dataset in the search of biomarkers.


Poor comprehenders in the classroom: teacher ratings of behavior in children with poor reading comprehension and its relationship with individual differences in working memory.
Differing etiological explanations have been proposed to account for poor comprehenders' difficulties with reading comprehension, with some researchers emphasizing working memory deficits and others arguing for oral language weaknesses playing a key causal role. The authors contrasted these two theoretical accounts using data obtained from direct measures of working memory and from teacher ratings of poor comprehenders' behavior in the classroom. At the group level, poor comprehenders showed weaknesses on verbal but not nonverbal working memory tasks, in keeping with the "language account." However, they also showed evidence of elevated levels of problem behaviors specifically associated with working memory deficits. Further analysis revealed that these group differences in working-memory-related problem behaviors were carried by a small subgroup of poor comprehenders who also displayed domain-general (verbal and nonverbal) working memory problems, argued to be reflective of "genuine" underlying working memory deficits.


Environmental efficiency of alternative dairy systems: a productive efficiency approach.
Agriculture across the globe needs to produce "more with less." Productivity should be increased in a sustainable manner so that the environment is not further degraded, management practices are both socially acceptable and economically favorable, and future generations are not disadvantaged. The objective of this paper was to compare the environmental efficiency of 2 divergent strains of Holstein-Friesian cows across 2 contrasting dairy management systems (grazing and nongrazing) over multiple years and so expose any genetic × environment (G × E) interaction. The models were an extension of the traditional efficiency analysis to account for undesirable outputs (pollutants), and estimate efficiency measures that allow for the asymmetric treatment of desirable outputs (i.e., milk production) and undesirable outputs. Two types of models were estimated, one considering production inputs (land, nitrogen fertilizers, feed, and cows) and the other not, thus allowing the assessment of the effect of inputs by comparing efficiency values and rankings between models. Each model type had 2 versions, one including 2 types of pollutants (greenhouse gas emissions, nitrogen surplus) and the other 3 (greenhouse gas emissions, nitrogen surplus, and phosphorus surplus). Significant differences were found between efficiency scores among the systems. Results indicated no G × E interaction; however, even though the select genetic merit herd consuming a diet with a higher proportion of concentrated feeds was most efficient in the majority of models, cows of the same genetic merit on higher forage diets could be just as efficient. Efficiency scores for the low forage groups were less variable from year to year, which reflected the uniformity of purchased concentrate feeds. The results also indicate that inputs play an important role in the measurement of environmental efficiency of dairy systems and that animal health variables (incidence of udder health disorders and body condition score) have a significant effect on the environmental efficiency of each dairy system. We conclude that traditional narrow measures of performance may not always distinguish dairy farming systems best fitted to future requirements.


Molecular changes in second primary lung and breast cancers after therapy for Hodgkin's disease.
The risk of lung and breast cancer is significantly increased after therapy for Hodgkin's disease (HD), but there are few data that describe the molecular profiles of these tumors. We investigated the genetic abnormalities in second primary lung (n = 19) and breast cancers (n = 19) that follow therapy for HD ("post-HD cancers") and compared these with changes observed in corresponding tumor types (57 lung and 20 breast cancers) arising in the general population ("sporadic cancers"). DNA obtained from archival tissues was examined using PCR-based analyses for loss of heterozygosity and microsatellite alterations (MAs) at several chromosomal regions, TP53 and K-ras gene mutations, and frameshift mutations at minisatellite sequences at the coding regions of several genes (TGF-betaRII, IGFIIR, BAX, hMSH6, and hMSH3). The occurrence of loss of heterozygosity at all chromosomal regions taken together and frequencies at most individual areas were similar for the post-HD and sporadic cancers for both lung and breast sites. The overall frequency of MAs in the post-HD tumors was substantially greater (lung, 2.4-fold, P = 0.004; breast, 4.2-fold, P = 0.16) than that in the respective sporadic cancers. No differences in the pattern of TP53 and K-ras mutations were detected between post-HD and sporadic cancers. No mutations were detected at the minisatellite sequences examined. MAs, which reflect widespread genomic instability, occur at greatly increased frequency in post-HD lung and breast cancers. Although the mechanisms underlying the development of increased MAs are unknown, they have been associated with immunosuppression and radiation exposure. Future research should address the role that MAs, as well as other influences, may play in the development of neoplasias that occur after therapy for HD.


Comparison of hemodynamic responses to endotracheal intubation with the GlideScope video laryngoscope and Macintosh laryngoscope in patients undergoing cardiovascular surgery.
This study aimed to compare hemodynamic response to endotracheal intubation using GlideScope and Macintosh laryngoscopes in patients who underwent cardiovascular surgery. A total of 74 patients were enrolled in the study. Patients were randomly assigned into two groups either a GlideScope (n=37) or a Macintosh laryngoscope (n=37). Laryngoscopy time, heart rate, invasive arterial pressure and rate pressure product were compared during induction and until five minutes after laryngoscopy at 11 time points. Seventy patients completed the study. The intubation time was similar in both groups (14.1±4.0 sec vs. 13.2±4.2 sec; p=0.22). Hemodynamic values including heart rate, systolic, diastolic and mean arterial pressure and rate pressure product were similar at all-time points. The laryngoscopy time was also similar between groups. The GlideScope video laryngoscope did not show any advantage on hemodynamic response in patients undergoing cardiovascular surgery when compared to Macintosh laryngoscope.


Validation of a new ENT emergencies course for first-on-call doctors.
First-on-call ENT cover is often provided by junior doctors with limited ENT experience; yet, they may have to manage life-threatening emergencies. An intensive 1-day simulation course was developed to teach required skills to junior doctors. A prospective, single-blinded design was used. Thirty-seven participants rated their confidence before the course, immediately following the course and after a two-month interval. Blinded assessors scored participant performance in two video-recorded simulated scenarios before and after the course. Participant self-rated confidence was increased in the end-of-course survey (score of 27.5 vs 53.0; p < 0.0001), and this was maintained two to four months after the course (score of 50.5; p < 0.0001). Patient assessment and management in video-recorded emergency scenarios was significantly improved following course completion (score of 9.75 vs 18.75; p = 0.0093). This course represents an effective method of teaching ENT emergency management to junior doctors. ENT induction programmes benefit from the incorporation of a simulation component.


International Group for Reducing Inappropriate Medication Use & Polypharmacy (IGRIMUP): Position Statement and 10 Recommendations for Action.
Globally, the number of drug prescriptions is increasing causing more adverse drug events, which is now a significant cause of mortality, morbidity, and disability that has reached epidemic proportions. The risk of adverse drug events is correlated to very old age, multiple co-morbidities, dementia, frailty, and limited life expectancy, with the major contributor being polypharmacy. Each characteristic alters the risk-benefit balance of medications, typically reducing anticipated benefits and amplifying risk. Current clinical guidelines are based on evidence proven in younger/healthier adult populations using a single disease model and their application to older adults with multimorbidity, in whom testing has not been conducted, yields a different risk-benefit prospect and makes inappropriate medication use and polypharmacy inevitable. Applying inappropriate clinical practice guidelines to older adults is antithetical to good healthcare, is likely to increase health inequity, and is associated with substantial negative clinical, economic, and social implications for health systems. The casualties are on the scale of a war or epidemic, yet are usually invisible in measures of healthcare quality and formal recommendations. Radical and rapid action is required to achieve a better quality of life for older populations and to remain true to the principles of medical professionalism and evidence-based medicine that place patients' interests and autonomy at the fore. This first International Group for Reducing Inappropriate Medication Use & Polypharmacy position statement briefly details the causes, consequences, and extent of inappropriate medication use and polypharmacy. This article outlines current strategies to reduce inappropriate medication use, provides evidence for their effect, and then proposes recommendations for moving forward with 10 recommendations for action and 12 recommendations for research. We conclude that an urgent integrated effort to reduce inappropriate medication use and polypharmacy should be a leading global target of the highest priority. The cornerstone of this position statement from the International Group for Reducing Inappropriate Medication Use & Polypharmacy is the understanding that without evidence of definite relevant benefit, when it comes to prescribing, for many older patients 'less is more'. This approach differs from most other current recommendations and guidance in medical care, as the focus is on what, when, and how to stop, rather than on when to start medications/interventions. Disrupting the framework that indiscriminately applies standard guidelines to older adults requires a new approach that better serves patients with multimorbidity. This transition requires a shift in medical education, research, and diagnostic frameworks, and re-examination of the measures used as quality indicators. In achieving this objective, we promote a return to some of the original concepts of evidence-based medicine: which considers scientific data (where it exists), clinical judgment, patient/family preference, and context. A shift is needed: from the current model that focuses on single conditions to one that simultaneously considers multiple conditions and patient priorities. This approach reframes the clinician's role as a professional providing care, rather than a disease technician.


Tricritical points in a Vicsek model of self-propelled particles with bounded confidence.
We study the orientational ordering in systems of self-propelled particles with selective interactions. To introduce the selectivity we augment the standard Vicsek model with a bounded-confidence collision rule: a given particle only aligns to neighbors who have directions quite similar to its own. Neighbors whose directions deviate more than a fixed restriction angle α are ignored. The collective dynamics of this system is studied by agent-based simulations and kinetic mean-field theory. We demonstrate that the reduction of the restriction angle leads to a critical noise amplitude decreasing monotonically with that angle, turning into a power law with exponent 3/2 for small angles. Moreover, for small system sizes we show that upon decreasing the restriction angle, the kind of the transition to polar collective motion changes from continuous to discontinuous. Thus, an apparent tricritical point with different scaling laws is identified and calculated analytically. We investigate the shifting and vanishing of this point due to the formation of density bands as the system size is increased. Agent-based simulations in small systems with large particle velocities show excellent agreement with the kinetic theory predictions. We also find that at very small interaction angles, the polar ordered phase becomes unstable with respect to the apolar phase. We derive analytical expressions for the dependence of the threshold noise on the restriction angle. We show that the mean-field kinetic theory also permits stationary nematic states below a restriction angle of 0.681π. We calculate the critical noise, at which the disordered state bifurcates to a nematic state, and find that it is always smaller than the threshold noise for the transition from disorder to polar order. The disordered-nematic transition features two tricritical points: At low and high restriction angle, the transition is discontinuous but continuous at intermediate α. We generalize our results to systems that show fragmentation into more than two groups and obtain scaling laws for the transition lines and the corresponding tricritical points. A numerical method to evaluate the nonlinear Fredholm integral equation for the stationary distribution function is also presented. This method is shown to give excellent agreement with agent-based simulations, even in strongly ordered systems at noise values close to zero.


Spinal Orthoses for Vertebral Osteoporosis and Osteoporotic Vertebral Fracture: A Systematic Review.
To systematically review the evidence of effectiveness of spinal orthoses for adults with vertebral osteoporosis. We conducted a systematic literature search using the databases of PubMed, MEDLINE, EMBASE, AMED, CINAHL, PEDro, and the Cochrane Library from January 1995 to October 2014. Two reviewers evaluated eligibility. Randomized controlled trials (RCTs), pilot RCTs, and prospective nonrandomized controlled studies of spinal orthoses for people with vertebral osteoporosis or osteopenia with and without osteoporotic vertebral fracture (OVF) that examined outcomes related to fracture consolidation, pain, strength, posture, balance, physical function, quality of life, and complications were eligible. Two reviewers independently extracted data and evaluated methodological quality using a domain-based risk-of-bias approach. Twelve studies were included: 8 RCTs or pilot RCTs and 4 nonrandomized studies involving 626 participants. Three studies (n=153) evaluated orthoses after acute OVF; none were of high quality. Complications were highest with rigid orthoses. Evidence that orthoses could affect vertebral deformity was lacking. Nine studies (n=473) of varying quality considered orthoses in subacute and longer rehabilitation. Three suggested a semirigid backpack thoracolumbar orthosis (TLO) could benefit strength, pain, posture, and quality of life. One found a weighted kypho-orthosis (WKO) improved balance. The limited evidence about orthoses after acute OVF is inconclusive; better evidence of efficacy is needed, particularly when considering complications. The promising evidence regarding the backpack TLO and WKO needs to be explored further in studies of sufficient size and quality that include men.


Chromatin remodeling and initiation of DNA replication.
While much has been learned in recent years about the process of chromatin remodeling and its role in activation of transcription, relatively little has been reported on the role of chromatin remodeling in DNA replication. However, it is well established that transcription factors and chromatin structure play an important role in replication origin usage. Recent work has begun to indicate that chromatin remodeling factors are likely to play an important role in the regulation of replication origin usage. The results to date are most consistent with the role for chromatin remodeling factors in DNA replication as being indirect, and very similar to their role in transcription. The current evidence suggests that transcription factors bind to auxiliary sequences adjacent to replication origins and recruit chromatin remodeling factors to create either nucleosome-free regions or regions of specifically spaced nucleosomes. This results in activation of the nearby origin, presumably by making the origin region more accessible to replication factors. Until recently, there has been very little evidence of direct interactions between chromatin remodeling factors and the DNA replication machinery. Recent studies have provided data indicating that direct interactions may exist between chromatin remodeling factors and two cellular replication factors, the Origin Recognition Complex and Proliferating Cell Nuclear Antigen. However, since these replication factors are also involved in other nuclear processes, such as transcriptional silencing and DNA repair, respectively, further study is necessary to establish whether these direct interactions are also important for DNA replication.


Air quality and acute respiratory illness in biomass fuel using homes in Bagamoyo, Tanzania.
Respiratory Diseases are public health concern worldwide. The diseases have been associated with air pollution especially indoor air pollution from biomass fuel burning in developing countries. However, researches on pollution levels and on association of respiratory diseases with biomass fuel pollution are limited. A study was therefore undertaken to characterize the levels of pollutants in biomass fuel using homes and examine the association between biomass fuel smoke exposure and Acute Respiratory Infection (ARI) disease in Nianjema village in Bagamoyo, Tanzania. Pollution was assessed by measuring PM10, NO2, and CO concentrations in kitchen, living room and outdoors. ARI prevalence was assessed by use of questionnaire which gathered health information for all family members under the study. Results showed that PM10, NO2, and CO concentrations were highest in the kitchen and lowest outdoors. Kitchen concentrations were highest in the kitchen located in the living room for all pollutants except CO. Family size didn't have effect on the levels measured in kitchens. Overall ARI prevalence for cooks and children under age 5 making up the exposed group was 54.67% with odds ratio (OR) of 5.5; 95% CI 3.6 to 8.5 when compared with unexposed men and non-regular women cooks. Results of this study suggest an association between respiratory diseases and exposure to domestic biomass fuel smoke, but further studies with improved design are needed to confirm the association.


Nanometric thin polymeric films based on molecularly imprinted technology: towards electrochemical sensing applications.
A new approach for assembling selective electrodes based on molecularly imprinted polymers (MIPs) is presented. The approach is based on the radical polymerization of a mixture of methacrylic acid (MAA) and ethyleneglycol dimethacrylate (EGDMA) in the presence of an initiator, benzoyl peroxide (BPO) and an activator, N,N'-dimethyl-p-toluidine (DMpT) at room temperature and atmospheric pressure. To form nanometric thin polymeric films the polymerization solution was spin-coated in the course of polymerization. The different physical and chemical parameters that affected the properties of the films, such as the spinning rate and the EGDMA:MAA ratio, were studied and optimized. A variety of techniques, e.g., rheoscopy, SEM, AFM, profilometry and electrochemistry, were used to characterize the films and the polymerization process. By optimizing the conditions very thin and reproducible films could be prepared and imprinted. The electrochemical behavior of the films showed that they were permeable to water-soluble electroactive species providing that either polyethylene glycol or template species were added to the polymerization mixture. Finally, we demonstrated that films imprinted with ferrocenylmethyl alcohol (Fc-MeOH) successfully extracted the imprinted species after their removal from MIPs.


A susceptibility allele from a non-diabetes-prone mouse strain accelerates diabetes in NOD congenic mice.
The nonobese diabetic (NOD) mouse is genetically predisposed for the spontaneous development of type 1 diabetes. Linkage analyses have identified at least 19 susceptibility loci (Idd1-Idd19) that contribute to disease pathogenesis in which lymphocytes mediate the specific destruction of insulin-producing beta-cells. Interestingly, nondiabetic mouse strains have been shown to confer susceptibility alleles to affected progeny in NOD outcrosses for some of the Idd loci. In particular, we noted that diabetic backcross progeny, derived from NOD and C57BL/6 (B6) mouse strains, demonstrated increased heterozygousity for an interval encompassing Idd14 on chromosome 13. This result suggested that B6 mice harbor a more diabetogenic allele(s) than NOD mice for this locus. To confirm this observation, a NOD congenic mouse strain, containing a B6-derived interval covering the majority of chromosome 13, was generated. Adding to the combination of already potent susceptibility alleles elsewhere in the NOD genome, the chromosome 13 B6-derived interval was able to increase the overall risk of developing type 1 diabetes, which resulted in an earlier onset and increased incidence of type 1 diabetes in congenic mice as compared with NOD mice. Furthermore, this B6-derived interval, in combination with the NOD genetic background, was able to overcome environmental conditions that typically suppressed type 1 diabetes in the NOD mouse strain.


[Concentration of soluble forms of selectins in serum and in cerebrospinal fluid in group of patients with neuroborreliosis--a preliminary study].
The results of the research already done, suggest an important role of selectins in inflammatory process of various etiology. Lack of selectins or their ligands causes severe complications, such as chronic inflammatory processes. The aim of this study was to analyze the role of selectins sL, sE and sP in the development and course of neuroborreliosis in the form of meningitis. We have also analyzed the influence of treatment on changes of selectins' concentration in serum and cerebrospinal fluid. We have analyzed 17 patients with neuroborreliosis presenting as meningitis, in whom we measured by immunoenzymatic method concentration of selectins sL, sP and sE in blood and cerebrospinal fluid before and after 4-week therapy with cefotaxim. We used Human sL-selectin, Human sE-selectin and Human sP-selectin kits produced by Bender Med. Systems, Austria. Control group for measurement of concentration of selectins in serum consisted of 8 healthy patients. Control group for measurement of concentration of selectins in cerebrospinal fluid consisted of 8 patients, in whom lumbar puncture excluded inflammatory disease of the central nervous system. In serum concentration of selectins sL and sP was significantly higher comparing to control group. After treatment concentration of these selectins decreased, but still was significantly higher than in control group. Only concentration of selectin sE was significantly lower than in control group and after treatment decreased further remaining lower comparing to control group. In cerebrospinal fluid concentration of selectin sL was significantly higher comparing to control group and increased after treatment. Concentration of selectins sE and sP increased before treatment and decreased after treatment, but still remained elevated comparing to control group. Persistence of increased concentration of selectins sP and sL in serum and also of selectin sE in cerebrospinal fluid in patients with neuroborreliosis after completed antibiotic therapy and regression of clinical symptoms can suggest permanence of chronic inflammatory state in consequence of survival of B. burgdorferi spirochetes in affected tissues.


Canadian Contraception Consensus (Part 1 of 4).
To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality. Guidance for Canadian practitioners on overall effectiveness, mechanism of action, indications, contraindications, non-contraceptive benefits, side effects and risks, and initiation of cited contraceptive methods; family planning in the context of sexual health and general well-being; contraceptive counselling methods; and access to, and availability of, cited contraceptive methods in Canada. Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis and incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Chapter 1: Contraception in Canada Summary Statements 1. Canadian women spend a significant portion of their lives at risk of an unintended pregnancy. (II-2) 2. Effective contraceptive methods are underutilized in Canada, particularly among vulnerable populations. (II-2) 3. Long-acting reversible contraceptive methods, including contraceptive implants and intrauterine contraception (copper-releasing and levonorgestrel-releasing devices/systems), are the most effective reversible contraceptive methods and have the highest continuation rates. (II-1) 4. Canada currently does not collect reliable data to determine the use of contraceptive methods, abortion rates, and the prevalence of unintended pregnancy among reproductive-age women. (II-2) 5. A universal subsidy for contraceptive methods as provided by many of Canada's peer nations and a few Canadian provinces may produce health system cost-savings. (II-2) 6. Health Canada approval processes for contraceptives have been less efficient than those of other drug approval agencies and Health Canada processes for other classes of pharmaceuticals. (II-2) 7. It is feasible and safe for contraceptives and family planning services to be provided by appropriately trained allied health professionals such as midwives, registered nurses, nurse practitioners, and pharmacists. (II-2) Recommendations 1. Contraceptive counselling should include a discussion of typical use failure rates and the importance of using the contraceptive method consistently and correctly in order to avoid pregnancy. (II-2A) 2. Women seeking contraception should be counselled on the wide range of effective methods of contraception available, including long-acting reversible contraceptive methods (LARCs). LARCs are the most effective methods of reversible contraception, have high continuation rates, and should be considered when presenting contraceptive options to any woman of reproductive age. (II-2A) 3. Family planning counselling should include counselling on the decline of fertility associated with increasing female age. (III-A) 4. Health policy supporting a universal contraception subsidy and strategies to promote the uptake of highly effective methods as cost-saving measures that improve health and health equity should be considered by Canadian health decision makers. (III-B) 5. Canadian health jurisdictions should consider expanding the scope of practice of other trained professionals such as nurses, nurse practitioners, midwives, and pharmacists and promoting task-sharing in family planning. (II-2B) 6. The Canadian Community Health Survey should include adequate reproductive health indicators in order for health care providers and policy makers to make appropriate decisions regarding reproductive health policies and services in Canada. (III-B) 7. Health Canada processes and policies should be reviewed to ensure a wide range of modern contraceptive methods are available to Canadian women. (III-B) Chapter 2: Contraceptive Care and Access Summary Statements 8. Although there are many contraceptive options in Canada, only a narrow range of contraceptive methods are commonly used by those of reproductive age. (II-3) 9. Condom use decreases with longer relationship tenure and when the sexual partner is considered to be the main partner, likely due to a lower perceived risk of sexually transmitted infection in that relationship. Condom use may also decrease markedly as an unintended consequence when an effective non-barrier method, such as hormonal contraception or intrauterine contraception, is initiated. (II-3) 10. Family planning counselling provides a natural segue into screening for concerns about sexual function or intimate partner violence. (III) 11. Well-informed and well-motivated individuals who have developed skills to practise safer sex behaviours are more likely to use contraceptive and safer sex methods effectively and consistently. (II-2) Recommendations 8. Comprehensive family planning services, including abortion services, should be accessible to all Canadians regardless of geographic location. These services should be confidential, non-judgemental, and respectful of individuals' privacy and cultural contexts. (III-A) 9. A contraceptive visit should include history taking, screening for contraindications, dispensing or prescribing a method of contraception, and exploring contraceptive choice and adherence in the broader context of the individual's sexual behaviour, reproductive health risk, social circumstances, and relevant belief systems. (III-B) 10. Health care providers should provide practical information on the wide range of contraceptive options and their potential non-contraceptive benefits and assist women and their partners in determining the best user-method fit. (III-B) 11. Health care providers should assist women and men in developing the skills necessary to negotiate the use of contraception and the correct and consistent use of a chosen method. (III-B) 12. Contraceptive care should include discussion and management of the risk of sexually transmitted infection, including appropriate recommendations for condom use and dual protection, STI screening, post-exposure prophylaxis, and Hepatitis B and human papillomavirus vaccination. (III-B) 13. Health care providers should emphasize the use of condoms not only for protection against sexually transmitted infection, but also as a back-up method when adherence to a hormonal contraceptive may be suboptimal. (I-A) 14. Health care providers should be aware of current media controversies in reproductive health and acquire relevant evidence-based information that can be briefly and directly communicated to their patients. (III-B) 15. Referral resources for intimate partner violence, sexually transmitted infections, sexual dysfunction, induced abortion services, and child protection services should be available to help clinicians provide contraceptive care in the broader context of women's health. (III-B) Chapter 3: Emergency Contraception Summary Statements 12. The copper intrauterine device is the most effective method of emergency contraception. (II-2) 13. A copper intrauterine device can be used for emergency contraception up to 7 days after unprotected intercourse provided that pregnancy has been ruled out and there are no other contraindications to its insertion. (II-2) 14. Levonorgestrel emergency contraception is effective up to 5 days (120 hours) after intercourse; its effectiveness decreases as the time between unprotected intercourse and ingestion increases. (II-2) 15. Ulipristal acetate for emergency contraception is more effective than levonorgestrel emergency contraception up to 5 days after unprotected intercourse. This difference in effectiveness is more pronounced as the time from unprotected intercourse increases, especially after 72 hours. (I) 16. Hormonal emergency contraception (levonorgestrel emergency contraception and ulipristal acetate for emergency contraception) is not effective if taken on the day of ovulation or after ovulation. (II-2) 17. Levonorgestrel emergency contraception may be less effective in women with a body mass index > 25 kg/m2 and ulipristal acetate for emergency contraception may be less effective in women with a body mass index > 35 kg/m2. However, hormonal emergency contraception may still retain some effectiveness regardless of a woman's body weight or body mass index. (II-2) 18. Hormonal emergency contraception is associated with higher failure rates when women continue to have subsequent unprotected intercourse. (II-2) 19. Hormonal contraception can be initiated the day of or the day following the use of levonorgestrel emergency contraception, with back-up contraception used for the first 7 days. (III) 20. Hormonal contraception can be initiated 5 days following the use of ulipristal acetate for emergency contraception, with back-up contraception used for the first 14 days. (III) Recommendations 16. All emergency contraception should be initiated as soon as possible after unprotected intercourse. (II-2A) 17. Women should be informed that the copper intrauterine device (IUD) is the most effective method of emergency contraception and can be used by any woman with no contraindications to IUD use. (II-3A) 18.


DehazeNet: An End-to-End System for Single Image Haze Removal.
Single image haze removal is a challenging ill-posed problem. Existing methods use various constraints/priors to get plausible dehazing solutions. The key to achieve haze removal is to estimate a medium transmission map for an input hazy image. In this paper, we propose a trainable end-to-end system called DehazeNet, for medium transmission estimation. DehazeNet takes a hazy image as input, and outputs its medium transmission map that is subsequently used to recover a haze-free image via atmospheric scattering model. DehazeNet adopts convolutional neural network-based deep architecture, whose layers are specially designed to embody the established assumptions/priors in image dehazing. Specifically, the layers of Maxout units are used for feature extraction, which can generate almost all haze-relevant features. We also propose a novel nonlinear activation function in DehazeNet, called bilateral rectified linear unit, which is able to improve the quality of recovered haze-free image. We establish connections between the components of the proposed DehazeNet and those used in existing methods. Experiments on benchmark images show that DehazeNet achieves superior performance over existing methods, yet keeps efficient and easy to use.


Chromosome misalignment is associated with PLK1 activity at cenexin-positive mitotic centrosomes.
The mitotic kinase, polo-like kinase 1 (PLK1), facilitates the assembly of the two mitotic spindle poles, which are required for the formation of the microtubule-based spindle that ensures appropriate chromosome distribution into the two forming daughter cells. Spindle poles are asymmetric in composition. One spindle pole contains the oldest mitotic centriole, the mother centriole, where the majority of cenexin, the mother centriole appendage protein and PLK1 binding partner, resides. We hypothesized that PLK1 activity is greater at the cenexin-positive older spindle pole. Our studies found that PLK1 asymmetrically localizes between spindle poles under conditions of chromosome misalignment, and chromosomes tend to misalign toward the oldest spindle pole in a cenexin- and PLK1-dependent manner. During chromosome misalignment, PLK1 activity is increased specifically at the oldest spindle pole, and this increase in activity is lost in cenexin-depleted cells. We propose a model where PLK1 activity elevates in response to misaligned chromosomes at the oldest spindle pole during metaphase.


Picosecond pulse duration laser treatment for dermal melanocytosis in Asians : A retrospective review.
Background and aims: Recently novel picosecond duration lasers (ps-lasers) have been developed for the treatment of multicolored and recalcitrant tattoos, and safety and efficacy have been reported. We therefore hypothesized that the ps-laser could be an alternative treatment for dermal pigmented lesions and performed a retrospective review to evaluate the efficacy and safety of the ps-laser. Subjects and methods: A retrospective photographic review of 10 patients with dermal pigmented lesions was performed (ages from 4 months to 52 yr), 6 nevus of Ota, 3 ectopic Mongolian spots and 1 Mongolian spots. The patients were treated in the Ohshiro Clinic with picosecond 755 nm alexandrite laser (ps-Alex laser) and picosecond 1064 nm Nd:YAG laser (ps-Nd:YAG laser) from April 2014 to December 2015 (ps-Alex laser, 7 patients; ps-Nd:YAG laser, 3 patients, 1 to 3 treatment sessions). Improvement was evaluated as percentage of pigmentation clearance comparing the baseline findings with those at 3 months after the final treatment using a five category grading scale: Poor, 0-24%; Fair, 25-49%; Good, 50-74%; Excellent, 75-94%; and Complete, 95-100% improvement. Adverse events were also assessed. Results: All ten patients obtained clinical improvement ranging from fair to excellent. Treatment with the ps-Alex laser caused transient hyperpigmentation followed by improvement to complete resolution at 3 months follow-up. The ps-Nd:YAG laser caused severe transient erythema and swelling but no post-inflammatory hyperpigmentation. Conclusions: Our results suggest that the 755 nm and 1064 nm ps-lasers are efficacious for the treatment of dermal pigment lesions, with minimum adverse events.


Terahertz spectroscopy for quantifying refined oil mixtures.
In this paper, the absorption coefficient spectra of samples prepared as mixtures of gasoline and diesel in different proportions are obtained by terahertz time-domain spectroscopy. To quantify the components of refined oil mixtures, a method is proposed to evaluate the best frequency band for regression analysis. With the data in this frequency band, dualistic linear regression fitting is used to determine the volume fraction of gasoline and diesel in the mixture based on the Beer-Lambert law. The minimum of regression fitting R-Square is 0.99967, and the mean error of fitted volume fraction of 97# gasoline is 4.3%. Results show that refined oil mixtures can be quantitatively analyzed through absorption coefficient spectra in terahertz frequency, which it has bright application prospects in the storage and transportation field for refined oil.


Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells.
Hepatocellular carcinomas (HCCs) contain a sub-population of cancer stem cells (CSCs) that are responsible for tumor relapse, metastasis, and chemoresistance. We recently showed that loss of macroH2A1, a variant of the histone H2A and an epigenetic regulator of stem-cell function, in HCC leads to CSC-like features such as resistance to chemotherapeutic agents and growth of large and relatively undifferentiated tumors in xenograft models. These HCC cells silenced for macroH2A1 also exhibited stem-like metabolic changes consistent with enhanced glycolysis. However, there is no consensus as to the metabolic characteristics of CSCs that render them adaptable to microenvironmental changes by conveniently shifting energy production source or by acquiring intermediate metabolic phenotypes. Here, we assessed long-term proliferation, energy metabolism, and central carbon metabolism in human hepatoma HepG2 cells depleted in macroH2A1. MacroH2A1-depleted HepG2 cells were insensitive to serum exhaustion and showed two distinct, but interdependent changes in glucose and lipid metabolism in CSCs: (1) massive upregulation of acetyl-coA that is transformed into enhanced lipid content and (2) increased activation of the pentose phosphate pathway, diverting glycolytic intermediates to provide precursors for nucleotide synthesis. Integration of metabolomic analyses with RNA-Seq data revealed a critical role for the Liver X Receptor pathway, whose inhibition resulted in attenuated CSCs-like features. These findings shed light on the metabolic phenotype of epigenetically modified CSC-like hepatic cells, and highlight a potential approach for selective therapeutic targeting.


Do genetic predictors of pain sensitivity associate with persistent widespread pain?
Genetic risk factors for pain sensitivity may also play a role in susceptibility to chronic pain disorders, in which subjects have low pain thresholds. The aim of this study was to determine if proposed functional single nucleotide polymorphisms (SNPs) in the GTP cyclohydrolase (GCH1) and mu opioid receptor (OPRM1) genes previously associated with pain sensitivity affect susceptibility to chronic widespread pain (CWP). Pain data was collected using body manikins via questionnaire at three time-points over a four year period from subjects aged 25-65 in the North-West of England as part of a population based cohort study, EPIFUND. CWP was defined at each time point using standard criteria. Three SNPs forming a proposed "pain-protective" haplotype in GCH1 (rs10483639, rs3783641 and rs8007267) and two SNPs in OPRM1 (rs1777971 (A118G) and rs563649) were genotyped in cases with persistent CWP (CWP present at >or=2 time-points) and controls who were pain-free at all time-points. The expectation-maximisation algorithm was used to estimate haplotype frequencies. The frequency of the "pain-protective" (CAT - C allele of rs10483639, A allele of rs3783641 and T allele of rs8007267) haplotype was compared to the frequency of the other haplotypes between cases and controls using the chi2 test. Allele frequencies and carriage of the minor allele was compared between cases and controls using chi2 tests for the OPRM1 SNPs. The frequency of the proposed GCH1 "pain-protective" haplotype (CAT) did not significantly differ between cases and controls and no significant associations were observed between the OPRM1 SNPs and CWP. In conclusion, there was no evidence of association between proposed functional SNPs, previously reported to influence pain sensitivity, in GCH1 and OPRM1 with CWP. Further evidence of null association in large independent cohorts is required to truly exclude these SNPs as genetic risk factors for CWP.


PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease.
A hallmark of Parkinson's disease (PD) is the preferential loss of substantia nigra dopamine neurons. Here, we identify a new parkin interacting substrate, PARIS (ZNF746), whose levels are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human PD brain. PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons in a PARIS-dependent manner. Moreover, overexpression of PARIS leads to the selective loss of DA neurons in the substantia nigra, and this is reversed by either parkin or PGC-1α coexpression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.


An investigation of emotional wellbeing and its relationship to contemporary nursing practice.
This paper is an investigation of emotional wellbeing and its relationship to contemporary nursing practice for women community health nurses (CHNs) who are providing palliative care. Palliative care provision has been acknowledged as a source of job satisfaction for many nurses however emotional interactions place increasing strain on nurses' wellbeing. Psychosocial aspects of care are reported as having a personal as well as a professional impact. Work related stress places nurses at increased risk of harm and impaired wellbeing. An emancipatory methodology was chosen for this study. Semi-structured interviews and reflective journaling were the methods used. The data was collected over a 16-month period during 2006-2007. There were fifteen participants. This qualitative study explored Australian rural and urban community nurses' experiences with wellbeing, emotional work and their professional practice. The findings revealed opposing social forces, an inner 'dialectical' tension between the nurses' expectations of their professional practices and what is valued in their practice settings. In terms of emotional wellbeing, two overarching themes will be discussed: feeling balanced and feeling out of balance. Workplace environments that were not always conducive to healing increased the emotional strain on nurses. Nurses' work promotes the healing of others therefore to deny the healing of nurses' is to deny others of healing. The need for further qualitative research investigating the emotional wellbeing and professional practice of community nurses who provide palliative care is necessary.


Efficacy of Honeydew Honey and Blossom Honey on Full-thickness Wound Healing in Mice.
The wound healing properties of honey, including blossom honey, are well known; however, the effects of honeydew honey during the wound healing process have not yet been investigated and thus remain unclear. This study compares the effects of honeydew honey with those of blossom honey. A total of 140 mice were divided into 2 control groups, which received either a hydrocolloid dressing (HCD; n = 22) or gauze (n = 22), and 4 experimental groups: honeydew honey (n = 23), Acacia honey (n = 23), Manuka honey (n = 22), and Japanese Pharmacopoeia honey (n = 28). Two circular full-thickness wounds were made and measured for 14 days. Each wound in the experimental groups was treated with 0.1 mL of honey and covered with gauze. Dressings in the control and experimental groups were changed daily. The wounds in all of the honey groups and the HCD group were moist by day 14, while those in the gauze group were dry. The ratio of wound area to initial wound area and the number of inflammatory cells decreased during the inflammatory phase in all honey groups. However, the honey groups exhibited reepithelialization rates of < 40%, numerous neutrophils, weak wound contraction, and impaired collagen deposition in wounds after day 11. These results suggest honeydew honey and blossom honey both exert anti-inflammatory effects during the inflammatory phase. However, all of the honeys examined were less effective at promoting full-thickness wound healing than the controls. Further studies are warranted.


How to bridge the gap in human resources for health.
Human resources are the crucial core of a health system, but they have been a neglected component of health-system development. The demands on health systems have escalated in low income countries, in the form of the Millennium Development Goals and new targets for more access to HIV/AIDS treatment. Human resources are in very short supply in health systems in low and middle income countries compared with high income countries or with the skill requirements of a minimum package of health interventions. Equally serious concerns exist about the quality and productivity of the health workforce in low income countries. Among available strategies to address the problems, expansion of the numbers of doctors and nurses through training is highly constrained. This is a difficult issue involving the interplay of multiple factors and forces.


Limited usefulness of initial blood cultures in community acquired pneumonia.
The incidence of community acquired pneumonia (CAP) is about 4 million cases per year, with a hospitalisation rate of 20%. In non-immunocompromised patients hospitalised for CAP the rate of bacteraemia is less than 7% with predictable pathogens. Despite this, guidelines still recommend use of blood cultures (BCs) to direct treatment. This study tested the primary hypothesis that the proportion of false positive BCs would exceed the proportion of true positives. A secondary aim was to quantify the frequency with which antibiotic therapy was changed based on BC results. Consecutive adults hospitalised from an urban emergency department (ED) with CAP between January 1999 and March 2001 were assessed retrospectively for study eligibility. Those with an infiltrate consistent with pneumonia on the admission chest radiograph and at least one set of BCs taken in the ED before antibiotics were given were entered into the study. Patients hospitalised within the previous two weeks, nursing home residents, and immunosuppressed patients were excluded. 821 patients were admitted for CAP and 355 met inclusion criteria. The proportion of false positive BCs (10%) exceeded the proportion of true positives (9%), by 1% (95%CI -3.3% to 5.5%). Antibiotic therapy was changed on the basis of BC results in 5% of patients (95%CI 3% to 8%). The rate of false positive BCs in patients hospitalised with CAP is similar to the rate of true positives. BCs only infrequently lead to changes in antibiotic therapy, and in no instance were therapeutic changes driven by detection of resistant organisms. The results question the utility of routine BCs in immunocompetent patients with CAP.


Layer-specificity in the effects of attention and working memory on activity in primary visual cortex.
Neuronal activity in early visual cortex depends on attention shifts but the contribution to working memory has remained unclear. Here, we examine neuronal activity in the different layers of the primary visual cortex (V1) in an attention-demanding and a working memory task. A current-source density analysis reveales top-down inputs in the superficial layers and layer 5, and an increase in neuronal firing rates most pronounced in the superficial and deep layers and weaker in input layer 4. This increased activity is strongest in the attention task but it is also highly reliable during working memory delays. A visual mask erases the V1 memory activity, but it reappeares at a later point in time. These results provide new insights in the laminar circuits involved in the top-down modulation of activity in early visual cortex in the presence and absence of visual stimuli.


Total IgA and IgA reactivity to antigen I/II epitopes in HLA-DRB1*04 positive subjects.
Bacterial adherence to the acquired dental pellicle, important in dental caries (caries), is mediated by receptor-adhesins such as salivary agglutinin binding to Streptococcus mutans antigen I/II (I/II). Ten selected I/II epitopes were chosen to determine their reactivity to human salivary IgA. Previous studies suggested that a specific HLA biomarker group (HLA-DRB1*04) may have differential influence of immune responses to I/II. However, it was not known whether secretory IgA (SIgA) responses to the selected epitopes from HLA-DRB1*04 positive subjects were different compared to controls, or across other caries-related factors such as total IgA (TIgA). Thirty-two total subjects were matched according to HLA type, gender, ethnicity and age. HLA genotyping, oral bacterial, immunoglobulin and antibody analyses were performed. A large observed difference emerged with regard to the natural immune reservoir of TIgA in HLA-DRB1*04 positive subjects, specifically, a 27.6% reduction compared to controls. In contrast to all other epitopes studied, HLA-DRB1*04 positive subjects also exhibited reduced reactivity to I/II epitope 834-853. HLA-DRB1*04 positive subjects exhibited lower specific SIgA activity/TIgA to 834-853 and also a lower specific reactivity to 834-853/whole cell S. mutans UA159. Furthermore, HLA-DRB1*04 positive subjects exhibited lower responses to I/II in its entirety. The large observed difference in TIgA and the 834-853 reactivity pattern across multiple measures suggest potentially important connections pertaining to the link between HLA-DRB1*04 and caries.


Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma.
Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment.


Effect of chronic morphine exposure on the synaptic plasma-membrane subproteome of rats: a quantitative protein profiling study based on isotope-coded affinity tags and liquid chromatography/mass spectrometry.
The effect of chronic morphine exposure on the synaptic plasma-membrane subproteome in rats was studied by the isotope-coded affinity tag (ICAT) method coupled with capillary reversed-phase liquid chromatography/electrospray ionization mass spectrometry and tandem mass spectrometry. ICAT-labeled tryptic peptides of synaptic membrane proteins were successfully identified using tandem mass spectrometry in conjunction with protein database searching. Several important synaptic plasma-membrane proteins displayed significant regulation changes as a result of chronic morphine exposure in vivo. In particular, an integral membrane protein Na(+)/K+ ATPase (alpha-subunit) involved in regulation of the cell membrane potential by controlling sodium and potassium ion permeability was downregulated by 39 +/- 2%. This result was in excellent agreement with the reduction in electrogenic Na+, K+ pumping due to about 40% downregulation of Na(+)/K+ ATPase alpha3-isoform in myenteric S-neurons of morphine-exposed guinea-pigs measured by others via immunohistochemistry. The decrease in the abundance of non-erythroid alpha II-spectrin in the synaptic plasma-membrane fraction was also observed, which was hypothetically associated with the breakdown of the protein due to the upregulation of the proteolytic enzyme caspase-3 upon chronic morphine exposure.


A population-based study of genotypic and phenotypic variability in children with spinal muscular atrophy.
To describe the occurrence of spinal muscular atrophy (SMA) in childhood; to evaluate if any of the genes in the SMA region on chromosome 5q13 correlates with disease severity; to make genotype-phenotype correlations; to evaluate the variability of different disease alleles in carriers and the sensitivity of multiplex ligation-dependent probe amplification (MLPA) for detecting carriers. In a population-based study from Western Sweden MLPA was used to determine the copy-numbers of several genes in the SMA region (SMN1, SMN2, BIRC1, GTF2H2 and SERF1A) in SMA-patients and their parents. We estimated the incidence of SMN1-related SMA in childhood at 1 in 11 800 live births and confirmed the relationship between the number of SMN2 copies and the severity of disease. No other direct relationships were found. All but one of the analysed parents were confirmed as carriers by MLPA analysis. A total of at least 30 different disease alleles were identified and no specific disease allele represented more than 15% of the total. The childhood incidence of SMA in the Swedish population is around 1 in 12,000 live births and it is unlikely that there is any founder effect involved in SMA in western Sweden.


The sunflower genome provides insights into oil metabolism, flowering and Asterid evolution.
The domesticated sunflower, Helianthus annuus L., is a global oil crop that has promise for climate change adaptation, because it can maintain stable yields across a wide variety of environmental conditions, including drought. Even greater resilience is achievable through the mining of resistance alleles from compatible wild sunflower relatives, including numerous extremophile species. Here we report a high-quality reference for the sunflower genome (3.6 gigabases), together with extensive transcriptomic data from vegetative and floral organs. The genome mostly consists of highly similar, related sequences and required single-molecule real-time sequencing technologies for successful assembly. Genome analyses enabled the reconstruction of the evolutionary history of the Asterids, further establishing the existence of a whole-genome triplication at the base of the Asterids II clade and a sunflower-specific whole-genome duplication around 29 million years ago. An integrative approach combining quantitative genetics, expression and diversity data permitted development of comprehensive gene networks for two major breeding traits, flowering time and oil metabolism, and revealed new candidate genes in these networks. We found that the genomic architecture of flowering time has been shaped by the most recent whole-genome duplication, which suggests that ancient paralogues can remain in the same regulatory networks for dozens of millions of years. This genome represents a cornerstone for future research programs aiming to exploit genetic diversity to improve biotic and abiotic stress resistance and oil production, while also considering agricultural constraints and human nutritional needs.


Readiness to change and barriers to treatment seeking in college students with a mental disorder.
College students have high prevalence of mental disorders and suicidal thoughts and behaviours, and low rates of treatment uptake. This study assesses treatment access, intentions to seek help, and perceived barriers to help-seeking, considering gender and suicidal thoughts or behaviours (STBs) as predictors. Data is from the Ulster University Student Wellbeing study (2015) conducted in Northern Ireland (NI), as part of the WHO World Mental Health Surveys International College Student Project. Participants are 392 new college entrants (162 males (41.3%)/230 females (58.7%)), who all reported some lifetime mental disorder or STBs. Receipt of treatment was low (37.8%), particularly among males and those with no STBs. Males were less likely to intend to access external professional services and were less likely than females to rate embarrassment (OR = 0.60) or worry about being treated differently (OR = 0.63) as important reasons for not seeking treatment. Those with STBs rated wanting to handle things on their own as a more important barrier those with no STBs (OR = 0.55 for non STBs group) and rated being unsure where to go as a less important barrier than those with no STBs (OR = 1.80 for non STBs group). Data is correlational and concerns lifetime criteria for mental disorder, with no consideration of current mental status nor disorder type. These findings have implications for the active screening and intervention for vulnerable college students, particularly males and those with mental disorders but no STBs.


Feedback Control for Steering Needles Through 3D Deformable Tissue Using Helical Paths.
Bevel-tip steerable needles are a promising new technology for improving accuracy and accessibility in minimally invasive medical procedures. As yet, 3D needle steering has not been demonstrated in the presence of tissue deformation and uncertainty, despite the application of progressively more sophisticated planning algorithms. This paper presents a feedback controller that steers a needle along 3D helical paths, and varies the helix radius to correct for perturbations. It achieves high accuracy for targets sufficiently far from the needle insertion point; this is counterintuitive because the system is highly under-actuated and not locally controllable. The controller uses a model predictive control framework that chooses a needle twist rate such that the predicted helical trajectory minimizes the distance to the target. Fast branch and bound techniques enable execution at kilohertz rates on a 2GHz PC. We evaluate the controller under a variety of simulated perturbations, including imaging noise, needle deflections, and curvature estimation errors. We also test the controller in a 3D finite element simulator that incorporates deformation in the tissue as well as the needle. In deformable tissue examples, the controller reduced targeting error by up to 88% compared to open-loop execution.


Benefit of left atrial appendage electrical isolation for persistent and long-standing persistent atrial fibrillation: a systematic review and meta-analysis.
The long-term outcomes of left atrial appendage electrical isolation (LAAEI) in patients with non-paroxysmal atrial fibrillation (AF) have corroborated the significant role of the LAA in this arrhythmia. We sought to investigate the incremental benefit of LAAEI in patients undergoing catheter ablation for persistent AF or long-standing persistent AF (LSPAF). A systematic review of Medline, Cochrane, and Embase for all the clinical studies in which assessment LAAEI in non-paroxysmal AF patients was performed. The benefit of LAAEI in patients with AF was analysed from seven studies that enrolled a total of 930 patients [mean age 63 ± 5 years; male: 69%]. All studies included patients with either persistent AF or LSPAF or the combination of them. The overall freedom from all-arrhythmia recurrence at 12 months of follow-up off antiarrhythmic medications in patients who underwent LAAEI was 75.5% vs. 43.9% in those in whom only standard ablation was performed [56% relative reduction and 31.6% absolute reduction; risk ratio (RR) 0.44, 95% confidence interval (95% CI) 0.31-0.64; P < 0.0001]. The rate of ischaemic stroke in the LAAEI group was 0.4% and in the control group 2.1% at 12 months follow-up (RR 0.40, 95% CI 0.12-1.30; P = 0.13). Acute complications rates were identical between groups [LAAEI 5.5%, control 5.5% (RR 0.99, 95% CI 0.46-2.16; P = 0.99)]. Left atrial appendage electrical isolation in addition to standard ablation appears to have a substantial incremental benefit to achieve freedom from ALL atrial arrhythmias in patients with persistent AF and LSPAF without increasing acute procedural complications and without raising the risk of ischaemic stroke.


DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV.
HIV sequence diversity and the propensity of eliciting immunodominant responses targeting variable regions of the HIV proteome are hurdles in the development of an effective AIDS vaccine. An HIV-derived conserved element (CE) p24gag plasmid DNA (pDNA) vaccine is able to redirect immunodominant responses to otherwise subdominant and often more vulnerable viral targets. By homology to the HIV immunogen, seven CE were identified in SIV p27Gag Analysis of 31 rhesus macaques vaccinated with full-length SIV gag pDNA showed inefficient induction (58% response rate) of cellular responses targeting these CE. In contrast, all 14 macaques immunized with SIV p27CE pDNA developed robust T cell responses recognizing CE. Vaccination with p27CE pDNA was also critical for the efficient induction and increased the frequency of Ag-specific T cells with cytotoxic potential (granzyme B+ CD107a+) targeting subdominant CE epitopes, compared with the responses elicited by the p57gag pDNA vaccine. Following p27CE pDNA priming, two booster regimens, gag pDNA or codelivery of p27CE+gag pDNA, significantly increased the levels of CE-specific T cells. However, the CE+gag pDNA booster vaccination elicited significantly broader CE epitope recognition, and thus, a more profound alteration of the immunodominance hierarchy. Vaccination with HIV molecules showed that CE+gag pDNA booster regimen further expanded the breadth of HIV CE responses. Hence, SIV/HIV vaccine regimens comprising CE pDNA prime and CE+gag pDNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth.


Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database.
Systemic sclerosis (SSc) is a rare disease requiring multicentre collaboration to reveal comprehensive details of disease-related causes for morbidity and mortality. The European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group initiated a database to prospectively gather key data of patients with SSc using a minimal essential dataset that was reorganised in 2008 introducing new items. Baseline visit data of patients who were registered between 2004 and 2011 were analysed using descriptive statistics. In June 2011, 7655 patients (2838 with diffuse cutaneous (dc) and 4481 with limited cutaneous (lc) SSc who fulfilled the American College of Rheumatology diagnostic criteria had been registered in 174 centres, mainly European. The most prominent hallmarks of disease were Raynaud's phenomenon (96.3%), antinuclear antibodies (93.4%) and a typical capillaroscopic pattern (90.9%). Scleroderma was more common on fingers and hands than on any other part of the skin. Proton pump inhibitors (65.2%), calcium channel blockers (52.7%), and corticosteroids (45.3%) were most often prescribed. Among the immunosuppressant agents, cyclophosphamide was used more often in dcSSc than in lcSSc. The EUSTAR database provides an abundance of information on the true clinical face of SSc that will be helpful in improving the classification of SSc and its subsets and for developing more specific therapeutic recommendations.


[Extracorporeal renal replacement therapies in lithium intoxication].
Drug poisoning is a significant source of morbidity, mortality and health care expenditure worldwide. Lithium, methanol, ethylene glycol and salicylates are the most important ones, included in the list of poisons, that may require extracorporeal depuration. Lithium is the cornerstone of treatment for bipolar disorders, but it has a narrow therapeutic window. The therapeutic range is 0.6-1.2 mEq/L and toxicity manifestations begin to appear as soon as serum levels exceed 1.5 mEq/L. Severe toxicity can be observed when plasma levels are more than 3.5 mEq/L. Lithium poisoning can be life threatening and extracorporeal renal replacement therapies can reverse toxic symptoms. Currently, conventional intermittent hemodialysis (IHD) is the preferred extracorporeal treatment modality. Preliminary data with prolonged intermittent renal replacement (PIRRT) therapies - hybrid forms of renal replacement therapy (RRT) such as sustained low efficiency dialysis (SLED) - seem to justify their role as potential alternative to conventional IHD. Indeed, SLED allows rapid and effective lithium removal with resolution of symptoms, also minimizing rebound phenomenon.


Evidence for a synergistic interaction between phenytoin and phenobarbital in experimental animals.
Combined anticonvulsant effects of phenytoin and phenobarbital in mice and rabbits were studied using the isobolographic method which was based on the plasma concentrations of these drugs. Anticonvulsant activity of test drugs alone or in combination was determined by the method of maximal electroshock seizure test. Response of each animal to drug action was recorded as abolition of the tonic hindlimb extensor component of maximal electroshock seizure. It was demonstrated that the minimal effective plasma concentrations of phenytoin and phenobarbital alone for protection against maximal electroshock seizure was 5.9 +/- 0.2 and 18.1 +/- 0.4 microgram/ml (+/- SE) in mice and 14.7 +/- 0.5 and 17.5 +/- 0.6 microgram/ml (+/-SE) in rabbits, respectively. Isobolograms for mice and rabbits were constructed by identifying and plotting each responder and nonresponder for its corresponding plasma phenytoin and phenobarbital concentrations when these drugs were given in combination. The isoboles in mice and rabbits were concave bowing toward the origin, indicated synergism (potentiation). The apparent synergism between phenytoin and phenobarbital cannot be explained by changes in the amount of these drugs entering into the brain from the blood, since the relationship between brain and plasma concentrations of either drug was not altered by the presence of the other. These results, therefore, suggest that the synergistic action between these two anticonvulsants occurs within the central nervous system; this provides experimental support for the combined use of phenytoin and phenobarbital in the clinical treatment of epilepsy.


The effects of health education and promotion with regard to severe fever with thrombocytopenia syndrome (SFTS) in rural residents: A pilot study in China.
Severe fever with thrombocytopenia syndrome (SFTS) has spread throughout Asia, including China, South Korea, and Japan. In China, the main victims of SFTS were farmers. Measures to protect farmers were urgently needed but limited, and health education and promotion was proposed as an option. A pilot community trial was conducted to provide health education about SFTS in 2013 in Daishan County, Zhejiang Province, China, and results indicated that health education had promise. An educational campaign was conducted for three years. The incidence of SFTS decreased 0.3 per 1,000 person-years, and rural residents' awareness of SFTS increased substantially. Numerous habits or work practices that increased the likelihood of tick bites have also been changed. In the future, education could emphasize adopting healthy habits or work practices to reduce tick bites and thus reduce the incidence of SFTS, like regularly weeding around a house surrounded by shrubs, not sitting or lying on the ground when resting, and protecting one's self when doing farm work.


Organization of pontocerebellar projections to identified climbing fiber zones in the rat.
The organization of pontocerebellar projections to the paravermis and hemisphere of the posterior cerebellum of the rat was studied in relation to the organization of climbing fibers. Small injections of cholera toxin subunit B were placed in the cerebellar cortex at locations predetermined by evoked climbing fiber potentials from selected body parts or based on coordinates. The injection site was characterized with respect to the zebrin pattern and by the distribution of retrogradely labeled neurons in the inferior olive. The following zones were studied: hindlimb-related zones C1 and C2 of lobule VIII; forelimb-related zones C1, C2, and D0/D1 of the paramedian lobule; and face-related zones A2 of the paramedian lobule and C2 and D0 of crus 2B. The results show that the distribution of pontine neurons is closely related to the climbing fiber somatotopy. Injections centered on face-related zones result in distribution of pontine neurons within the pontine core region. Forelimb regions surround this core, whereas hindlimb regions are mostly supplied by caudal pontine regions and by a single patch of more rostrally located neurons. This distribution fits well with published data on the somatotopy of the corticopontine projection from the rat primary somatosensory cortex. However, apart from differences in the participation of ipsilaterally projecting cells, the distribution of pontine neurons does not change significantly when the injection covers different zones of the same lobule such as C1 and C2 of lobule VIII; C1, C2, and D0/D1 of the paramedian lobule; A2 of the paramedian lobule; and C2 and D0 of crus 2B.


Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial.
We evaluated etanercept, a human soluble tumor necrosis factor receptor: Fc fusion protein, for the treatment of active Crohn's disease. Forty-three patients with moderate to severe Crohn's disease were enrolled in an 8-week placebo-controlled trial. Patients were randomized to subcutaneous etanercept 25 mg or placebo twice weekly. The primary outcome measure was clinical response at week 4, defined as a decrease in the baseline Crohn's Disease Activity Index score > or =70 points or a Crohn's Disease Activity Index score <150 points. At week 4, 39% of etanercept-treated patients had clinical response as compared with 45% of placebo-treated patients (P = 0.763). The frequency of common adverse events including headache, new injection site reaction, asthenia, abdominal pain, Crohn's disease-related anemia, and skin disorders was similar in both groups. Likewise, the frequency of severe or serious adverse events was similar in both groups. Subcutaneous etanercept at a dose of 25 mg twice weekly is safe, but not effective, for the treatment of patients with moderate to severe Crohn's disease. The dose of etanercept administered in this study is that approved for rheumatoid arthritis. Higher doses or more frequent dosing may be required to attain a response in patients with active Crohn's disease.


Continuous-wave mode-locked operation of a chromium-doped forsterite laser.
Mode-locked operation of chromium-doped forsterite (Cr:Mg(2)SiO(4)) has been achieved for the first time to our knowledge. The chromium-doped forsterite laser has been mode locked by using two methods: active mode locking, which produced pulses as short as 31 ps tunable between 1204 and 1277 nm, and synchronously pumped mode locking, which produced pulses of 260-ps duration tunable between 1195 and 1295 nm.


Engineering better vaccines for foot-and-mouth disease.
Although efficacious and safe, current vaccines for FMD suffer from drawbacks. Among these are that the immune response to the vaccine interferes with the ability to detect vaccinated animals that have subsequently become infected and could carry and shed the virus, creating an obstacle to re-instating disease-free status to countries/regions that vaccinate to control outbreaks. Multiple diagnostic tests are available to identify animals that have been infected with FMDV by detection of antibodies to viral non-structural proteins (NSP) that are present in low concentration in traditional vaccines and are poorly immunogenic in vaccine preparations. However, these tests are not 100% reliable. To circumvent this problem, we have developed a new generation of vaccines that express the "empty capsid" subunit of the virus, in the absence of one of the most immunogenic NSPs, 3Dpol. Here we describe delivery of the empty capsid subunits by recombinant replication-defective human adenovirus type 5 (Ad5). These Ad5-vectored empty capsid vaccines can protect pigs from FMDV challenge as early as 7 days post-vaccination. A second problem with current FMD vaccines is that they do not induce protective immunity quickly, a drawback that is likely to be shared by our Ad5-vectored empty capsid vaccine. To overcome this problem, we have developed a prophylactic antiviral treatment consisting of an Ad5 encoding porcine interferon alpha (pIFNalpha). Administration of Ad5-pIFNalpha protects swine from FMD as early as one day post-administration. The combination of this antiviral treatment and the empty capsid subunit vaccine should induce rapid and complete protection from FMD, and could overcome current diagnostic problems.


Cold reacting anti-M causing delayed hemolytic disease of the newborn.
Hemolytic disease of the fetus and newborn (HDFN) is due to passively transferred maternal antibodies directed against fetal red blood cell (RBC) antigens and can lead to severe morbidity and mortality. Anti-M is usually a naturally occurring antibody of low clinical significance, although occasionally severe cases of HDFN are seen. Two M+ sisters are presented, each developing hemolysis during the first 2 weeks of life due to maternal anti-M, resulting in severe anemia and requiring blood transfusion. RBC agglutination was observed in peripheral blood samples of both infants at room temperature with dissociation at 37°C. Maternal anti-M detected by column indirect agglutination technique, was of low titer (1:16) and demonstrated low thermal amplitude, reacting in saline at 4°C but was not detectable in saline at 37°C. Anti-M of low thermal amplitude may cause hemolytic disease of the newborn with laboratory features resembling cold agglutinin disease.


Clinical predictors of response to pharmacotherapy with selective serotonin reuptake inhibitors in obsessive-compulsive disorder.
The objective of this study was to investigate the clinical predictors of response to treatment with selective serotonin reuptake inhibitors (SSRI) in a sample of patients with obsessive-compulsive disorder (OCD). A total of 55 patients diagnosed as OCD according to revised 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders criteria underwent a 12-week standardized SSRI treatment. According to 'treatment response', defined as at least a 35% drop in the Yale-Brown Obsessive-Compulsive Scale total score, OCD patients were divided into two groups. A total of 32 (58.2%) patients who responded to treatment and 23 (41.8%) who did not, were compared in terms of sociodemographic and clinical characteristics. The authors' findings demonstrated that the severity of obsession-compulsions and disability in work, social and family lives at the beginning of treatment were significantly higher in OCD patients who did not respond to treatment in comparison to those who did. Linear regression analysis, however, revealed that Sheehan Disability Scale-work score at baseline was a predictor of response to SSRI treatment. The higher levels of disability at the beginning of treatment in patients with OCD are associated with a poorer response to SSRI.


Water soluble hydrophobic peptoids via a minor backbone modification.
Peptoids - oligomers of N-substituted glycine - are an important class of peptide mimics that are widely used in areas ranging from biology and medicine to metal binding and catalysis. The utility of peptoids, however, especially for applications in aqueous solutions, is often hampered by the hydrophobic nature of their sequences dictated by structural and functional requirements. Herein we describe a simple method to solubilize hydrophobic peptoids in water without modifying their original sequences, via the insertion of biocompatible and low cost piperazine or homopiperazine groups at the N- or C-terminus of the peptoid backbone. We show that our method can be applied for the production of α-, β- and azapeptoids, which display high water solubility for long periods of time. Moreover, circular dichroism (CD) spectroscopy revealed that the incorporation of piperazine groups within α-peptoids, having chiral naphthyl monomers, β-peptoids and unstructured azapeptoids results in peptoids that exhibit high conformational order in water.


Influence of Progenitor-Derived Regeneration Markers on Hepatitis C Virus-Related Cirrhosis Outcome (ANRS CO12 CirVir Cohort).
Progenitor-derived regeneration gives rise to the aberrant expression of biliary markers such as cytokeratin 7 (K7) and epithelial cell adhesion molecule (EpCAM) in hepatocytes. We aimed to describe the expression of these molecules in patients with compensated hepatitis C virus (HCV)-related cirrhosis and to investigate its potential influence on cirrhosis complications. Among patients with Child-Pugh A uncomplicated HCV-related cirrhosis enrolled in the prospective ANRS CO12 CirVir cohort, we selected individuals with a liver biopsy collected within 2 years before inclusion in the study. K7 and EpCAM immunostaining identified intermediate hepatobiliary cells. The influence of biliary marker expres-sion in hepatocytes on decompensation events and the occurrence of hepatocellular carcinoma (HCC) was studied using a multivariate Cox proportional hazards regression model. Among the 337 patients eligible for the study (men, 67%; median age, 52 years), 198 (58.8%) had biopsies with K7-positive hepatocytes including extensive staining in 40 (11.9%) and 203 had EpCAM-positive hepatocytes (60.6%). During follow-up (median, 54.2 months), 47 patients (14%) experienced a decompensation event, and HCC was diagnosed in 37 patients (11%). Extensive K7 staining was independently associated with the occurrence of a decompensation event (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.30-6.89; P = 0.010). EpCAM expression was independently associated with HCC occurrence (HR, 2.37; 95% CI, 1.07-5.23; P =0.033) along with age and a low prothrombin ratio. Progenitor-derived regeneration depicted by K7 and EpCAM immunostaining of hepatocytes in liver biopsies of patients with compensated HCV-related cirrhosis marks a cirrhosis stage more prone to develop complications. (HEPATOLOGY 2018; 68:1534-1548).


Anxious solitude across contexts: girls' interactions with familiar and unfamiliar peers.
Cross-situational continuity and change in anxious solitary girls' behavior and peer relations were examined in interactions with familiar versus unfamiliar playmates. Fourth-grade girls (N=209, M age=9.77 years, half African American, half European American) were identified as anxious solitary or behaviorally normative using observed and teacher-reported behavior among classmates. Subsequently, girls participated in 1-hr play groups containing 5 same-race familiar or unfamiliar girls for 5 consecutive days. Results support both cross-situational continuity and change in anxious solitary girls' behavior and peer relations. Although anxious solitary girls exhibited difficulty interacting with both familiar and unfamiliar playmates relative to behaviorally normative girls, elements of their behavior improved in unfamiliar play groups, a context in which they received less peer mistreatment.


Accurate method to quantify binding in supramolecular chemistry.
An approach for accurate and comparable measurement of host-guest binding affinities is introduced whereby differences in binding strength (ΔlogKass values) are measured between two host molecules toward a particular guest under identical solvent conditions. Measuring differences instead of absolute values enables obtaining highly accurate results, because many of the uncertainty sources (the solvation/association state of the guest in solution, deviations in solvent composition, etc.) cancel out. As a proof of concept, this method was applied to the measurement of the binding strength of 28 synthetic anion receptors toward acetate in acetonitrile containing 0.5% water. The receptors included differently substituted indolocarbazoles, ureas, thioureas, and some others. Possible deprotonation of more acidic receptors of each compound class by acetate was checked by measuring their acidities (ΔpKa values) relative to acetic acid in the same solvent. A self-consistent (consistency standard deviation 0.04 log units) binding affinity scale ranging for around 2.7 log units was constructed from the results. Absolute logKass values were found by anchoring the scale to the absolute logKass values of two receptor molecules, determined independently by direct measurements. This new approach is expected to find use in accurate quantification of a wide range of binding processes relevant to supramolecular chemistry.


Time courses of growth and remodeling of porcine aortic media during hypertension: a quantitative immunohistochemical examination.
Arteries undergo marked structural and functional changes in human and experimental hypertension that generally involve smooth muscle cell (SMC) hypertrophy/hyperplasia as well as abnormal extracellular matrix turnover. In this study we examined time courses of changes in SMC activity and matrix protein content in a novel mini-pig aortic coarctation model. Cell proliferation was evaluated by immunostaining of Ki-67, apoptosis was assessed by TUNEL, and phenotypic changes were monitored by immunostaining three SMC contractile markers (caldesmon, calponin, and smoothelin). Changes in medial collagen and elastin were examined by picrosirius red and Verhoeff-van Gieson staining, respectively. LabVIEW-based image analysis routines were developed to objectively and efficiently quantify the (immuno)histochemical results. We found that significant cell proliferation and matrix production occurred in the early stages of this coarctation model and then declined gradually; the SMCs also tended to exhibit a less contractile phenotype following these cellular and extracellular changes. Specifically, different aspects of the phenotypic changes associated with hypertension occurred at different rates: cell proliferation and collagen production occurred early and peaked by 2 weeks, whereas changes in contractile protein expression continued to decrease over the entire 8-week study period. Temporal changes found in this study emphasize the importance of simultaneously tracing time courses of SMC growth and differentiation as well as matrix protein production and content. SMCs are multifunctional, and caution must be used to not overdefine phenotype. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.


Does the bronchial circulation contribute to congestion in heart failure?
Pulmonary congestion is a hallmark feature of heart failure and is a major reason for hospital admissions in this patient population. Heart failure patients often demonstrate restrictive and obstructive pulmonary function abnormalities; however, the mechanisms of these changes remain controversial. It has been suggested that the bronchial circulation may play an important role in the development of these pulmonary abnormalities and in the symptoms associated with pulmonary congestion. Congestion may occur in the bronchial circulation from either a marked increase in flow or an increase in blood volume but with a reduction in flow due to high cardiac filling pressures and high pulmonary vascular pressures (a stasis like condition). Either may lead to thickened bronchial mucosal and submucosal tissues and reduced airway compliance resulting in airway obstruction and restriction and a lack of airway distensibility. These structural changes may contribute to "cardiac asthma" and dyspnea, characteristic features common in HF patients. Thus the bronchial circulation may be a potential target for therapeutic interventions. The aim of this paper is to review factors governing the control of the bronchial circulation, how bronchial vascular conductance may change with HF and to pose arguments, both supporting and in opposition to the bronchial circulation contributing to congestion and altered pulmonary function in HF. We ultimately hypothesize that the engorgement of the bronchial circulatory bed may play a role in pulmonary function abnormalities that occur in HF patients and contribute to symptoms such as orthopnea and exertional dyspnea.


Elevated CD54 Expression Renders CD4+ T Cells Susceptible to Natural Killer Cell-Mediated Killing.
Natural killer (NK) cells are an important type of effector cell in the innate immune response, and also have a role in regulation of the adaptive immune response. Several studies have indicated that NK cells may influence CD4+ T cells during HIV infection. In total, 51 HIV-infected individuals and 15 healthy controls participated in this study. We performed the flow cytometry assays and real-time PCR for the phenotypic analysis and the functional assays of NK cell-mediated deletion of CD4+ T cells, phosphorylation of nuclear factor-κB (NF-κB/p65) and the intervention of metformin. Here we detected high CD54 expression on CD4+ T cells in HIV-infected individuals, and demonstrate that upregulated CD54 is associated with disease progression in individuals infected with HIV. We also show that CD54 expression leads to the deletion of CD4+ T cells by NK cells in vitro, and that this is modulated by NF-κB/p65 signaling. Further, we demonstrate that metformin can suppress CD54 expression on CD4+ T cells by inhibiting NF-κB/p65 phosphorylation. Our data suggest that further studies to evaluate the potential role of metformin as adjunctive therapy to reconstitute immune function in HIV-infected individuals are warranted.


Comparison of two types of synthetic biodegradable barriers for GTR in interproximal infrabony defects: clinical and radiographic 24-month results.
The aim of the present study was to compare the efficacy of guided tissue regeneration (GTR) using two different biodegradable barriers (polylactide acetyltributyl citrate; polydioxanon) in three- and two-walled infrabony defects. The polydioxanon barrier is an experimental GTR membrane that consists of a continuous occlusive barrier with a layer of slings on the side that is meant to face the mucoperiosteal flap. Fifteen patients provided 15 pairs of similar contralateral periodontal defects: 12 predominantly two-walled and 18 predominantly three-walled infrabony defects. Each defect was randomly assigned to treatment with polylactide acetyltributyl citrate (control) or polydioxanon (test) devices. At baseline, 6, 12, 18, and 24 months after surgery, clinical measurements were performed and standardized radiographs obtained (not at 18 months). Both treatments revealed a significant Gingival Index reduction, probing depth reduction, and vertical probing attachment level gain 24 months after surgery. Both treatments showed slight resorption of the crestal alveolar ridge after 24 months, which failed to reach statistical significance. A statistically significant bone gain within the infrabony pockets was measured for both treatment options 24 months postsurgical. Regarding Gingival Index and probing depth reduction as well as vertical probing attachment level and bone gain, there were neither statistically significant nor clinically relevant differences between test and control barriers. The use of both biodegradable barriers in GTR therapy may be recommended.