Oxytocin, vasopressin and pair bonding: implications for autism.
Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a species-specific repetitive element, or 'microsatellite', in the 5' regulatory region of the gene encoding V1aR (avpr1a). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders.


Gene-x-environment analysis supports protective effects of eveningness chronotype on self-reported and actigraphy-derived sleep duration among those who always work night shifts in the UK Biobank.
Previous research has linked having an eveningness chronotype with a higher tolerance for night shift work, suggesting the ability to work nights without health consequences may partially depend upon having a circadian clock optimized for these times. As chronotypes entrain over time to environmental cues, it remains unclear whether higher relative eveningness among healthy night workers reflects a moderating or mediating effect of chronotype on health. We address these concerns conducting a genome-wide association study and utilizing a polygenic score (PGS) for eveningness as a time-invariant measure of chronotype. On a sample of 53 211 workers in the UK Biobank (2006-2018), we focus on the effects of night shift work on sleep duration, a channel through which night shift work adversely affects health. We ask whether a higher predisposition toward eveningness promotes night shift work tolerance. Results indicate that regular night shift work is associated with a 13-minute (3.5%) reduction in self-reported sleep per night relative to those who never work these hours (95% confidence interval [CI] = -17:01, -8:36). We find that eveningness has a strong protective effect on night workers: a one-SD increase in the PGS is associated with a 4-minute (28%) reduction in the night shift work sleep penalty per night (CI = 0:10, 7:04). This protective effect is pronounced for those working the longest hours. Consistent patterns are observed with an actigraphy-derived measure of sleep duration. These findings indicate that solutions to health consequences of night shift work should take individual differences in chronotype into account.


Practice- and Community-Based Interventions to Increase Human Papillomavirus Vaccine Coverage: A Systematic Review.
Vaccines against human papillomavirus (HPV) are recommended for routine use in adolescents aged 11 to 12 years in the United States, but uptake remains suboptimal. Educational interventions focused on parents and patients to increase coverage have not generally demonstrated effectiveness. To systematically review the literature on effectiveness of interventions conducted at the practice or community level to increase uptake of HPV vaccines in the United States. Keyword searches of the PubMed, Web of Science, and MEDLINE databases identified studies of adolescents that included the outcome of HPV vaccination published through July 2014. References of identified articles were also reviewed. A total of 366 records were screened, 38 full-text articles were reviewed, and 14 published studies were included. Results were summarized by different intervention approaches. Practice- and community-based intervention approaches included reminder and recall (n = 7), physician-focused interventions (eg, audit and feedback) (n = 6), school-based programs (n = 2), and social marketing (n = 2) (2 interventions tested multiple approaches). Seven studies used a randomized design, and 8 used quasiexperimental approaches (one used both). Thirteen studies included girls, and 2 studies included boys. Studies were conducted in a variety of populations and geographic locations. Twelve studies reported significant increases in at least one HPV vaccination outcome, one reported a nonsignificant increase, and one reported mixed effects. Most practice- and community-based interventions significantly increased HPV vaccination rates using varied approaches across diverse populations. This finding is in stark contrast to a recent review that did not find effects to warrant widespread implementation for any educational intervention. To address the current suboptimal rates of HPV vaccination in the United States, future efforts should focus on programs that can be implemented within health care settings, such as reminder and recall strategies and physician-focused efforts, as well as the use of alternative community-based locations, such as schools.


Health disparities in Canada today: some evidence and a theoretical framework.
This paper documents contemporary evidence on patterns of health disparities in Canada and suggests theoretical mechanisms that give rise to these patterns. The overall health of Canadians, as measured by life expectancy or mortality, has improved dramatically over the past 30 years and some disparities have diminished slightly (e.g., life expectancy by income group for men), while others have increased (e.g., diabetes for Aboriginal peoples). Arguably the most egregious health disparities in Canada are those existing between Aboriginals and the rest of the Canadian population. This paper focuses specifically on three social determinants and their effects on disparities in health; Aboriginal status, income, and place. Overall we take the approach that disparities in health could be alleviated by reducing inequities in the distribution of these determinants. We further argue that these social determinants are proxies for opportunities, resources and constraints; all of which influence health outcomes. We suggest that policies focus on reducing the social inequities that lead to health disparities in Canada, rather than focusing on the disparities in health alone. Since the social determinants described here have been found to influence an array of disease outcomes, tackling them, rather than their outcomes, may have a greater overall influence on the health of the population.


Advocacy for outpatient cardiac rehabilitation globally.
Cardiovascular diseases (CVD) are the leading cause of death globally. Cardiac rehabilitation (CR) is an evidence-based intervention recommended for patients with CVD, to prevent recurrent events and to improve quality of life. However, despite the proven benefits, only a small percentage of those would benefit from CR actually receive it worldwide. This paper by the International Council of Cardiovascular Prevention and Rehabilitation forwards the groundwork for successful CR advocacy to achieve broader reimbursement, and hence implementation. First, the results of the International Council's survey on national CR reimbursement policies by government and insurance companies are summarized. Second, a multi-faceted approach to CR advocacy is forwarded. Finally, as per the advocacy recommendations, the economic impact of CVD and the corresponding benefits of CR and its cost-effectiveness are summarized. This provides the case for CR reimbursement advocacy. Thirty-one responses were received, from 25 different countries: 18 (58.1 %) were from high-income countries, 10 (32.4 %) from upper middle-income, and 3 (9.9 %) from lower middle-income countries. When asked who reimburses at least some portion of CR services in their country, 19 (61.3 %) reported the government, 17 (54.8 %) reported patients pay out-of-pocket, 16 (51.6 %) reported insurance companies, 12 (38.7 %) reported that it is shared between the patient and another source, and 7 (22.6 %) reported another source. Many patients pay out-of-pocket for CR. CR reimbursement around the world is inconsistent and insufficient. Advocacy campaigns forwarding the CR cause, supported by the relevant literature, enlisting sources of support in a unified manner with an organized plan, are needed, and must be pursued persistently.


Myocardial protection via coronary sinus interventions: superior effects of arterialization compared with intermittent occlusion.
It has been reported that infarct size can be reduced by several interventions, by which arterial blood is delivered retrogradely to the ischemic myocardium through the cardiac veins or alternatively the cardiac venous system is intermittently occluded. Accordingly, we studied several modalities of myocardial protection that used the cardiac venous system and compared them by means of a quantitative technique for measuring infarct size. Thus 73 anesthetized dogs with coronary arterial occlusion were randomized into the following groups: group I (n = 9), 6 hr of occlusion without any intervention; group II (n = 11), venovenous shunt (60 ml/min) to the great cardiac vein; group III (n = 11), arteriovenous shunt to the anterior interventricular vein; group IV (n = 12), high flow arteriovenous shunt to the anterior interventricular vein (60 ml/min); group V (n = 11), arteriovenous shunt to the great cardiac vein (60 ml/min); group VI (n = 10), arteriovenous shunt to the great cardiac vein (60 ml/min) combined with diastolic occlusion of the great cardiac vein; group VII (n = 9), intermittent pressure-controlled occlusion of the great cardiac vein without arterialization. The arteriovenous shunt (groups III to VI) or venovenous shunt (group II) was done by selective catheterization of the anterior interventricular vein or the great cardiac vein, advancing a catheter from the jugular vein through the right atrium and coronary sinus under fluoroscopic control. This catheter was then connected to a cannula located either in the carotid artery (groups III to VI) or in the right atrium (group II). One minute after occlusion, 99mTc-labeled albumin microspheres (8 mCi) were injected into the left atrium for the subsequent assessment of the hypoperfused zone, which is the area at risk for infarction.(ABSTRACT TRUNCATED AT 250 WORDS)


Cosmopolitan cities: the frontier in the twenty-first century?
People with independent (vs. interdependent) social orientation place greater priority on personal success, autonomy, and novel experiences over maintaining ties to their communities of origin. Accordingly, an independent orientation should be linked to a motivational proclivity to move to places that offer economic opportunities, freedom, and diversity. Such places are cities that can be called "cosmopolitan." In support of this hypothesis, Study 1 found that independently oriented young adults showed a preference to move to cosmopolitan rather than noncosmopolitan cities. Study 2 used a priming manipulation and demonstrated a causal impact of independence on residential preferences for cosmopolitan cities. Study 3 established ecological validity by showing that students who actually moved to a cosmopolitan city were more independent than those who either moved to a noncosmopolitan city or never moved. Taken together, the findings illuminate the role of cosmopolitan settlement in the contemporary cultural change toward independence and have implications for urban development and economic growth.


Biology-Driven Gene-Gene Interaction Analysis of Age-Related Cataract in the eMERGE Network.
Bioinformatics approaches to examine gene-gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge-driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty-three SNP-SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)-rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell-to-cell adhesion signaling, cell-cell junction organization, and cell-cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP-SNP models, which included signal transduction and PI3K-Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology-driven method, applicable for any genome-wide association study dataset.


Social responsibility in tobacco production? Tobacco companies' use of green supply chains to obscure the real costs of tobacco farming.
Tobacco companies have come under increased criticism because of environmental and labour practices related to growing tobacco in developing countries. Analysis of tobacco industry documents, industry websites and interviews with tobacco farmers in Tanzania and tobacco farm workers, farm authorities, trade unionists, government officials and corporate executives from global tobacco leaf companies in Malawi. British American Tobacco and Philip Morris created supply chains in the 1990 s to improve production efficiency, control, access to markets and profits. In the 2000s, the companies used their supply chains in an attempt to legitimise their portrayals of tobacco farming as socially and environmentally friendly, rather than take meaningful steps to eliminate child labour and reduce deforestation in developing countries. The tobacco companies used nominal self-evaluation (not truly independent evaluators) and public relations to create the impression of social responsibility. The companies benefit from $1.2 billion in unpaid labour costs because of child labour and more than $64 million annually in costs that would have been made to avoid tobacco-related deforestation in the top 12 tobacco growing developing countries, far exceeding the money they spend nominally working to change these practices. The tobacco industry uses green supply chains to make tobacco farming in developing countries appear sustainable while continuing to purchase leaf produced with child labour and high rates of deforestation. Strategies to counter green supply chain schemes include securing implementing protocols for the WHO Framework Convention on Tobacco Control to regulate the companies' practices at the farm level.


Multilocus DNA fingerprinting and RAPD reveal similar genetic relationships between strains of Oreochromis niloticus (Pisces: Cichlidae).
Two molecular techniques which reveal highly variable DNA polymorphisms, RAPD and multilocus DNA fingerprinting, were used to evaluate genetic diversity between six aquacultural strains of Oreochromis niloticus (tilapia) from the Philippines. The results using both techniques were in close agreement. Within-strain heterozygosity values were similar and were correlated between the two data sets, but statistical errors associated with the RAPD data set were lower. Although genetic distances between strains were greater using DNA fingerprinting, the distances measured using both methods were significantly correlated. Both methods were useful in estimating variation between strains, but they offered different advantages. RAPD was technically easier to perform and produced results with low statistical error, whereas DNA fingerprinting detected greater genetic differentiation between strains. The theoretical basis for using RAPD and multilocus minisatellite markers for population studies is discussed.


Sugaring the pill: ethics and uncertainties in the use of sucrose for newborn infants.
Sucrose is widely used for the management of procedural pain in newborn infants, including capillary blood sampling, venepuncture, and vascular cannulation. Multiple randomized controlled trials have demonstrated that sweet-tasting solutions reduce behavioral responses to acute painful stimuli. It has been claimed that sucrose should be a standard of care in neonatal units and that further placebo-controlled trials of sucrose are unnecessary and unethical. However, recently published data cast doubt on the analgesic properties of sucrose. We review this new evidence and analyze the philosophical and ethical questions that it raises, including the "problem of other minds." Sugar may be better understood not as an analgesic, removing or relieving pain, but as a compensating pleasure. There is a need for further research on the mechanism of sucrose's effect on pain behavior and on the long-term effects of sucrose treatment. Such trials will require comparison with placebo or with other interventions. Given uncertainty about the benefit of sucrose, it may be wise to use alternative analgesics or nonpharmacological interventions where these are available and appropriate. Sucrose may not be the answer to procedural pain in newborns.


Gene order is conserved within the human chromosome 21 linkage group on mouse chromosome 10.
One hundred progeny from each of two intersubspecific mouse backcrosses were used to construct a comparative genetic map of a region of mouse chromosome 10 (MMU10) that is homologous to the distal tip of the long arm of human chromosome 21 (HSA21). The analysis included five genes and three simple sequence repeat markers, two of which flanked the HSA21-homologous cluster on either side. Analysis of 200 backcross progeny detected at least one crossover between each pair of adjacent genes and demonstrated that the proximal to distal orientation of the cluster was reversed between human and mouse. The order was determined to be Fyn-1-D10Mit20-S100b-Col6a1-Itgb2-Pfkl+ ++/D10Mit7-D10Mit11. Comparative mapping supports the order of corresponding markers on HSA21 determined using pulsed-field gel electrophoresis and radiation hybrid line data. However, sequence tagged site content mapping of human yeast artificial chromosomes (YACs) yielded conflicting data on the relative positions of human COL6A1 and S100B on HSA21. This discrepancy was resolved here by demonstrating that several key YACs used in the human contig analysis were mistyped for S100B. The murine map reported here provides a scaffold for construction of physical maps and yeast artificial chromosome contigs that will be useful in the development of mouse models for the study of Down syndrome.


Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice.
The agent of Lyme borreliosis, Borrelia burgdorferi, evades host immunity and establishes persistent infections in its varied mammalian hosts. This persistent biology may pose challenges to effective antibiotic treatment. Experimental studies in dogs, mice, and non-human primates have found persistence of B. burgdorferi DNA following treatment with a variety of antibiotics, but persisting spirochetes are non-cultivable. Persistence of B. burgdorferi DNA has been documented in humans following treatment, but the significance remains unknown. The present study utilized a ceftriaxone treatment regimen in the C3H mouse model that resulted in persistence of non-cultivable B. burgdorferi in order to determine their long-term fate, and to examine their effects on the host. Results confirmed previous studies, in which B. burgdorferi could not be cultured from tissues, but low copy numbers of B. burgdorferi flaB DNA were detectable in tissues at 2, 4 and 8 months after completion of treatment, and the rate of PCR-positive tissues appeared to progressively decline over time. However, there was resurgence of spirochete flaB DNA in multiple tissues at 12 months, with flaB DNA copy levels nearly equivalent to those found in saline-treated mice. Despite the continued non-cultivable state, RNA transcription of multiple B. burgdorferi genes was detected in host tissues, flaB DNA was acquired by xenodiagnostic ticks, and spirochetal forms could be visualized within ticks and mouse tissues by immunofluorescence and immunohistochemistry, respectively. A number of host cytokines were up- or down-regulated in tissues of both saline- and antibiotic-treated mice in the absence of histopathology, indicating host response to the presence of non-cultivable, despite the lack of inflammation in tissues.


Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation.
The molecular bases of inwardly rectifying K(+) (Kir) currents and K(+)-induced dilations were examined in cerebral arteries of mice that lack the Kir2.1 and Kir2.2 genes. The complete absence of the open reading frame in animals homozygous for the targeted allele was confirmed. Kir2.1(-/-) animals die 8 to 12 hours after birth, apparently due to a complete cleft of the secondary palate. In contrast, Kir2.2(-/-) animals are viable and fertile. Kir currents were observed in cerebral artery myocytes isolated from control neonatal animals but were absent in myocytes from Kir2.1(-/-) animals. Voltage-dependent K(+) currents were similar in cells from neonatal control and Kir2.1(-/-) animals. An increase in the extracellular K(+) concentration from 6 to 15 mmol/L caused Ba(2+)-sensitive dilations in pressurized cerebral arteries from control and Kir2.2 mice. In contrast, arteries from Kir2.1(-/-) animals did not dilate when the extracellular K(+) concentration was increased to 15 mmol/L. In summary, Kir2.1 gene expression in arterial smooth muscle is required for Kir currents and K(+)-induced dilations in cerebral arteries.


The Morphologic Spectrum of Sertoliform Cystadenoma of the Rete Testis: A Series of 15 Cases.
Sertoliform cystadenoma of the rete testis (SCRT) is rare with only 9 cases reported to date in the literature, none with follow-up. Four large genitourinary pathology consult services were searched. We identified 15 cases of SCRT. Men were 21 to 84 years old (mean, 46 y) and had testicular discomfort or mass. Other findings were seminoma (n=1), spermatocele (n=2), hydrocele (n=1), varicocele (n=1), and scrotal hematoma (n=1). Eight had preoperative serum tumor markers, which were normal. Tumors ranged from 0.3 to 4 cm (mean, 1.5 cm). All of them were well circumscribed with solid and cystic features and occupied on average, 73% of the rete (20% to 100%). The tumors were mostly confined within dilated channels of the rete testis and showed classic features consisting of: (1) tubules with well-formed lumina in 87% of cases; (2) well-formed tubules with no lumina in 87% of cases; and (3) cords/nests in hyalinized or myxoid stroma in 73% of cases. Other patterns included: (1) solid/sheet growth in 26% of cases; (2) individual cells in 13% of cases; (3) festoons in 13% of cases; (4) branching tubules in 7% of cases; and (5) papillary in 7% of cases. Cells were cuboidal with round to oval nuclei with small nucleoli, except at the periphery where projections into rete tubules had a more columnar appearance. In the festooning pattern, nuclei were pseudostratified and columnar with prominent nucleoli and nuclear grooves. In 4 cases, tumor extended into adjacent seminiferous tubules surrounded by dense peritubular fibrosis, with in some cases small cysts lined by flattened epithelium containing pale lightly granular material. All cases lacked necrosis and significant atypia. Mitoses ranged from 0 to 2 per 10 high-power field. Follow-up ranged from 4 to 170 months with mean of 97 months. For the 13 cases with information, all patients were alive, except for 3 who died of either unrelated causes (9.2 and 10 y) or of unknown cause (4.8 y at age 89 y). We performed immunohistochemistry for steroidogenic factor 1 and inhibin in 4 of our cases, where 3 (75%) were positive for both markers. We also describe 2 additional cases which morphologically resembled SCRT but had more atypical features. This study highlights that SCRT has variable morphology. We also verify the benign nature of the lesion and its lack of association with any syndromes.


Methane-consuming archaea revealed by directly coupled isotopic and phylogenetic analysis.
Microorganisms living in anoxic marine sediments consume more than 80% of the methane produced in the world's oceans. In addition to single-species aggregates, consortia of metabolically interdependent bacteria and archaea are found in methane-rich sediments. A combination of fluorescence in situ hybridization and secondary ion mass spectrometry shows that cells belonging to one specific archaeal group associated with the Methanosarcinales were all highly depleted in 13C (to values of -96 per thousand). This depletion indicates assimilation of isotopically light methane into specific archaeal cells. Additional microbial species apparently use other carbon sources, as indicated by significantly higher 13C/12C ratios in their cell carbon. Our results demonstrate the feasibility of simultaneous determination of the identity and the metabolic activity of naturally occurring microorganisms.


Robotic Roux-en-Y gastric bypass: Our centre's technique with short-term experience.
Roux-en-Y gastric bypass (RYGB) is one of the most widely performed bariatric surgeries in the world. Performing an RYGB by a Da Vinci Surgical System is a new advancement. The aim of this study is to describe single docking-single quadrant technique and its short-term results. Between January 2013 and December 2013, 140 robotic RYGB were performed. The RYGB was performed through single docking, single quadrant approach. The data were analysed retrospectively. Intra- and post-operative details of every patient were documented. Follow-up was done as per protocol at 6 months; 1 and 2 years. In total, 120 patients completed the follow-up protocol as per our database. Mean age of the patients was 42.7 ± 12.11 years. Ratio of males: females were equal. The mean operative time was 97.48 ± 23.79 min. Early mortality was seen 7 days post-surgery. Two late complications were documented with no late mortality. The average length of stay was 2.89 ± 1.06 days. Average blood loss was 55.79 ± 11.91 ml. There was no hospital re-admission after the surgery. Single docking-single quadrant technique is simple, effective and time saving without having complicated port position, multiple docking with minimal complications.


Inpatient morbidity and mortality after adult spinal deformity surgery in teaching versus nonteaching hospitals.
OBJECTIVE The goal of this study was to compare inpatient morbidity and mortality after adult spinal deformity (ASD) surgery in teaching versus nonteaching hospitals in the US. METHODS The Nationwide Inpatient Sample was used to identify surgical patients with ASD between 2002 and 2011. Only patients > 21 years old and elective cases were included. Patient characteristics, inpatient morbidity, and inpatient mortality were compared between teaching and nonteaching hospitals. A multivariable logistic regression analysis was performed to examine the effect of hospital teaching status on surgical outcomes. RESULTS A total of 7603 patients were identified, with 61.2% (n = 4650) in the teaching hospital group and 38.8% (n = 2953) in the nonteaching hospital group. The proportion of patients undergoing revision procedures was significantly different between groups (5.2% in teaching hospitals vs 3.9% in nonteaching hospitals, p = 0.008). Likewise, complex procedures (defined as fusion of 8 or more segments and/or osteotomy) were more common in teaching hospitals (27.3% vs 21.7%, p < 0.001). Crude overall complication rates were similar in teaching hospitals (47.9%) compared with nonteaching hospitals (49.8%, p = 0.114). After controlling for patient characteristics, case complexity, and revision status, patients treated at teaching hospitals were significantly less likely to develop a complication when compared with patients treated at a nonteaching hospital (OR 0.89; 95% CI 0.82-0.98). The mortality rate was 0.4% in teaching hospitals and < 0.4% in nonteaching hospitals (p = 0.210). CONCLUSIONS Patients who undergo surgery for ASD at a teaching hospital may have significantly lower odds of complication development compared with patients treated at a nonteaching hospital.


Presence of pancreatic intraepithelial neoplasia in the pancreatic transection margin does not influence outcome in patients with R0 resected pancreatic cancer.
Margin status is one of the strongest prognosticators after resection of pancreatic ductal adenocarcinoma (PDAC). The clinical significance of pancreatic intraepithelial neoplasia (PanIN) at a surgical margin has not been established. A total of 208 patients who underwent R0 resection for PDAC between 2004 and 2008 were selected. Intraoperative frozen section slides containing the final pancreatic parenchymal transection margin were evaluated for presence or absence, number, and grade of PanINs. Data were compared to clinicopathologic factors, including patient survival. PanIN lesions were present in margins in 107 of 208 patients (51.4%). Median number of PanINs per pancreatic resection margin was 1 (range, 1-11). A total of 72 patients had PanIN-1 (34.6%), 44 had PanIN-2 (21.1%), and 16 had PanIN-3 (7.2%) at their margin. Overall median survival was 17.9 (95% confidence interval, 14-21.9) months. Neither the presence nor absence of PanIN nor histological grade had any significant correlation with important clinicopathologic characteristics. There were no significant survival differences between patients with or without PanIN lesions at the resection margin or among patients with PanIN-3 (carcinoma in situ) versus lower PanIN grades. However, patients with R1 resection had a significantly worse outcome compared with patients without invasive cancer at a margin irrespective of the presence of PanIN (P=0.02). The presence of PanINs at a resection margin does not affect survival in patients who undergo R0 resection for PDAC. These results have significant clinical implications for surgeons, because no additional resection seems to be indicated when intraoperative frozen sections reveal even high-grade PanIN lesions.


Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma.
We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the vessels that encapsulate tumor clusters (VETC), previously linked to HCC metastatic dissemination. VETC was assessed in a large multi-institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small-sized tissues of tissue microarray. VETC HCCs represented 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated with several clinical and pathological features such as high alfa-fetoprotein (AFP) level, tumor size greater than 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (hazard ratio [HR]: 1.52 [1.06-2.19], P = 0.023), disease-free survival (HR: 1.66 [1.21-2.27], P = 0.002), and overall survival (HR: 2.26 [1.37-3.72], P = 0.001) at multivariable analysis. VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (β-catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype, which was seen in 7.8% (42 of 541) of patients and associated with high AFP levels and poor differentiation. Conclusion: The VETC pattern was found to be easily detectable in a consistent fraction of HCC and a powerful pathological finding affecting survival. This study suggests that the heterogeneous pattern of angiogenesis is involved in HCC behavior.


The uniform data system for medical rehabilitation: report of patients with lower limb joint replacement discharged from rehabilitation programs in 2000-2007.
To provide benchmarking information from a large national sample of patients receiving inpatient rehabilitation after lower limb joint replacement. Secondary data analysis from 893 medical rehabilitation facilities located in the United States that contributed information to the Uniform Data System for Medical Rehabilitation from January 2000 through December 2007. Variables analyzed included demographic information (age, sex, marital status, race/ethnicity, prehospital living setting, discharge setting), hospitalization information (length of stay, program interruptions, payer, onset date, rehabilitation impairment group, International Classification of Diseases, 9th revision codes for admitting diagnosis, comorbidities), and functional status information (FIM instrument ["FIM"] ratings at admission and discharge, FIM efficiency, FIM gain). Descriptive statistics from 705,345 patients showed an overall mean length of stay of 8.9 (±4.7) days. FIM total admission and discharge ratings declined during the 8-yr study period. Mean admission ratings decreased from 83.5 (±11.3) to 73.2 (±12.9). Mean discharge ratings decreased from 108.4 (±11.0) to 101.7 (±12.9). Conversely, mean FIM change increased from 24.9 (±9.2) to 28.6 (±12.2). The percent of persons discharged to the community decreased from 94.5% to 91.9%. All results are likely to be influenced by various policy changes affecting classification or documentation processes or both. National rehabilitation data from persons with lower limb joint replacement in 2000-2007 indicate that inpatient rehabilitation lengths of stay have remained relatively stable and that patients are experiencing improvements in functional independence during their stay. In addition, more than 9 of 10 patients are discharged to community settings after inpatient rehabilitation.


Spirulina Liquid Extract Protects against Fibrosis Related to Non-Alcoholic Steatohepatitis and Increases Ursodeoxycholic Acid.
Non-alcoholic steatohepatitis (NASH) is characterized by an excess of lipids and oxidative stress in the liver. Spirulina was reported to possess hypolipemic and antioxidative effects and might counteract NASH development. C57Bl/6J mice were fed a western diet (WD) during 25 weeks with or without spirulina liquid extract (SLE) at 2 different doses (WDS1 and WDS2 groups) in drinking water. Liver histology, inflammation, and oxidative stress were assessed as well as glucose tolerance status, lipid metabolism, and gallbladder bile acid profile. WDS2 gained significantly less weight than WD. Liver weight-to-body weight ratio and plasma alanine aminotransferase were significantly lower in WDS2 mice. A reduced liver fibrosis and NFκBp65 protein expression were measured in the supplemented group as a lower accumulation of superoxide anion, nitric oxide, and thiobarbituric reactive substances. WDS2 mice showed also a preserved glucose tolerance, a strong decrease of plasma cholesterol, and a significant increase of gallbladder ursodeoxycholic acid and β-muricholic acid. Our findings demonstrate a protective effect of SLE against WD induced NASH that is related to less inflammation and oxidative stress, a preserved glucose tolerance, and less hepatotoxic bile acid profile.


Adjuvant Hysterectomy in Patients With Residual Disease After Radiation for Locally Advanced Cervical Cancer: A Prospective Longitudinal Study.
The aim of the study was to evaluate the efficacy of hysterectomy in the control of pelvic disease in patients with post-irradiated residual cervical cancer. Forty patients were treated at either National Institute of Cancer Research and Hospital (NICRH) or Delta Cancer Hospital in Dhaka, Bangladesh, with International Federation of Gynecology and Obstetrics stage IIB to IIIB disease with residual disease after the following: either concurrent chemoradiation with or without brachytherapy, induction chemotherapy and external-beam radiotherapy (EBRT) with or without brachytherapy, or only EBRT. Patients were treated by either radical hysterectomy or extrafascial hysterectomy. From 2009 to June 2013, 55 patients were evaluated for central residual disease on their presentations to NICRH or Delta Hospital. Patients with distant recurrences after primary radiation were excluded. Forty patients had invasive cancer on biopsy and underwent either radical hysterectomy or extrafascial hysterectomy. Surgery was performed 14 to 18 weeks after the initial treatment. Of the 29 women who underwent extrafascial hysterectomy, four (13.8%) developed recurrent disease, and one died; none of the 11 patients treated by radical hysterectomy experienced recurrences during the study period. Morbidity was increased in patients who underwent radical hysterectomy. Overall 90% of patients (36 of 40 patients) who underwent surgery had no evidence of disease at 5 years of follow-up. Surgery is a viable treatment option for patients with residual cervical cancer after radiation. Radical hysterectomy after radiation is more morbid but has better tumor control than extrafascial hysterectomy.


Spontaneously ruptured renal cell carcinoma during hemodialysis in two patients with end-stage renal disease.
Spontaneously ruptured renal cell carcinoma (RCC) in end-stage kidney disease is very rare. Preoperative diagnosis is difficult because of the relatively small tumor size, associated hematoma, and surrounding acquired cysts. Two middle-aged men who were maintained on hemodialysis (HD) for over 10 years suddenly developed flank pain during HD. Computed tomography scans revealed an enhancing ruptured renal mass in one patient, and no obvious tumor lesion except for a hematoma in the other, both of which were later confirmed as RCCs by pathologic specimens.


Examining the Mechanical Equilibrium of Microscopic Stresses in Molecular Simulations.
The microscopic stress field provides a unique connection between atomistic simulations and mechanics at the nanoscale. However, its definition remains ambiguous. Rather than a mere theoretical preoccupation, we show that this fact acutely manifests itself in local stress calculations of defective graphene, lipid bilayers, and fibrous proteins. We find that popular definitions of the microscopic stress violate the continuum statements of mechanical equilibrium, and we propose an unambiguous and physically sound definition.


Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine.
Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine. Unexpectedly, we do not find a chlorpromazine molecule in the channel pore of ELIC, but behind the β8-β9 loop in the extracellular ligand-binding domain. The β8-β9 loop is localized downstream from the neurotransmitter binding site and plays an important role in coupling of ligand binding to channel opening. In combination with electrophysiological recordings from ELIC cysteine mutants and a thiol-reactive derivative of chlorpromazine, we demonstrate that chlorpromazine binding at the β8-β9 loop is responsible for receptor inhibition. We further use molecular-dynamics simulations to support the X-ray data and mutagenesis experiments. Together, these data unveil an allosteric binding site in the extracellular ligand-binding domain of ELIC. Our results extend on previous observations and further substantiate our understanding of a multisite model for allosteric modulation of Cys-loop receptors.


Prostaglandin E2-EP3 signaling induces inflammatory swelling by mast cell activation.
PGE2 has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE2 as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE2-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE2-induced response was suppressed by histamine H1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE2-induced response in mast cell-deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE2 treatment in wild-type but not in EP3-deficient mice. Consistently, PGE2-EP3 signaling elicited histamine release in mouse peritoneal and bone marrow-derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca(2+) ions. These results demonstrate that PGE2 triggers mast cell activation via an EP3-Gi/o-Ca(2+) influx/PI3K pathway, and this mechanism underlies PGE2-induced vascular permeability and consequent edema formation.


A computational method for the investigation of multistable systems and its application to genetic switches.
Genetic switches exhibit multistability, form the basis of epigenetic memory, and are found in natural decision making systems, such as cell fate determination in developmental pathways. Synthetic genetic switches can be used for recording the presence of different environmental signals, for changing phenotype using synthetic inputs and as building blocks for higher-level sequential logic circuits. Understanding how multistable switches can be constructed and how they function within larger biological systems is therefore key to synthetic biology. Here we present a new computational tool, called StabilityFinder, that takes advantage of sequential Monte Carlo methods to identify regions of parameter space capable of producing multistable behaviour, while handling uncertainty in biochemical rate constants and initial conditions. The algorithm works by clustering trajectories in phase space, and iteratively minimizing a distance metric. Here we examine a collection of models of genetic switches, ranging from the deterministic Gardner toggle switch to stochastic models containing different positive feedback connections. We uncover the design principles behind making bistable, tristable and quadristable switches, and find that rate of gene expression is a key parameter. We demonstrate the ability of the framework to examine more complex systems and examine the design principles of a three gene switch. Our framework allows us to relax the assumptions that are often used in genetic switch models and we show that more complex abstractions are still capable of multistable behaviour. Our results suggest many ways in which genetic switches can be enhanced and offer designs for the construction of novel switches. Our analysis also highlights subtle changes in correlation of experimentally tunable parameters that can lead to bifurcations in deterministic and stochastic systems. Overall we demonstrate that StabilityFinder will be a valuable tool in the future design and construction of novel gene networks.


Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, and its prevalence is increasing worldwide. It currently affects approximately 30% of adults and 10% of children in the United States. NAFLD represents a wide spectrum of conditions ranging from simple fatty liver which in general follows a benign nonprogressive clinical course, to nonalcoholic steatohepatitis (NASH), which is a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. At present, a liver biopsy remains the only reliable way to diagnose NASH and establish the presence of fibrosis. Current noninvasive clinically available tests lack accuracy and reliability. In light of the dramatic increase in the prevalence of NAFLD in conjunction with the significant research effort in developing novel therapies for patients with NASH, noninvasive, simple, reproducible, and reliable biomarkers are greatly needed. They will not only help in the diagnosis of NASH, but also be useful for assessment of treatment response and prognosis and remain a research priority in the NAFLD field.


How do midwives facilitate women to give birth during physiological second stage of labour? A systematic review.
Both nationally and internationally, midwives' practices during the second stage of labour vary. A midwife's practice can be influenced by education and cultural practices but ultimately it should be informed by up-to-date scientific evidence. We conducted a systematic review of the literature to retrieve evidence that supports high quality intrapartum care during the second stage of labour. A systematic literature search was performed to September 2019 in collaboration with a medical information specialist. Bibliographic databases searched included: PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Maternity and Infant Care Database and The Cochrane Library, resulting in 6,382 references to be screened after duplicates were removed. Articles were then assessed for quality by two independent researchers and data extracted. 17 studies focusing on midwives' practices during physiological second stage of labour were included. Two studies surveyed midwives regarding their practice and one study utilising focus groups explored how midwives facilitate women's birthing positions, while another focus group study explored expert midwives' views of their practice of preserving an intact perineum during physiological birth. The remainder of the included studies were primarily intervention studies, highlighting aspects of midwifery practice during the second stage of labour. The empirical findings were synthesised into four main themes namely: birthing positions, non-pharmacological pain relief, pushing techniques and optimising perineal outcomes; the results were outlined and discussed. By implementing this evidence midwives may enable women during the second stage of labour to optimise physiological processes to give birth. There is, however, a dearth of evidence relating to midwives' practice, which provides a positive experience for women during the second stage of labour. Perhaps this is because not all midwives' practices during the second stage of labour are researched and documented. This systematic review provides a valuable insight of the empirical evidence relating to midwifery practice during the physiological second stage of labour, which can also inform education and future research. The majority of the authors were members of the EU COST Action IS1405: Building Intrapartum Research Through Health (BIRTH). The study protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration CRD42018088300) and is published (Verhoeven, Spence, Nyman, Otten, Healy, 2019).


The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.
Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.


Anti-inflammatory and pro-angiogenic effects of beta blockers in a canine model of chronic ischemic cardiomyopathy: comparison between carvedilol and metoprolol.
There is controversy regarding the superiority of carvedilol (C) over metoprolol (M) in congestive heart failure. We hypothesized that C is superior to M in chronic ischemic cardiomyopathy because of its better anti-inflammatory and pro-angiogenic effects. In order to test our hypothesis we used a chronic canine model of multivessel ischemic cardiomyopathy where myocardial microcatheters were placed from which interstitial fluid was collected over time to measure leukocyte count and cytokine levels. After development of left ventricular dysfunction, the animals were randomized into four groups: sham (n = 7), placebo (n = 8), M (n = 11), and C (n = 10), and followed for 3 months after treatment initiation. Tissue was examined for immunohistochemistry, oxidative stress, and capillary density. At 3 months both rest and stress wall thickening were better in C compared to the other groups. At the end of 3 months of treatment end-systolic wall stress also decreased the most in C. Similarly resting myocardial blood flow (MBF) improved the most in C as did the stress endocardial/epicardial MBF. Myocardial interstitial fluid showed greater attenuation of leukocytosis with C compared to M, which was associated with less fibrosis and oxidative stress. C also had higher IL-10 level and capillary density. In conclusion, in a chronic canine model of multivessel ischemic cardiomyopathy we found 3 months of C treatment resulted in better resting global and regional function as well as better regional function at stress compared to M. These changes were associated with higher myocardial levels of the anti-inflammatory cytokine IL-10 and less myocardial oxidative stress, leukocytosis, and fibrosis. Capillary density and MBF were almost normalized. Thus in the doses used in this study, C appears to be superior to M in a chronic canine model of ischemic cardiomyopathy from beneficial effects on inflammation and angiogenesis. Further studies are required for comparing additional doses of these drugs.


The Role of the Rating-of-Perceived-Exertion Template in Pacing.
The rating-of-perceived-exertion (RPE) template is thought to regulate pacing and has been shown to be very robust in different circumstances. The primary purpose was to investigate whether the RPE template can be manipulated by changing the race distance during the course of a time trial. The secondary purpose was to study how athletes cope with this manipulation, especially in terms of the RPE template. Trained male subjects (N = 10) performed 3 cycling time trials: a 10-km (TT10), a 15-km (TT15), and a manipulated 15-km (TTman). During the TTman, subjects started the time trial believing that they were going to perform a 10-km time trial. However, at 7.5 km they were told that it was a 15-km time trial. A significant main effect of time-trial condition on RPE scores until kilometer 7.5 was found (P = .016). Post hoc comparisons showed that the RPE values of the TT15 were lower than the RPE values of the TT10 (difference 0.60; CI95% 0.11, 1.0) and TTman (difference 0.73; CI95% 0.004, 1.5). After the 7.5 km, a transition phase occurs, in which an interaction effect is present (P = .011). After this transition phase, the RPE values of TTman and TT15 did not statistically differ (P = 1.00). This novel distance-endpoint manipulation demonstrates that it is possible to switch between RPE templates. A clear shift in RPE during the TTman is present between the RPE templates of the TT10 and TT15. The shift strongly supports suggestions that pacing is regulated using an RPE template.


Genes come and go: the evolutionarily plastic path of budding yeast RNase III enzymes.
Our recent finding that the Candida albicans RNase III enzyme CaDcr1 is an unusual, multifunctional RNase III coupled with data on the RNase III enzymes from other fungal species prompted us to seek a model that explained the evolution of RNase III's in modern budding yeast species. CaDcr1 has both dicer function (generates small RNA molecules from dsRNA precursors) and Rnt1 function, (catalyzes the maturation of 35S rRNA and U4 snRNA). Some budding yeast species have two distinct genes that encode these functions, a Dicer and RNT1, whereas others have only an RNT1 and no Dicer. As none of the budding yeast species has the canonical Dicer found in many other fungal lineages and most eukaryotes, the extant species must have evolved from an ancestor that lost the canonical Dicer, and evolved a novel Dicer from the essential RNT1 gene. No single, simple model could explain the evolution of RNase III enzymes from this ancestor because existing sequence data are consistent with two equally plausible models. The models share an architecture for RNase III evolution that involves gene duplication, loss, subfunctionalization, and neofunctionalization. This commentary explains our reasoning, and offers the prospect that further genomic data could further resolve the dilemma surrounding the budding yeast RNase III's evolution.


Phonological devices in poems by English and Italian children.
Poems were elicited from 133 English children between two and six and 171 Italian children between three and seven, using a similar technique, and the results were compared. Both groups produced large numbers of poems. There were great similarities and some differences. The majority of poems in both samples contained phonological devices (mostly rhyme and alliteration) and the proportion was higher (87%) in the Italian sample than in the English sample (59%). The proportion of poems that contained rhyme was close to 45% in each sample, with no consistent age difference in either sample. About one-third of Italian poems and just over a fifth of English poems contained alliteration. The frequency of alliteration declined with age in the English sample but not in the Italian sample. Possible reasons for the differences between the samples are considered. It is argued that the similarities are more important, and their theoretical implications are discussed.


Clinical assessment and characterization of a dual tube kilovoltage X-ray localization system in the radiotherapy treatment room.
Although flat-panel based X-ray imaging has been well tested in diagnostic radiology, its use as an image-guided-radiotherapy (IGRT) system in a treatment room is new and requires systematic assessment. BrainLab Novalis IGRT system was used for this study. It consists of two floor mounted kV X-ray tubes projecting obliquely into two flat-panel detectors mounted on the ceiling. The system automatically fuses the 2D localization images with 3D simulation CT image to provide positioning guidance. The following characteristics of the system were studied: (1) Coincidence of the isocenters between the IGRT and Linac; (2) Image quality; (3) Exposure; (4) Linearity, uniformity and repeatability. (1) Localization accuracy and coincidence of the isocenters between the IGRT and Linac was better than 1-mm. (2) The spatial resolution was quantified using the relative modulation-transfer-function with f50=0.7-0.9 lp/mm. The variation of contrast-noise-ratio with technical settings was measured. (3) The maximal exposure of an image was less than 95 mR. An empirical relation between the exposure and the X-ray technical setting was derived. (4) The linearity, uniformity and repeatability of the system generally meet the requirements. The system can be safely and reliably used as a target localization device.


Abnormal temporal discrimination threshold in patients with multiple system atrophy.
The temporal discrimination threshold (TDT), the shortest time interval that allows two temporally separated successive stimuli to be perceived as two different stimuli, is a constituent of kinesthetic sensation. Intact kinesthesia is a necessity for well-controlled voluntary movements. In patients with Parkinson's disease and dystonia, abnormally increased TDT has been reported and it may contribute to the pathophysiology of motor deficits. We explored the integrity and clinical significance of TDT in patients with multiple system atrophy (MSA). A total of 30 de novo patients with MSA and 11 age-matched normal controls were included. The TDT values were measured in the feet with four different paradigms (ascending and descending interstimuli intervals; same and different point stimulation). The Unified Parkinson's Disease Rating Scale (UPDRS) Motor and the International Cooperative Ataxia Rating Scale (ICARS) scores were measured for parkinsonian and cerebellar deficits, respectively. Means of the TDT values of the patients with MSA were higher than those of the controls. The TDT values correlated with UPDRS Motor scores independent of ICARS scores. Among the parkinsonian motor deficits, only the UPDRS Motor subscores representing bradykinesia correlated with the TDT values. In patients with MSA, abnormal somatic sensory processing seems to be associated with damage to the nigrostriatal dopaminergic and/or striatal neurons.


Dose-dependent effects of nicotine on proliferation and differentiation of human bone marrow stromal cells and the antagonistic action of vitamin C.
A range of biological and molecular effects caused by nicotine are considered to effect bone metabolism. Vitamin C functions as a biological antioxidant. This study was to evaluate the in vitro effects of nicotine on human bone marrow stromal cells and whether Vitamin C supplementation show the antagonism action to high concentration nicotine. We used CCK-8, alkaline phosphatase (ALP) activity assay, Von Kossa staining, real-time polymerase chain reaction and Western Blot to evaluate the proliferation and osteogenic differentiation. The results indicated that the proliferation of BMSCs increased at the concentration of 50, 100 ng/ml, got inhibited at 1,000 ng/ml. When Vitamin C was added, the OD for proliferation increased. For ALP staining, we found that BMSCs treated with 50 and 100 ng/ml nicotine showed a higher activity compared with the control, and decreased at the 1,000 ng/ml. Bone morphogenetic protein-2 (BMP-2) expression and the calcium depositions decreased at 100 and 1,000 ng/ml nicotine, while the addition of Vitamin C reversed the down regulation. By real-time PCR, we detected that the mRNA expression of collagen type I (COL-I) and ALP were also increased in 50 and 100 ng/ml nicotine groups (P < 0.05), while reduced at 1,000 ng/ml (P < 0.05). When it came to osteocalcin (OCN), the changes were similar. Taken all together, it is found that nicotine has a two-phase effect on human BMSCs, showing that low level of nicotine could promote the proliferation and osteogenic differentiation while the high level display the opposite effect. Vitamin C could antagonize the inhibitory effect of higher concentration of nicotine partly.


Control and femtosecond time-resolved imaging of torsion in a chiral molecule.
We study how the combination of long and short laser pulses can be used to induce torsion in an axially chiral biphenyl derivative (3,5-difluoro-3',5'-dibromo-4'-cyanobiphenyl). A long, with respect to the molecular rotational periods, elliptically polarized laser pulse produces 3D alignment of the molecules, and a linearly polarized short pulse initiates torsion about the stereogenic axis. The torsional motion is monitored in real-time by measuring the dihedral angle using femtosecond time-resolved Coulomb explosion imaging. Within the first 4 picoseconds (ps), torsion occurs with a period of 1.25 ps and an amplitude of 3° in excellent agreement with theoretical calculations. At larger times, the quantum states of the molecules describing the torsional motion dephase and an almost isotropic distribution of the dihedral angle is measured. We demonstrate an original application of covariance analysis of two-dimensional ion images to reveal strong correlations between specific ejected ionic fragments from Coulomb explosion. This technique strengthens our interpretation of the experimental data.


Why faces may be special: evidence of the inversion effect in chimpanzees.
Five chimpanzees were tested on their ability to discriminate faces and automobiles presented in both their upright and inverted orientations. The face stimuli consisted of 30 black and white photographs, 10 each of unfamiliar chimpanzees (Pan troblodytes), brown capuchins (Cebus apella), and humans (Homo sapiens). Ten black and white photographs of automobiles were also used. The stimuli were presented in a sequential matching-to-sample (SMTS) format using a computerized joystick-testing apparatus. Subjects performed better on upright than inverted stimuli in all classes. Performance was significantly better on upright than inverted presentations of chimpanzee and human faces but not on capuchin monkey faces or automobiles. These data support previous studies in humans that suggest the inversion effect occurs for stimuli for which subjects have developed an expertise. Alternative explanations for the inversion effect based on the type of spatial frequency contained in the stimuli are also discussed. These data are the first to provide evidence for the inversion effect using several classes of face stimuli in a great ape species.


Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats.
Antiangiogenic strategies have been proposed as a promising new approach for the therapy of portal hypertension and chronic liver disease. Pigment epithelium-derived factor (PEDF) is a powerful endogenous angiogenesis inhibitor whose role in portal hypertension remains unknown. Therefore, we aimed at determining the involvement of PEDF in cirrhotic portal hypertension and the therapeutic efficacy of its supplementation. PEDF expression profiling and its relationship with vascular endothelial growth factor (VEGF), neovascularisation and fibrogenesis was determined in bile duct-ligated (BDL) rats and human cirrhotic livers. The ability of exogenous PEDF overexpression by adenovirus-mediated gene transfer (AdPEDF) to inhibit angiogenesis, fibrogenesis and portal pressure was also evaluated in BDL rats, following prevention and intervention trials. PEDF was upregulated in cirrhotic human and BDL rat livers. PEDF and VEGF protein expression and localisation in mesentery and liver increased in parallel with portal hypertension progression, being closely linked in time and space with mesenteric neovascularisation and liver fibrogenesis in BDL rats. Furthermore, AdPEDF increased PEDF bioavailability in BDL rats, shifting the net balance in the local abundance of positive (VEGF) and negative (PEDF) angiogenesis drivers in favour of attenuation of portal hypertension-associated pathological neovascularisation. The antiangiogenic effects of AdPEDF targeted only pathological angiogenesis, without affecting normal vasculature, and were observed during early stages of disease. AdPEDF also significantly decreased liver fibrogenesis (through metalloproteinase upregulation), portosystemic collateralisation and portal pressure in BDL rats. This study provides compelling experimental evidence indicating that PEDF could be a novel therapeutic agent worthy of assessment in portal hypertension and cirrhosis.


Survey of North American Multidisciplinary Cleft Palate and Craniofacial Team Clinic Administration.
This study aims to provide an understanding of the ways cleft palate (CP) and craniofacial teams address billing, administration, communication of clinical recommendations, appointment scheduling, and diagnosis-specific protocols. An online clinic administration survey was developed using data from an open-ended telephone questionnaire. The online survey was distributed by e-mail to the American Cleft Palate-Craniofacial Association (ACPA) nurse coordinator electronic mailing list, used regularly by the ACPA and its members to communicate with teams. The response was 34.1% (42/123). Two incomplete records were excluded, as were any inconsistent responses of 3 teams submitting duplicate records. Six (15.8%) of 38 teams do not charge for clinic visits. For all other teams, some or all providers bill individually for services (68.4%) or a single lump sum applies (10.5%). Patients of 34 (89.5%) of 38 teams occasionally or often neglect to schedule or attend follow-up appointments. Twenty-six (66.7%) of 39 team directors were plastic surgeons. Phone is a common method of contacting families for scheduling (60.0%) and appointment reminders (82.5%). Most teams' providers (90.0%) routinely communicate findings to each other during postclinical conference. Most teams saw patients with isolated cleft lip (43.6%), cleft lip and palate (64.1%), or isolated CP (59.0%) annually. The breadth of strategies team clinic administration strategies warrants further exploration of the variations and their effects on patient-centered outcomes including the quality of life, satisfaction, cost, and resource utilization.


Validation of an enzyme-linked immunosorbent assay for the quantification of citrullinated histone H3 as a marker for neutrophil extracellular traps in human plasma.
There is an emerging interest in the diverse functions of neutrophil extracellular traps (NETs) in a variety of disease settings. However, data on circulating NETs rely largely upon surrogate NET markers such as cell-free DNA, nucleosomes, and NET-associated enzymes. Citrullination of histone H3 by peptidyl arginine deiminase 4 (PAD4) is central for NET formation, and citrullinated histone H3 (H3Cit) is considered a NET-specific biomarker. We therefore aimed to optimize and validate a new enzyme-linked immunosorbent assay (ELISA) to quantify the levels of H3Cit in human plasma. A standard curve made of in vitro PAD4-citrullinated histones H3 allows for the quantification of H3Cit in plasma using an anti-histone antibody as capture antibody and an anti-histone H3 citrulline antibody for detection. The assay was evaluated for linearity, stability, specificity, and precision on plasma samples obtained from a human model of inflammation before and after lipopolysaccharide injection. The results revealed linearity and high specificity demonstrated by the inability of detecting non-citrullinated histone H3. Coefficients of variation for intra- and inter-assay variability ranged from 2.1 to 5.1% and from 5.8 to 13.5%, respectively, allowing for a high precision. Furthermore, our results support an inflammatory induction of a systemic NET burden by showing, for the first time, clear intra-individual elevations of plasma H3Cit in a human model of lipopolysaccharide-induced inflammation. Taken together, our work demonstrates the development of a new method for the quantification of H3Cit by ELISA that can reliably be used for the detection of NETs in human plasma.


Implications of moderate altitude training for sea-level endurance in elite distance runners.
Elite distance runners participated in one of two studies designed to investigate the effects of moderate altitude training (inspiratory partial pressure of oxygen approximately 115-125 mmHg) on submaximal, maximal and supramaximal exercise performance following return to sea-level. Study 1 (New Mexico, USA) involved 14 subjects who were assigned to a 4-week altitude training camp (1500-2000 m) whilst 9 performance-matched subjects continued with an identical training programme at sea-level (CON). Ten EXP subjects who trained at 1640 m and 19 CON subjects also participated in study 2 (Krugersdorp, South Africa). Selected metabolic and cardiorespiratory parameters were determined with the subjects at rest and during exercise 21 days prior to (PRE) and 10 and 20 days following their return to sea-level (POST). Whole blood lactate decreased by 23% (P < 0.05 vs PRE) during submaximal exercise in the EXP group only after 20 days at sea-level (study 1). However, the lactate threshold and other measures of running economy remained unchanged. Similarly, supramaximal performance during a standardised track session did not change. Study 2 demonstrated that hypoxia per se did not alter performance. In contrast, in the EXP group supramaximal running velocity decreased by 2% (P < 0.05) after 20 days at sea-level. Both studies were characterised by a 50% increase in the frequency of upper respiratory and gastrointestinal tract infections during the altitude sojourns, and two male subjects were diagnosed with infectious mononucleosis following their return to sea-level (study 1). Group mean plasma glutamine concentrations at rest decreased by 19% or 143 (74) microM (P < 0.001) after 3 weeks at altitude, which may have been implicated in the increased incidence of infectious illness.


The Semantic Object Retrieval Test (SORT) in amnestic mild cognitive impairment.
Between 10% and 15% of patients with the amnestic variety of Mild Cognitive Impairment (MCI) convert to Alzheimer disease (AD) per year. Characterize cognitive markers that may herald conversion from MCI to AD and directly assess semantic memory in patients meeting criteria for amnestic MCI. Thirty-five amnestic MCI patients and 121 healthy aging controls enrolled at an Alzheimer Disease Center received a battery of standard neuropsychologic tests, and the Semantic Object Retrieval Test (SORT), a test that we have developed for the assessment of semantic memory and subsequent name production, and that has been shown to be able to differentiate between normals and patients with AD. On the basis of normative data from the SORT, the MCI subjects could be divided into 2 groups: 10 patients (29%) with a significant semantic impairment (SI+) and 25 without a semantic memory deficit (SI-). There was a significant correlation between all SORT variables and performance on the Boston Naming Test. In this MCI population, significantly impaired SORT performance was associated with a relative decrease in performance on tests of frontal lobe functions, although disruption of thalamic-related processes cannot be excluded as an etiology for semantic memory impairment. The SORT is a specific test of semantic memory, and is a sensitive measure of semantic memory deficits in patients who otherwise meet criteria for amnestic MCI. Using this specific assessment tool, a significant number of MCI patients were found to have semantic memory deficits. As these patients may be early in the course of possible progression toward dementia, the SORT or other tests of semantic memory may provide important diagnostic or prognostic information in patients with MCI.


Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury.
Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)-dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB's regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation.


Effects of peripheral sensory input on cortical inhibition in humans.
Cortical inhibitory systems play an important role in motor output. The motor cortex can be inhibited by intracortical mechanisms and by peripheral sensory inputs. We examined whether cortical inhibition from peripheral sensory input is mediated through previously identified intracortical inhibitory systems and how these inhibitory systems interact. Two types of intracortical inhibition were assessed by paired-pulse transcranial magnetic stimulation (TMS). Short-interval intracortical inhibition (SICI) was determined with a subthreshold conditioning stimulus (CS) followed by a test stimulus 2 ms later and long-interval intracortical inhibition (LICI) with suprathreshold conditioning and test stimuli 100 ms apart. Cortical inhibition from peripheral sensory input was induced by median nerve stimulation (MNS) of the right hand and followed by a suprathreshold TMS over the left motor cortex 200 ms later. The first set of experiments tested the effects of different test stimulus intensities on SICI, LICI and cortical inhibition induced by median nerve stimulation (MNSI). With higher test stimulus intensities, LICI and MNSI decreased whereas SICI showed a trend towards an increase. The extent of SICI, LICI and MNSI did not correlate. The second experiment assessed the interaction between MNSI and LICI. The results of applying MNSI and LICI simultaneously were compared with MNSI and LICI alone. MNSI was virtually abolished in the presence of LICI and LICI was also significantly decreased in the presence of MNSI. Thus, the effects of MNSI and LICI when applied together were much less than their expected additive effects when applied alone. The degree of interaction between MNSI and LICI was related to the combined strength of MNSI and LICI but not to the strength of LICI alone. The third experiment investigated the interaction between SICI and MNSI. MNSI and SICI were applied together and the results were compared with MNSI and SICI alone. SICI remained unchanged in the presence of MNSI. We conclude that MNSI is mediated by circuits distinct from those mediating LICI or SICI. The MNSI circuits seem to have an inhibitory interaction with the LICI circuits, whereas the SICI and MNSI circuits do not seem to interact.


Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo.
Lymphangiogenesis is an important process that contributes to the spread of cancer. Here we show that insulin-like growth factors 1 (IGF-1) and 2 (IGF-2) induce lymphangiogenesis in vivo. In a mouse cornea assay, IGF-1 and IGF-2 induce lymphangiogenesis as detected with LYVE-1, a specific marker for lymphatic endothelium. Interestingly, IGF-1-induced lymphangiogenesis could not be blocked by a soluble vascular endothelial growth factor receptor 3, suggesting that the vascular endothelial growth factor receptor 3-signaling pathway is not required for IGF-induced lymphangiogenesis. In vitro, IGF-1 and IGF-2 significantly stimulated proliferation and migration of primary lymphatic endothelial cells. IGF-1 and IGF-2 induced phosphorylation of intracellular signaling components, such as Akt, Src, and extracellular signal-regulated kinase in lymphatic endothelial cells. Immunohistochemistry, RT-PCR, and Affymetrix GeneChip microarray analysis showed that the receptors for IGFs are present in lymphatic endothelium. Together, our findings suggest that IGFs might act as direct lymphangiogenic factors, although any indirect roles in the induction of lymphangiogenesis cannot be excluded. Because members of the IGF ligand and receptor families are widely expressed in various types of solid tumors, our findings suggest that these factors are likely to contribute to lymphatic metastasis.


The Clinical Phenotype of Idiopathic Rapid Eye Movement Sleep Behavior Disorder at Presentation: A Study in 203 Consecutive Patients.
To describe the clinical phenotype of idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) at presentation in a sleep center. Clinical history review of 203 consecutive patients with IRBD identified between 1990 and 2014. IRBD was diagnosed by clinical history plus video-polysomnographic demonstration of REM sleep with increased electromyographic activity linked to abnormal behaviors. Patients were 80% men with median age at IRBD diagnosis of 68 y (range, 50-85 y). In addition to the already known clinical picture of IRBD, other important features were apparent: 44% of the patients were not aware of their dream-enactment behaviors and 70% reported good sleep quality. In most of these cases bed partners were essential to convince patients to seek medical help. In 11% IRBD was elicited only after specific questioning when patients consulted for other reasons. Seven percent did not recall unpleasant dreams. Leaving the bed occurred occasionally in 24% of subjects in whom dementia with Lewy bodies often developed eventually. For the correct diagnosis of IRBD, video-polysomnography had to be repeated in 16% because of insufficient REM sleep or electromyographic artifacts from coexistent apneas. Some subjects with comorbid obstructive sleep apnea reported partial improvement of RBD symptoms following continuous positive airway pressure therapy. Lack of therapy with clonazepam resulted in an increased risk of sleep related injuries. Synucleinopathy was frequently diagnosed, even in patients with mild severity or uncommon IRBD presentations (e.g., patients who reported sleeping well, onset triggered by a life event, nocturnal ambulation) indicating that the development of a neurodegenerative disease is independent of the clinical presentation of IRBD. We report the largest IRBD cohort observed in a single center to date and highlight frequent features that were not reported or not sufficiently emphasized in previous publications. Physicians should be aware of the full clinical expression of IRBD, a sleep disturbance that represents a neurodegenerative disease. A commentary on this article appears in this issue on page 7.


The utility of diffusion-weighted magnetic resonance imaging in differentiation of endometriomas from hemorrhagic ovarian cysts.
The aim was to determine the utility of diffusion-weighted magnetic resonance imaging (DW MRI) and apparent diffusion coefficient (ADC) measurements in differentiation of endometrioma and hemorrhagic ovarian cyst. A total of 24 female patients who underwent pelvic MRI with an initial diagnosis of ovarian cyst were included in the study. The final diagnosis was endometrioma in 12 patients and hemorrhagic ovarian cyst in 12 patients. We observed significantly lower ADC values in endometriomas compared with hemorrhagic ovarian cysts in all b values. DW MRI with quantitative ADC measurements can be used for differentiation of endometrioma from hemorrhagic ovarian cysts.


Cognitive factors involved in the onset and maintenance of posttraumatic stress disorder (PTSD) after physical or sexual assault.
Cognitive factors hypothesised to influence the development and maintenance of PTSD were investigated. 92 assault victims completed questionnaires assessing a range of cognitive variables. Factors relating to onset of PTSD were investigated by comparing victims who did and who did not suffer PTSD. Factors relating to maintenance of PTSD were investigated by comparing victims who had recovered from PTSD with victims who had persistent PTSD. Cognitive factors associated with both onset and maintenance of PTSD were: appraisal of aspects of the assault itself (mental defeat, mental confusion, appraisal of emotions); appraisal of the sequelae of the assault (appraisal of symptoms, perceived negative responses of others, permanent change); dysfunctional strategies (avoidance/safety seeking) and global beliefs impacted by assault. Cognitive factors that were associated only with the onset of PTSD were: detachment during assault; failure to perceive positive responses from others and mental undoing. Relationships between the cognitive variables and PTSD remained significant when variations in perceived and objective assault severity were statistically controlled. The cognitive factors identified in the study may contribute to PTSD directly, by generating a sense of ongoing threat, or indirectly, by motivating cognitive and behavioural strategies that prevent recovery, or by affecting the nature of the traumatic memory.


Histopathological Evidence of Lymph Node Metastasis in Papillary Thyroid Carcinoma.
Prophylactic lymph node dissection is still controversial due to the potentially surgery-related morbidity in management of papillary thyroid carcinomas. So, some histopathological predictors for lymph node metastasis in thyroidectomy specimens may reveal importance. The objective of this study was to define histomorphological indicators of lymph node metastasis in the patients who had been performed thyroidectomy without lymph node dissection. Clinicopathological features of patients archived in Department of Pathology at Trakya University Medical Faculty were reviewed. A total of 211 patients who had been diagnosed as papillary carcinoma and had been performed total thyroidectomy/lobectomy with central/cervical lymph node dissection were included in the study. Clinical features (age, gender, preoperative/postoperative clinical, and laboratory findings) and histopathological features (histological variant, tumor size, focality, extrathyroidal extension, tumor border, lateral tubular growth, intraglandular dissemination, stromal and lymphocytic tumor response, lymphocytic thyroiditis, lymphovascular invasion, lymph node metastasis, number of metastatic lymph nodes, extranodal extension, size of the metastatic foci) were evaluated. Male gender, conventional variant, tumor size greater than 10 mm, multifocality, extrathyroidal extension, lateral tubular growth, intraglandular dissemination, lymphocytic and stromal tumor response, and absence of lymphocytic thyroiditis were predictive, and older age (≥45 years) and follicular variant PTC were protective for lymph node metastasis. In order to optimize the management of papillary thyroid carcinomas, pathologists should search for the clues of lymph node metastasis particularly intraglandular dissemination, lateral tubular growth, tumor border and lymphocytic/stromal tumor response, multifocality, concomitant lymphocytic thyroiditis besides the actual prognostic criteria especially in younger aged male patients.


Evaluation of Computed Tomography for Lymph Node Staging in Bladder Cancer Prior to Radical Cystectomy.
To retrospectively evaluate the value of CT for lymph node (LN) staging in bladder cancer. Two uroradiologists reviewed CT scans of 231 patients who underwent radical cystectomy and pelvic lymphadenectomy according to a predefined 12-field template. A 5-step model was used to grade the radiological likelihood of a LN to represent malignant spread based on size, configuration and structure as well as regional clustering. Statistical analyses were performed both on patient- and field-based levels. LN metastases were found in 59 of 231 patients (25.5%). On a patient-based level, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 52.6, 93.6, 73.2, 85.6 and 83.4%, respectively. Using the field-based approach, a total of 1,649 anatomical fields were evaluable, of which 114 fields showed malignancy (6.9%). On a field basis, sensitivity, specificity, PPV, NPV and accuracy were 30.2, 98, 51.5, 94.5 and 93.3%, respectively. Concerning local staging (pT category), the overall accuracy was 78%; overstaging occurred in 6% and understaging in 16%. In line with prior studies, the sensitivity of CT imaging for the detection of LN metastases was low, while high values for specificity were achieved. This was further underlined by analyzing standardized anatomical fields. Concerning local staging, postoperative changes after TURB-T rarely led to overstaging.


Embolisation for pulmonary arteriovenous malformation.
Pulmonary arteriovenous malformations are abnormal direct connections between the pulmonary artery and pulmonary vein which result in a right-to-left shunt. They are associated with substantial morbidity and mortality mainly from the effects of paradoxical emboli. Potential complications include stroke, cerebral abscess, pulmonary haemorrhage and hypoxaemia. Embolisation is an endovascular intervention based on the occlusion of the feeding arteries the pulmonary arteriovenous malformations thus eliminating the abnormal right-to-left-shunting. This is an update of a previously published review. To determine the efficacy and safety of embolisation in patients with pulmonary arteriovenous malformations including a comparison with surgical resection and different embolisation devices. We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register; date of last search: 10 April 2017.We also searched the following databases: the Australian New Zealand Clinical Trials Registry; ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Register; International Clinical Trials Registry Platform Search Portal (last searched 27 August 2017). to be updatedWe checked cross-references and searched references from review articles. Trials in which individuals with pulmonary arteriovenous malformations were randomly allocated to embolisation compared to no treatment, surgical resection or embolisation using a different embolisation device. Studies identified for potential inclusion were independently assessed for eligibility by two authors, with excluded studies further checked by a third author. No trials were identified for inclusion in the review and hence no analysis was performed. There were no randomised controlled trials included in the review; one ongoing trial has been identified which may be eligible for inclusion in the future. There is no evidence from randomised controlled trials for embolisation of pulmonary arteriovenous malformations. However, randomised controlled trials are not always feasible on ethical grounds. Accumulated data from observational studies suggest that embolisation is a safe procedure which reduces morbidity and mortality. A standardised approach to reporting with long-term follow-up through registry studies can help to strengthen the evidence for embolisation in the absence of randomised controlled trials.


Imagined futures: how experiential knowledge of disability affects parents' decision making about fetal abnormality.
Knowledge of disability is considered key information to enable informed antenatal screening decisions by expectant parents. However, little is known about the role of experiential knowledge of disability in decisions to terminate or continue with a pregnancy diagnosed with a fetal abnormality. To explore the role that expectant parents' experiential knowledge of disabilities and conditions can play in real-life decisions to continue or end a pregnancy with a fetal abnormality. Secondary analysis of qualitative narrative interview data informed by contextual systems framework. Participants were recruited throughout the United Kingdom and interviewed between 2004 and 2006. Twenty-four women and four of their male partners who had direct or indirect experience of disability or illness and who had proceeded with or ended a pregnancy diagnosed with a fetal abnormality. Most respondents recounted using their experiential knowledge of disability, whether of their unborn baby's condition or of a different condition, to try to imagine the future for their unborn child, themselves and their family when making their decision. Some, who were considering continuing their pregnancy and had little or no experience of their unborn baby's specific disability, sought out others' experiences of the condition following antenatal diagnosis.The nature of a parent's experiential knowledge did not predict whether they continued with or terminated their pregnancy. Prospective parents may find it helpful to discuss their existing knowledge of their unborn baby's condition with health professionals who are aware of the influence this might have on parents' decisions.


The male factor: Outcomes from a cluster randomized field experiment with a couples-based HIV prevention intervention in a South African township.
This study examined the effects of the Couples Health CoOp intervention on heavy drinking, condom use, and HIV incidence. Thirty neighborhoods from one South African township were cluster randomized into three intervention arms: Couples Health CoOp (CHC), Women's Health CoOp/Men's Health CoOp (WHC/MHC), or a comparison arm. We recruited 290 men from informal drinking establishments who reported drinking alcohol regularly. We also recruited their main heterosexual sex partners. At 6-month follow-up, men in the CHC arm were less likely to report heavy drinking (OR 0.47, 95% CI: 0.25, 0.90) and were more likely to report consistent condom use during the past month (OR 2.66, 95% CI: 1.23, 5.76) than men in the comparison arm. At baseline, 26% of women and 13% of men were HIV-infected; at 6-month follow-up, 16 females and 5 males had seroconverted. HIV incidence was significantly lower among women in the CHC arm (IRR 0.22, 95% CI: 0.04, 1.01) than in the WHC/MHC arm. A couples-based intervention focusing on intersecting risks for HIV can improve biobehavioral outcomes, underscoring the importance of engaging couples together in HIV prevention.


Metabolic syndrome, components, and cardiovascular disease prevalence in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.
Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD. We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study. Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately. The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.


Sex and age specificity of susceptibility genes modulating survival at old age.
We aimed to investigate the influence of the genetic variability of candidate genes on survival at old age in good health. First, on the basis of a synthetic survival curve constructed using historic mortality data taken from the Italian population from 1890 onward, we defined three age classes ranging from 18 to 106 years. Second, we assembled a multinomial logistic regression model to evaluate the effect of dichotomous variables (genotypes) on the probability to be assigned to a specific category (age class). Third, we applied the regression model to a cross-sectional dataset (10 genes; 972 subjects selected for healthy status) categorized according to age and sex. We found that genetic factors influence survival at advanced age in good health in a sex- and age-specific way. Furthermore, we found that genetic variability plays a stronger role in males than in females and that, in both genders, its impact is especially important at very old ages. The analyses presented here underline the age-specific effect of the gene network in modulating survival at advanced age in good health.


A Diel Flux Balance Model Captures Interactions between Light and Dark Metabolism during Day-Night Cycles in C3 and Crassulacean Acid Metabolism Leaves.
Although leaves have to accommodate markedly different metabolic flux patterns in the light and the dark, models of leaf metabolism based on flux-balance analysis (FBA) have so far been confined to consideration of the network under continuous light. An FBA framework is presented that solves the two phases of the diel cycle as a single optimization problem and, thus, provides a more representative model of leaf metabolism. The requirement to support continued export of sugar and amino acids from the leaf during the night and to meet overnight cellular maintenance costs forces the model to set aside stores of both carbon and nitrogen during the day. With only minimal constraints, the model successfully captures many of the known features of C3 leaf metabolism, including the recently discovered role of citrate synthesis and accumulation in the night as a precursor for the provision of carbon skeletons for amino acid synthesis during the day. The diel FBA model can be applied to other temporal separations, such as that which occurs in Crassulacean acid metabolism (CAM) photosynthesis, allowing a system-level analysis of the energetics of CAM. The diel model predicts that there is no overall energetic advantage to CAM, despite the potential for suppression of photorespiration through CO2 concentration. Moreover, any savings in enzyme machinery costs through suppression of photorespiration are likely to be offset by the higher flux demand of the CAM cycle. It is concluded that energetic or nitrogen use considerations are unlikely to be evolutionary drivers for CAM photosynthesis.