Gonadotropin-releasing hormone neurons express K(ATP) channels that are regulated by estrogen and responsive to glucose and metabolic inhibition.
Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner that is dependent on circulating 17beta-estradiol (E2) and glucose concentrations. However, the intrinsic conductances responsible for the episodic firing pattern underlying pulsatile release and the effects of E2 and glucose on these conductances are primarily unknown. Whole-cell recordings from mouse enhanced green fluorescent protein-GnRH neurons revealed that the K(ATP) channel opener diazoxide induced an outward current that was antagonized by the sulfonylurea receptor 1 (SUR1) channel blocker tolbutamide. Single-cell reverse transcription (RT)-PCR revealed that the majority of GnRH neurons expressed Kir6.2 and SUR1 subunits, which correlated with the diazoxide/tolbutamide sensitivity. Also, a subpopulation of GnRH neurons expressed glucokinase mRNA, a marker for glucose sensitivity. Indeed, GnRH neurons decreased their firing in response to low glucose concentrations and metabolic inhibition. The maximum diazoxide-induced current was approximately twofold greater in E2-treated compared with oil-treated ovariectomized females. In current clamp, estrogen enhanced the diazoxide-induced hyperpolarization to a similar degree. However, based on quantitative RT-PCR, estrogen did not increase the expression of Kir6.2 or SUR1 transcripts in GnRH neurons. In the presence of ionotropic glutamate and GABA(A) receptor antagonists, tolbutamide depolarized and significantly increased the firing rate of GnRH neurons to a greater extent in E2-treated females. Finally, tolbutamide significantly increased GnRH secretion from the preoptic-mediobasal hypothalamus. Therefore, it appears that K(ATP) channels and glucokinase are expressed in GnRH neurons, which renders them directly responsive to glucose. In addition, K(ATP) channels are involved in modulating the excitability of GnRH neurons in an estrogen-sensitive manner that ultimately regulates peptide release.


Pachyosteosclerosis suggests archaic Homo frequently collected sessile littoral foods.
Fossil skeletons of Homo erectus and related specimens typically had heavy cranial and postcranial bones, and it has been hypothesised that these represent adaptations, or are responses, to various physical activities such as endurance running, heavy exertion, and/or aggressive behavior. According to the comparative biological data, however, skeletons that show a combination of disproportionally large diameters, extremely compact bone cortex, and very narrow medullary canals are associated with aquatic or semi-aquatic tetrapods that wade, and/or dive for sessile foods such as hard-shelled invertebrates in shallow waters. These so-called pachyosteosclerotic bones are less supple and more brittle than non-pachyosteosclerotic bones, and marine biologists agree that they function as hydrostatic ballast for buoyancy control. This paper discusses the possibility that heavy skeletons in archaic Homo might be associated with part-time collection of sessile foods in shallow waters.


Prevalence of herpes simplex type 2 and syphilis serology among young adults in a rural Gambian community.
To estimate prevalence and risk factors for herpes simplex 2 (HSV2) positivity, syphilis and Chlamydia trachomatis infection among rural people aged 15-34 in the Gambia. Questionnaires and serum samples were collected from 1076 men and women aged 15-34 during a cross sectional prevalence survey in a rural area of the Gambia. Sera were screened for antibodies to herpes simplex virus type 2 (HSV2), and for syphilis using Treponema pallidum haemagglutination assay (TPHA) and rapid plasma reagin (RPR) tests. Urine was tested by polymerase chain reaction (PCR) for C trachomatis infection. 28% of women and 5% of men were HSV2 ELISA positive; 10% of women and 2% of men were TPHA positive; and 7% of women and 1% of men were both RPR and TPHA positive. Out of 1030 urine sample tested only six were positive for C trachomatis. 7% of those who reported never having sex were positive for one or other of these tests. Prevalences of all STIs increased with age and were higher in women than men. Women were much less likely than men to seek treatment for STI symptoms at a health centre. Married people were at increased risk of an STI compared with single people. Jola and Fula women had a higher prevalence of HSV2 than women from other ethnic groups, and Fulas also had a higher prevalence of RPR/TPHA positivity. The limited number of sexual behaviour questions were not significantly associated with STIs after adjustment for age, marital status, and ethnic group. The prevalences of the ulcerative infections HSV2 and syphilis in this population are a cause for concern. In a setting where HIV1 prevalence remains low this indicates an urgent need for STI control and behaviour change programmes to prevent an HIV epidemic. Concerns about the validity of reported sexual behaviour data high light the necessity of biological markers in the evaluation of behaviour change programmes.


Molecular characterization of the EhaG and UpaG trimeric autotransporter proteins from pathogenic Escherichia coli.
Trimeric autotransporter proteins (TAAs) are important virulence factors of many Gram-negative bacterial pathogens. A common feature of most TAAs is the ability to mediate adherence to eukaryotic cells or extracellular matrix (ECM) proteins via a cell surface-exposed passenger domain. Here we describe the characterization of EhaG, a TAA identified from enterohemorrhagic Escherichia coli (EHEC) O157:H7. EhaG is a positional orthologue of the recently characterized UpaG TAA from uropathogenic E. coli (UPEC). Similarly to UpaG, EhaG localized at the bacterial cell surface and promoted cell aggregation, biofilm formation, and adherence to a range of ECM proteins. However, the two orthologues display differential cellular binding: EhaG mediates specific adhesion to colorectal epithelial cells while UpaG promotes specific binding to bladder epithelial cells. The EhaG and UpaG TAAs contain extensive sequence divergence in their respective passenger domains that could account for these differences. Indeed, sequence analyses of UpaG and EhaG homologues from several E. coli genomes revealed grouping of the proteins in clades almost exclusively represented by distinct E. coli pathotypes. The expression of EhaG (in EHEC) and UpaG (in UPEC) was also investigated and shown to be significantly enhanced in an hns isogenic mutant, suggesting that H-NS acts as a negative regulator of both TAAs. Thus, while the EhaG and UpaG TAAs contain some conserved binding and regulatory features, they also possess important differences that correlate with the distinct pathogenic lifestyles of EHEC and UPEC.


LIPGENE food-exchange model for alteration of dietary fat quantity and quality in free-living participants from eight European countries.
Controlled human intervention trials are required to confirm the hypothesis that dietary fat quality may influence insulin action. The aim was to develop a food-exchange model, suitable for use in free-living volunteers, to investigate the effects of four experimental diets distinct in fat quantity and quality: high SFA (HSFA); high MUFA (HMUFA) and two low-fat (LF) diets, one supplemented with 1.24 g EPA and DHA/d (LFn-3). A theoretical food-exchange model was developed. The average quantity of exchangeable fat was calculated as the sum of fat provided by added fats (spreads and oils), milk, cheese, biscuits, cakes, buns and pastries using data from the National Diet and Nutrition Survey of UK adults. Most of the exchangeable fat was replaced by specifically designed study foods. Also critical to the model was the use of carbohydrate exchanges to ensure the diets were isoenergetic. Volunteers from eight centres across Europe completed the dietary intervention. Results indicated that compositional targets were largely achieved with significant differences in fat quantity between the high-fat diets (39.9 (sem 0.6) and 38.9 (sem 0.51) percentage energy (%E) from fat for the HSFA and HMUFA diets respectively) and the low-fat diets (29.6 (sem 0.6) and 29.1 (sem 0.5) %E from fat for the LF and LFn-3 diets respectively) and fat quality (17.5 (sem 0.3) and 10.4 (sem 0.2) %E from SFA and 12.7 (sem 0.3) and 18.7 (sem 0.4) %E MUFA for the HSFA and HMUFA diets respectively). In conclusion, a robust, flexible food-exchange model was developed and implemented successfully in the LIPGENE dietary intervention trial.


Predicting the offshore distribution and abundance of marine birds with a hierarchical community distance sampling model.
Proposed offshore wind energy development on the Atlantic Outer Continental Shelf has brought attention to the need for baseline studies of the distribution and abundance of marine birds. We compiled line transect data from 15 shipboard surveys (June 2012-April 2014), along with associated remotely sensed habitat data, in the lower Mid-Atlantic Bight off the coast of Delaware, Maryland, and Virginia, USA. We implemented a recently developed hierarchical community distance sampling model to estimate the seasonal abundance of 40 observed marine bird species. Treating each season separately, we included six oceanographic parameters to estimate seabird abundance: three static (distance to shore, slope, sediment grain size) and three dynamic covariates (sea surface temperature [SST], salinity, primary productivity). We expected that avian bottom-feeders would respond primarily to static covariates that characterize seafloor variability, and that surface-feeders would respond more to dynamic covariates that quantify surface productivity. We compared the variation in species-specific and community-level responses to these habitat features, including for rare species, and we predicted species abundance across the study area. While several protected species used the study area in summer during their breeding season, estimated abundance and observed diversity were highest for nonbreeding species in winter. Distance to shore was the most common significant predictor of abundance, and thus useful in estimating the potential exposure of marine birds to offshore development. In many cases, our expectations based on feeding ecology were confirmed, such as in the first winter season, when bottom-feeders associated significantly with the three static covariates (distance to shore, slope, and sediment grain size), and surface-feeders associated significantly with two dynamic covariates (SST, primary productivity). However, other cases revealed significant relationships between static covariates and surface-feeders (e.g., distance to shore) and between dynamic covariates and bottom-feeders (e.g., primary productivity during that same winter). More generally, we found wide interannual, seasonal, and interspecies variation in habitat relationships with abundance. These results show the importance of quantifying detection and determining the ecological drivers of a community's distribution and abundance, within and among species, for evaluating the potential exposure of marine birds to offshore development.


Differences in Timed Up and Go Subtasks Between Older People With Mild Cognitive Impairment and Mild Alzheimer's Disease.
This study compared performances of timed up and go test subtasks between 40 older people with preserved cognition, 40 with mild cognitive impairment, and 38 with mild Alzheimer's disease. The assessment consisted of anamneses and timed up and go test subtasks (sit-to-stand, walking forward, turn, walking back, and turn-to-sit). Data were captured by Qualisys Track Manager software and processed by Visual3D software. The MATLAB program was applied to detect and analyze timed up and go test subtasks. All subtasks differentiated people with Alzheimer's disease and preserved cognition, except the sit-to-stand subtask, which did not distinguish any group. The walking forward subtask differed older people with preserved cognition from mild cognitive impairment, specifically on minimum peak of knee, average value of knee, and hip (pitch axis) during stance phase. The walking back, turn, and turn-to-sit subtasks distinguished subjects with Alzheimer's disease from mild cognitive impairment. The separated analysis of transition and walking subtasks is important in identifying mobility patterns among cognitive profiles.


Using verbal autopsy to measure causes of death: the comparative performance of existing methods.
Monitoring progress with disease and injury reduction in many populations will require widespread use of verbal autopsy (VA). Multiple methods have been developed for assigning cause of death from a VA but their application is restricted by uncertainty about their reliability. We investigated the validity of five automated VA methods for assigning cause of death: InterVA-4, Random Forest (RF), Simplified Symptom Pattern (SSP), Tariff method (Tariff), and King-Lu (KL), in addition to physician review of VA forms (PCVA), based on 12,535 cases from diverse populations for which the true cause of death had been reliably established. For adults, children, neonates and stillbirths, performance was assessed separately for individuals using sensitivity, specificity, Kappa, and chance-corrected concordance (CCC) and for populations using cause specific mortality fraction (CSMF) accuracy, with and without additional diagnostic information from prior contact with health services. A total of 500 train-test splits were used to ensure that results are robust to variation in the underlying cause of death distribution. Three automated diagnostic methods, Tariff, SSP, and RF, but not InterVA-4, performed better than physician review in all age groups, study sites, and for the majority of causes of death studied. For adults, CSMF accuracy ranged from 0.764 to 0.770, compared with 0.680 for PCVA and 0.625 for InterVA; CCC varied from 49.2% to 54.1%, compared with 42.2% for PCVA, and 23.8% for InterVA. For children, CSMF accuracy was 0.783 for Tariff, 0.678 for PCVA, and 0.520 for InterVA; CCC was 52.5% for Tariff, 44.5% for PCVA, and 30.3% for InterVA. For neonates, CSMF accuracy was 0.817 for Tariff, 0.719 for PCVA, and 0.629 for InterVA; CCC varied from 47.3% to 50.3% for the three automated methods, 29.3% for PCVA, and 19.4% for InterVA. The method with the highest sensitivity for a specific cause varied by cause. Physician review of verbal autopsy questionnaires is less accurate than automated methods in determining both individual and population causes of death. Overall, Tariff performs as well or better than other methods and should be widely applied in routine mortality surveillance systems with poor cause of death certification practices.


Transtympanic versus sustained-release administration of gentamicin: kinetics, morphology, and function.
Transtympanic gentamicin therapy has become a popular treatment modality for Meniere's disease, but questions regarding the ideal dose of medicine, the best administration paradigm, and the safest treatment end-point remain unanswered. The goal of this study is to examine the inner ear kinetics of transtympanic gentamicin and compare this with the kinetics of sustained-release delivery in a basic science model. In addition, we plan to examine the relationship of these kinetics curves to the effect of the two treatment modalities on inner ear function and morphology. It is hoped that this analysis will help clinicians to better apply local medical therapy to the ear. The study is a basic science project designed to examine perilymph gentamicin concentrations, hearing results, and inner ear morphology in an animal model. Gentamicin was applied to the right ear of chinchillas either through a transtympanic approach or in a sustained-release device. The left ear remained untreated as an internal control. At set time points the animals' hearing and balance function was studied and the perilymph was harvested, after which the animal was killed and preserved for histological evaluation. Kinetics curves were constructed for each of the two treatment paradigms and compared with histological and functional outcomes. The two groups yielded dramatically different kinetics curves. The transtympanic curve had a high peak level at 24 hours with rapid fall-off and almost total elimination by 48 hours, whereas the sustained-release curve was characterized by a long, flat plateau phase with a peak that was approximately one-third that of the transtympanic curve. In addition, the variability seen in perilymph concentrations was significantly higher in the transtympanic group than in the sustained-release group. Immunohistochemical analysis using antibodies against cleaved caspase-3 and cleaved caspase-7 demonstrated early damage in the spiral ganglion of both groups, before any obvious morphological change in the hair cells. The staining was significantly more dense in animals with transtympanic delivery. Cochlear and vestibular hair cell damage was seen at late time points in animals from both groups. Hearing loss (HL) progressed in an orderly fashion in the sustained-release group of animals, with no HL seen in the early time points and universal significant threshold shifts present by 72 hours. In the transtympanic group, the HL was more variable, with significant threshold shifts occurring as early as 4 hours after treatment, but with some animals demonstrating preserved hearing at the 72-hour time point. All animals demonstrated profound HL at the 6-day time point. There is a significant difference in the shape and variability of the perilymph kinetics curve when comparing sustained-release delivery to transtympanic delivery of gentamicin. High early peak levels of gentamicin seen with transtympanic therapy may have a profound effect on the spiral ganglion and produce early HL before obvious hair cell damage. Sustained delivery of gentamicin produces universal HL at 72 hours. The reliability of sustained-release delivery to the ear reduces functional and morphological variations between animals.


Notions of synergy for combinations of interventions against infectious diseases in heterogeneously mixing populations.
In public health programmes interventions are frequently combined with hoped for 'synergies'[22]. However, there is not yet a precise definition for synergy between interventions that captures the idea that there is added benefit at the population-level in using them together. To explore the synergy between interventions in the context of endemic disease, we consider a general model of infection spread in a heterogeneously mixing population. We consider interventions which may alter individuals' infectiousness, susceptibility, profile of infectiousness through time and survival while infected. Allowing general patterns of overlap and targeting in those receiving the interventions, we show how to compute changes to epidemiological indices such as R(0), and introduce a simple technique for calculating equilibrium prevalences and incidences via an iterated map. We argue for a particular definition of synergy and investigate its behaviour, both analytically and numerically, concluding that it is easiest to achieve synergy between interventions which perform poorly in isolation; implementation strategies that minimize the overlap of different interventions in the population tend to achieve more synergy; and that in populations with heterogeneous risk, interventions that are redundant when universally targeted can regain substantial synergy when applied in a targeted manner.


THE SEXUAL DOUBLE STANDARD AND ADOLESCENT PEER ACCEPTANCE.
The belief that women and men are held to different standards of sexual conduct is pervasive in contemporary American society. According to the sexual double standard, boys and men are rewarded and praised for heterosexual sexual contacts, whereas girls and women are derogated and stigmatized for similar behaviors. Although widely held by the general public, research findings on the sexual double standard remain equivocal, with qualitative studies and early attitudinal surveys generally finding evidence of the double standard and more recent experimental vignette designs often failing to find similar results. In this study, we extend prior research by directly measuring the social status of sexually permissive youth. We use data collected from the National Longitudinal Study of Adolescent Health to relate adolescents' self-reported numbers of sexual partners to a network measure of peer acceptance. Results suggest that the association between lifetime sexual partnerships and peer status varies significantly by gender, such that greater numbers of sexual partners are positively correlated with boys' peer acceptance, but negatively correlated with girls' peer acceptance. Moreover, the relationship between boys' sexual behaviors and peer acceptance is moderated by socioeconomic origins; sexually permissive boys from disadvantaged backgrounds are predicted to have more friendships than permissive boys from more advantaged backgrounds. Our results thus support the existence of an adolescent sexual double standard and suggest that sexual norms vary by both gender and socioeconomic origins.


Induction of pluripotent stem cells from human third molar mesenchymal stromal cells.
The expression of four transcription factors (OCT3/4, SOX2, KLF4, and MYC) can reprogram mouse as well as human somatic cells to induced pluripotent stem (iPS) cells. We generated iPS cells from mesenchymal stromal cells (MSCs) derived from human third molars (wisdom teeth) by retroviral transduction of OCT3/4, SOX2, and KLF4 without MYC, which is considered as oncogene. Interestingly, some of the clonally expanded MSCs could be used for iPS cell generation with 30-100-fold higher efficiency when compared with that of other clonally expanded MSCs and human dermal fibroblasts. Global gene expression profiles demonstrated some up-regulated genes regarding DNA repair/histone conformational change in the efficient clones, suggesting that the processes of chromatin remodeling have important roles in the cascade of iPS cells generation. The generated iPS cells resembled human embryonic stem (ES) cells in many aspects, including morphology, ES marker expression, global gene expression, epigenetic states, and the ability to differentiate into the three germ layers in vitro and in vivo. Because human third molars are discarded as clinical waste, our data indicate that clonally expanded MSCs derived from human third molars are a valuable cell source for the generation of iPS cells.


Transition-metal-free oxidative C5 C-H-halogenation of 8-aminoquinoline amides using sodium halides.
A simple and efficient transition-metal-free oxidative halogenation (Cl, Br) of the C5 C-H bond of 8-aminoquinoline amides has been developed. This method employed low-cost and innoxious sodium halides as halogenation reagents and oxone as an oxidant. The reactions demonstrated air and moisture tolerance, and good functional group compatibility, giving highly selective C5-halogenated products in good to excellent yields.


Effects of organic complexed or inorganic Co, Cu, Mn and Zn supplementation during a 45-day preconditioning period on productive and health responses of feeder cattle.
This experiment evaluated production and health parameters among cattle offered concentrates containing inorganic or organic complexed sources of supplemental Cu, Co, Mn and Zn during a 45-day preconditioning period. In total, 90 Angus×Hereford calves were weaned at 7 months (day -1), sorted by sex, weaning BW and age (261±2 kg; 224±2 days), and allocated to 18 drylot pens (one heifer and four steers per pen) on day 0; thus, all pens had equivalent initial BW and age. Pens were randomly assigned to receive a corn-based preconditioning concentrate containing: (1) Cu, Co, Mn and Zn sulfate sources (INR), (2) Cu, Mn, Co and Zn complexed organic source (AAC) or (3) no Cu, Co, Mn and Zn supplementation (CON). From day 0 to 45, cattle received concentrate treatments (2.7 kg/animal daily, as-fed basis) and had free-choice access to orchardgrass (Dactylis glomerata L.), long-stem hay and water. The INR and AAC treatments were formulated to provide the same daily amount of Co, Cu, Mn and Zn at a 50-, 16-, 8- and ninefold increase, respectively, compared with the CON treatment. On day 46, cattle were transported to a commercial feedlot, maintained as a single pen, and offered a free-choice receiving diet until day 103. Calf full BW was recorded on days -1 and 0, 45 and 46, and 102 and 103 for average daily gain (ADG) calculation. Liver biopsy was performed on days 0 (used as covariate), 22 and 45. Cattle were vaccinated against respiratory pathogens on days 15, 29 and 46. Blood samples were collected on days 15, 29, 45, 47, 49, 53 and 60. During preconditioning, mean liver concentrations of Co, Zn and Cu were greater (P⩽0.03) in AAC and INR compared with CON. No treatment effects were detected (P⩾0.17) for preconditioning feed intake, ADG or feed efficiency. No treatment effects were detected (P⩾0.48) for plasma concentrations of antibodies against Mannheimia haemolytica, bovine viral diarrhea types 1 and 2 viruses. Plasma haptoglobin concentrations were similar among treatments (P=0.98). Mean plasma cortisol concentration was greater (P⩽0.04) in CON compared with INR and AAC. No treatment effects were detected (P⩾0.37) for cattle ADG during feedlot receiving. Hence, INR and AAC increased liver concentrations of Co, Zn and Cu through preconditioning, but did not impact cattle performance and immunity responses during preconditioning and feedlot receiving.


Exercise as a calorie restriction mimetic: implications for improving healthy aging and longevity.
Calorie restriction (CR) is the only paradigm that has consistently increased lifespan in a wide variety of model organisms. Many hypotheses have been proposed as the underlying mechanism, including a reduction in body size and adiposity, which is commonly observed in calorie-restricted animals. This has led to investigations as to whether similar changes in body composition produced by increasing energy expenditure via exercise can replace or enhance the benefits of reducing energy intake. The goal of this chapter is to review and discuss the evidence regarding exercise as a CR mimetic for healthy aging and longevity. In rodents, the data clearly show that exercise, regardless of body weight changes, can improve health and survival, but unlike CR, fails to extend lifespan. In humans, short-term weight loss studies show that exercise and CR produce similar improvements in disease risk factors and biomarkers of aging, while some parameters clearly benefit more with exercise. Epidemiologic evidence in humans supports exercise as a strategy to reduce the risk of morbidity and mortality, but not to extend lifespan. It is unknown whether CR can extend human lifespan, but the metabolic profile of humans engaged in long-term CR shares many similarities with calorie restricted rodents and nonhuman primates. In conclusion, like CR, exercise can limit weight gain and adiposity, but only CR can extend lifespan. Therefore, in rodents, the ability of CR to slow aging is apparently more dependent on decreasing nutrient flux, rather than changes in energy balance and body composition.


Coronoid-temporalis pedicled rotation flap for middle skull base reconstruction.
We report on a patient who underwent maxillectomy and subsequent coronoid-temporalis flap reconstruction of the surgical defect to treat a maxillary sinus carcinoma invading the middle skull base. The patient underwent successful reconstruction of the middle skull base and displayed acceptable functional result. Middle skull base defects can be successfully repaired using a local coronoid-temporalis pedicled flap. The coronoid process of the mandible is advantageous as a local flap because it is close to the skull base defects and can easily be dissected from adjacent tissues. The use of a coronoid-temporalis pedicled flap offers excellent results without the need for further extensive surgery.


Reduction of Antibiotic Resistant Bacteria During Conventional and Advanced Wastewater Treatment, and the Disseminated Loads Released to the Environment.
The occurrence of new chemical and microbiological contaminants in the aquatic environment has become an issue of increasing environmental concern. Thus, wastewater treatment plants (WWTPs) play an important part in the distribution of so-called new emerging pathogens and antibiotic resistances. Therefore, the daily loads released by the WWTP were calculated including a model system for the distribution of these loads within the receiving water body. UV-, as well as ozone-treatment in separate or in combination for wastewater treatment were under investigation aiming at the reduction of these loads. Here, the impact of these treatments on the DNA integrity via antibody staining and PCR efficiencies experiments were included. All three facultative pathogenic bacteria [enterococci (23S rRNA), Pseudomonas aeruginosa (ecfX), and Escherichia coli (yccT)] and seven clinically relevant antibiotic resistance genes (ARGs) (mecA (methicillin resistance gene), ctx-M32 (β- lactame resistance gene), ermB (erythromycine resistance gene), bla TEM (β- lactame resistance gene), sul1 (sulfonamide resistance gene), vanA (vancomycin resistance gene), and intI1 (Integrase1 gene) associated with mobile genetic elements were detected in wastewaters. Different reduction efficiencies were analyzed during advanced wastewater treatments. ARGs were still found to be present in the effluents under the parameters of 1.0 g ozone per g dissolved organic carbon (DOC) and 400 J/m2, like ctx-M32, ermB, bla TEM, sul1, and intI1. Especially UV radiation induced thymidine dimerization which was analyzed via antibody mediated detection in the metagenome of the natural wastewater population. These specific DNA alterations were not observed during ozone treatment and combinations of UV/ozone treatment. The dimerization or potential other DNA alterations during UV treatment might be responsible for a decreased PCR efficiency of the 16S rRNA amplicons (176, 490, and 880 bp fragments) from natural metagenomes compared to the untreated sample. This impact on PCR efficiencies was also observed for the combination of ozone and UV treatment.


Chronic kidney disease at high altitude.
With a prevalence of 10 to 11% in the general population, it is likely that many patients with chronic kidney disease will visit or reside in mountainous areas. Little is known, however, about whether short- or long-duration, high-altitude exposure poses a risk in this patient population. Given that many areas of the kidney are marginally oxygenated even at sea level and that kidney disease may result in further renal hypoxia and hypoxia-associated renal injury, there is concern that high altitude may accelerate the progression of chronic kidney disease. In this review, we address how chronic kidney disease and its management is affected at high altitude. We postulate that arterial hypoxemia at high altitude poses a risk of faster disease progression in those with preexisting kidney disease. In addition, we consider the risks of developing acute altitude illness in patients with chronic kidney disease and the appropriate use of medications for the prevention and treatment of these problems.


Training general surgery residents in pediatric surgery: A Canadian survey.
The training of general surgeons in pediatric surgery is an important educational role of pediatric surgeons (PS). The authored surveyed this training process and the related expectations and perceptions of competence. The authors surveyed all practicing members of the Canadian Association of Paediatric Surgeons (CAPS) in Canada, all general surgery program directors (PD), and all final year general surgery residents (GS). Questions included exposure to pediatric surgery, expected and perceived competence in managing common pediatric general surgical problems, and trainee practice intentions. Response rate to date was 51% from PS, 69% from PD, and 19% from GS. Sixty-seven percent of PS considered the exposure to pediatric surgery satisfactory, yet only 1 of 7 residents planning on pursuing general surgery felt adequately prepared. Trainees were expected to be competent in the conditions polled by 65% of PS and 74% of PD, yet only 38% of the trainees actually felt competent in them. The largest discrepancies were found for infant hernia, newborn colostomy, and cryptorchidism. Presence of a fellowship program and size of training program had no impact on perceived competence. Training of general surgeons in pediatric surgery varies across Canadian programs. Perceived resident competence often lags behind program and faculty expectations. These data can be used for directing educational priorities in general surgery programs.


The impact of structured activities among Palestinian children in a time of conflict.
There is growing evidence of the impact on children's well-being of exposure to political conflict in such settings as the Palestinian territories. This study examined the impact of child-focused interventions involving structured activities, supported by provision of equipment and training of facilitators. The focus of interventions was participation in recreational, cultural and other non-formal activities supporting the development of resilience. Impacts were hypothesised on children's social and emotional well-being, relationships with parents and degree of future orientation. Two hundred and fifty children from the West Bank and 150 children from Gaza took part in the study. Of these 400 children, 300 comprised the intervention group. Fifty children from Gaza and 50 children from the West Bank comprised the comparison group. There were equal numbers of girls and boys in all groups, with similar proportions of children aged between 6 and 11 years, and between 12 and 17 years. Measures used were the Child Behavior Checklist (CBCL), the Parental Support Scale and the Hopefulness Scale: Youth Version. Assessment was made as children enrolled on the structured activity programmes (T1) and again twelve months later (T2). There was no difference in the CBCL Total, Internalising or Externalising problem scores at baseline (Time 1) between the children who subsequently took the intervention and those who did not. Compared to children in the comparison group, children in the intervention group had lower CBCL total problem scores, externalising problem scores, and internalising problem scores at Time 2 compared to Time 1. Exposure to the intervention was not associated with changes in children's hopefulness, but those receiving the intervention in the West Bank did report improved parental support at Time 2. The intervention appeared successful in improving children's emotional and behavioural well-being but not hopefulness. It was also linked with increased parental support in some areas (those located in the West Bank).


United Kingdom Alcohol Treatment Trial (UKATT): hypotheses, design and methods.
The United Kingdom Alcohol Treatment Trial (UKATT) is intended to be the largest trial of treatment for alcohol problems ever conducted in the UK. UKATT is a multicentre, randomized, controlled trial with blind assessment, representing a collaboration between psychiatry, clinical psychology, biostatistics, and health economics. This article sets out, in advance of data analysis, the theoretical background of the trial and its hypotheses, design, and methods. A projected total of 720 clients attending specialist services for treatment of alcohol problems will be randomized to Motivational Enhancement Therapy (MET) or to Social Behaviour and Network Therapy (SBNT), a novel treatment developed for the trial with strong support from theory and research. The trial will test two main hypotheses, expressed in null form as: (1) less intensive, motivationally based treatment (MET) is as effective as more intensive, socially based treatment (SBNT); (2) more intensive, socially based treatment (SBNT) is as cost-effective as less intensive, motivationally based treatment (MET). A number of subsidiary hypotheses regarding client-treatment interactions and therapist effects will also be tested. The article describes general features of the trial that investigators considered desirable, namely that it should: (1) be a pragmatic, rather than an explanatory, trial; (2) be an effectiveness trial based on "real-world" conditions of treatment delivery; (3) incorporate high standards of training, supervision and quality control of treatment delivery; (4) pay close attention to treatment process as well as treatment outcome; (5) build economic evaluation into the design at the outset. First results from UKATT are expected in 2002 and the main results in 2003.


Enhanced steady-state dissolution flux in reactive convective dissolution.
Chemical reactions can accelerate, slow down or even be at the very origin of the development of dissolution-driven convection in partially miscible stratifications when they impact the density profile in the host fluid phase. We numerically analyze the dynamics of this reactive convective dissolution in the fully developed non-linear regime for a phase A dissolving into a host layer containing a dissolved reactant B. We show for a general A + B → C reaction in solution, that the dynamics vary with the Rayleigh numbers of the chemical species, i.e. with the nature of the chemicals in the host phase. Depending on whether the reaction slows down, accelerates or is at the origin of the development of convection, the spatial distributions of species A, B or C, the dissolution flux and the reaction rate are different. We show that chemical reactions can enhance the steady-state flux as they consume A and can induce more intense convection than in the non-reactive case. This result is important in the context of CO2 geological sequestration where quantifying the storage rate of CO2 dissolving into the host oil or aqueous phase is crucial to assess the efficiency and the safety of the project.


Psychosine remodels model lipid membranes at neutral pH.
β-Galactosylsphingosine or psychosine (PSY) is a single chain sphingolipid with a cationic group, which is degraded in the lysosome lumen by β-galactosylceramidase during sphingolipid biosynthesis. A deficiency of this enzyme activity results in Krabbe's disease and PSY accumulation. This favors its escape to extralysosomal spaces, with its pH changing from acidic to neutral. We studied the interaction of PSY with model lipid membranes in neutral conditions, using phospholipid vesicles and monolayers as classical model systems, as well as a complex lipid mixture that mimics the lipid composition of myelin. At pH 7.4, when PSY is mainly neutral, it showed high surface activity, self-organizing into large structures, probably lamellar in nature, with a CMC of 38 ± 3 μM. When integrated into phospholipid membranes, PSY showed preferential partition into disordered phases, shifting phase equilibrium. The presence of PSY reduces the compactness of the membrane, making it more easily compressible. It also induces lipid domain disruption in vesicles composed of the main myelin lipids. The surface electrostatics of lipid membranes was altered by PSY in a complex manner. A shift to positive zeta potential values evidenced its presence in the vesicles. Furthermore, the increase of surface potential and surface water structuring observed may be a consequence of its location at the interface of the positively charged layer. As Krabbe's disease is a demyelinating process, PSY alteration of the membrane phase state, lateral lipid distribution and surface electrostatics appears important to the understanding of myelin destabilization at the supramolecular level.


Extreme sensitivity of adult neurogenesis to low doses of X-irradiation.
Therapeutic irradiation of the brain is associated with a number of adverse effects, including cognitive impairment. Although the pathogenesis of radiation-induced cognitive injury is unknown, it may involve loss of neural precursor cells from the subgranular zone (SGZ) of the hippocampal dentate gyrus and alterations in new cell production (neurogenesis). Young adult male C57BL mice received whole brain irradiation, and 6-48 h later, hippocampal tissue was assessed using immunohistochemistry for detection of apoptosis and numbers of proliferating cells and immature neurons. Apoptosis peaked 12 h after irradiation, and its extent was dose dependent. Forty-eight h after irradiation, proliferating SGZ cells were reduced by 93-96%; immature neurons were decreased from 40 to 60% in a dose-dependent fashion. To determine whether acute cell sensitivity translated into long-term changes, we quantified neurogenesis 2 months after irradiation with 0, 2, 5, or 10 Gy. Multiple injections of BrdUrd were given to label proliferating cells, and 3 weeks later, confocal microscopy was used to determine the percentage of BrdUrd-labeled cells that showed mature cell phenotypes. The production of new neurons was significantly reduced by X-rays; that change was dose dependent. In contrast, there were no apparent effects on the production of new astrocytes or oligodendrocytes. Measures of activated microglia indicated that changes in neurogenesis were associated with a significant inflammatory response. Given the known effects of radiation on cognitive function and the relationship between hippocampal neurogenesis and associated memory formation, our data suggest that precursor cell radiation response and altered neurogenesis may play a contributory if not causative role in radiation-induced cognitive impairment.


RAID3--An interleukin-6 receptor-binding aptamer with post-selective modification-resistant affinity.
Aptamers are an emerging class of highly specific targeting ligands. They can be selected in vitro for a large variety of targets, ranging from small molecules to whole cells. Most aptamers selected are nucleic acid-based, allowing chemical synthesis and easy modification. Although their properties make them interesting drug candidates for a broad spectrum of applications and an interesting alternative to antibodies or fusion proteins, they are not yet broadly used. One major drawback of aptamers is their susceptibility to abundant serum nucleases, resulting in their fast degradation in biological fluids. Using modified nucleic acids has become a common strategy to overcome these disadvantages, greatly increasing their half-life under cell culture conditions or even in vivo. Whereas pre-selective modifications of the initial library for aptamer selection are relatively easy to obtain, post-selective modifications of already selected aptamers are still generally very labor-intensive and often compromise the aptamers ability to bind its target molecule. Here we report the selection, characterization and post-selective modification of a 34 nucleotide (nt) RNA aptamer for a non-dominant, novel target site (domain 3) of the interleukin-6 receptor (IL-6R). We performed structural analyses and investigated the affinity of the aptamer to the membrane-bound and soluble forms (sIL-6R) of the IL-6R. Further, we performed structural analyses of the aptamer in solution using small-angle X-ray scattering and determined its overall shape and oligomeric state. Post-selective exchange of all pyrimidines against their 2'-fluoro analogs increased the aptamers stability significantly without compromising its affinity for the target protein. The resulting modified aptamer could be shortened to its minimal binding motif without loss of affinity.


Regional variation and other correlates of Department of Veterans Affairs Disability Awards for patients with posttraumatic stress disorder.
Minnesota, Minneapolis, Minnesota. Posttraumatic stress disorder (PTSD) is a chronic disabling condition affecting more than 600,000 United States veterans and is the most common psychiatric condition for which veterans seek Veterans Affairs disability benefits. Receipt of such benefits enhances veterans' access to Veteran Affairs health care and reduces their chance of poverty. We sought to determine whether previously identified regional variations in PTSD disability awards are explained by appropriate subject characteristics (eg, differences in PTSD symptomatology or dysfunction) and to estimate the impact of veterans' PTSD symptom severity or level of dysfunction on their odds of obtaining PTSD disability benefits. We used a mailed survey linked to administrative data. Subjects included 4918 representative, eligible men and women who filed PTSD disability claims between 1994 and 1998. A total of 3337 veterans returned useable surveys (68%). Before adjustment, PTSD disability claims approval rates ranged from 43% to 75% across regions. After adjustment, rates ranged from 33% to 72% (P <0.0001). Severer PTSD symptoms were associated with greater odds of having PTSD disability benefits (P <0.0001). Unexpectedly, poorer functional status was associated with lower odds of having benefits (P <0.0001). On average, clinical differences between veterans who did and did not have PTSD disability benefits were small but suggested slightly greater dysfunction among those without benefits. An almost twofold regional difference in claims approval rates was not explained by veterans' PTSD symptom severity, level of dysfunction, or other subject-level characteristics. Veterans who did not obtain PTSD disability benefits were at least as disabled as those who did receive benefits.


Hyperkalemia in heart failure: Foe or friend?
Hyperkalemia is a frequent and sometimes life-threatening condition that may be associated with arrhythmia and cardiac dysfunction in patients with heart failure (HF). High potassium levels in HF represent both a direct risk for cardiovascular complication and an indirect biomarker of the severity of the underlying disease, reflecting neurohormonal activation and renal dysfunction. Evaluating the prevalence and significance of hyperkalemia in HF patients is essential for optimizing the use of potassium sparing agents, such the renin-angiotensin-aldosterone system inhibitors (RAASi) or angiotensin receptor-neprilysin inhibitors and mineralocorticoid receptor antagonists, which represent a well-established cornerstone and life-saving therapy. In this review we discuss recent findings and current concepts related to the epidemiology, pathological mechanisms and implications of hyperkalemia, as well as novel therapeutic approaches to counteract it in patients with HF. The balance between optimizing life-saving potassium sparing medication and minimizing hyperkalemia-associated risk is much needed in patients with HF. Although older potassium-binding agents are associated with serious adverse events, novel potassium-binding drugs are effective in lowering potassium levels and are generally well tolerated. Novel potassium-binding drugs, such as patiromer and sodium zirconium cyclosilicate, may help to optimize therapy in HF and achieve guideline-recommended doses. Hyperkalemia is common in HF patients and is associated with a poorer prognosis and an increased risk of cardiovascular complications: Contrariwise, "moderate" potassium levels go with a better prognosis, while the emergence of new drugs, potassium binders, could allow target doses of RAASi to be achieved.


A Role of the Gelatinous Matrix in the Resistance of Root-Knot Nematode (Meloidogyne spp.) Eggs to Microorganisms.
The survival of eggs of the root-knot nematode Meloidogyne javanica was studied in a series of experiments comparing the infectivity of egg masses (EM) to that of separated eggs (SE). The EM or SE were placed in the centers of pots containing citrus orchard soil and incubated for 24 hours, 10 days, or 20 days. Following each incubation time, 10-day-old tomato plants were planted in each pot, and 3 to 4 weeks later the plants were harvested and the galling indices determined. In the EM treatments, galling indices of ca. 4.0 to 5.0 were recorded after all three incubation periods; in the SE treatments, the infectivity gradually declined to trace amounts by 20 days. Incubating EM and SE for 2 weeks in four different soil types showed the same pattern in all the soil types: EM caused heavy infection of the test plants while the infection rate from the SE was extremely low. Incubating EM and SE in soil disinfested with formaldehyde resulted in comparable galling indices in most treatments. In petri dish experiments, 100 mg of natural soil was spread at the perimeter of a Phytagel surface and EM or SE of M. incognita were placed in the center. Light microscopy revealed that within 5 to 10 days the SE were attacked by a broad spectrum of microorganisms and were obliterated while the eggs within the EM remained intact. Separated eggs placed within sections of gelatinous matrix (GM) were not attacked by the soil microorganisms. When selected microbes were placed on Phytagel surfaces with EM of M. incognita, electron microscopy demonstrated that at least some microbes colonized the GM. As the major difference between the EM and the SE was the presence of the GM, the GM may serve as a barrier to the invasion of some microorganisms.


A new wrinkle on liquid sheets: Turning the mechanism of viscous bubble collapse upside down.
Viscous bubbles are prevalent in both natural and industrial settings. Their rupture and collapse may be accompanied by features typically associated with elastic sheets, including the development of radial wrinkles. Previous investigators concluded that the film weight is responsible for both the film collapse and wrinkling instability. Conversely, we show here experimentally that gravity plays a negligible role: The same collapse and wrinkling arise independently of the bubble's orientation. We found that surface tension drives the collapse and initiates a dynamic buckling instability. Because the film weight is irrelevant, our results suggest that wrinkling may likewise accompany the breakup of relatively small-scale, curved viscous and viscoelastic films, including those in the respiratory tract responsible for aerosol production from exhalation events.


Structure-activity relationships at the monoamine transporters and sigma receptors for a novel series of 9-[3-(cis-3, 5-dimethyl-1-piperazinyl)propyl]carbazole (rimcazole) analogues.
9-[3-(cis-3,5-Dimethyl-1-piperazinyl)propyl]carbazole (rimcazole) has been characterized as a sigma receptor antagonist that binds to the dopamine transporter with moderate affinity (K(i) = 224 nM). Although the binding affinities at the dopamine transporter of rimcazole and cocaine are comparable, rimcazole only depressed locomotor activity in mice and antagonized the stimulant effects produced by cocaine. The neurochemical mechanisms underlying the attenuation of cocaine's effects are not understood, although interaction at a low affinity site/state of the dopamine transporter has been suggested. To explore further this class of compounds, a series of rimcazole analogues was designed and synthesized. Displacement of [(3)H]WIN 35,428 binding at the dopamine transporter in rat caudate-putamen revealed that aromatic substitutions on rimcazole were not well tolerated, generally, with significant reductions in affinity for the 3,6-dibromo (5; K(i) = 3890 nM), 1,3, 6-tribromo (6; K(i) = 30300 nM), 3-amino (8; K(i) = 2400 nM), and 3, 6-dinitro (9; K(i) = 174000 nM) analogues. The N-phenylpropyl group was the only terminal piperazine nitrogen substituent that retained moderate affinity at the dopamine transporter (11; K(i) = 263 nM). Analogues in which the carbazole ring was replaced with a freely rotating diphenylamine moiety were also prepared. Although the diphenylamino analogue in which the terminal piperazine nitrogen was unsubstituted, as in rimcazole, demonstrated relatively low binding affinity at the dopamine transporter (24; K(i) = 813 nM), the N-phenylpropyl analogue was found to have the highest affinity for the dopamine transporter within the series (25; K(i) = 61.0 nM). All of the analogues that had affinity for the dopamine transporter inhibited [(3)H]dopamine uptake in synaptosomes, and potencies for these two effects showed a positive correlation (r(2) = 0.7731, p = 0.0018). Several of the analogues displaced [(3)H]paroxetine from serotonin transporters with moderate to high affinity, with the N-phenylpropyl derivative (11) having the highest affinity (K(i) = 44.5 nM). In contrast, none of the analogues recognized the norepinephrine transporter with an affinity of <1.3 microM. Binding affinities for sigma(1) and sigma(2) receptors were also determined, and several of the compounds were more potent than rimcazole with affinities ranging from 97 nM to >6 microM at sigma(1) sites and 145 to 1990 nM at sigma(2) sites. The compound with the highest affinity (25) at sigma(1) sites was also the compound with highest affinity at the dopamine transporter. These novel rimcazole analogues may provide important tools with which to characterize the relationship between the low affinity site or state of the dopamine transporter, sigma receptors, and their potential roles in modulating cocaine's psychostimulant actions.


New insights and perspectives into biological materials for flexible electronics.
Biological materials have robust hierarchical structures capable of specialized functions and the incorporation of natural biologically active components, which have been finely tuned through millions of years of evolution. These highly efficient architectural designs afford remarkable transport and mechanical properties, which render them attractive candidates for flexible electronic sensing technologies. This review provides a comprehensive overview of the fundamental aspects and applications of biological materials for flexible electronic devices and discusses various classes of biological materials by describing their unique structures and functions. We discuss the effect of the biological activity of biological materials on the improved properties in detail, because this effect overcomes the limited bioavailability and restricted morphology of materials generally encountered in traditional flexible electronic devices. We also summarize various approaches for the design and functionalization of natural materials and their applications in flexible electronic devices for use in biomedical, electron, energy, environmental and optical fields. Finally, we provide new insights and perspectives to further describe trends for future generations of biological materials, which are likely to be critical components (building blocks or elements) in future flexible electronics.


A Targeted Proteomic Approach for Heat Shock Proteins Reveals DNAJB4 as a Suppressor for Melanoma Metastasis.
Heat shock proteins are molecular chaperones that are involved in protein folding. In this study, we developed a targeted proteomic method, relying on LC-MS/MS in the parallel-reaction monitoring (PRM) mode, for assessing quantitatively the human heat shock proteome. The method facilitated the coverage of approximately 70% of the human heat shock proteome and displayed much better throughput and sensitivity than the shotgun proteomic approach. We also applied the PRM method for assessing the differential expression of heat shock proteins in three matched primary/metastatic pairs of melanoma cell lines. We were able to quantify ∼45 heat shock proteins in each pair of cell lines, and the quantification results revealed that DNAJB4 is down-regulated in the three lines of metastatic melanoma cells relative to the corresponding primary melanoma cells. Interrogation of The Cancer Genome Atlas data showed that lower levels of DNAJB4 expression conferred poorer prognosis in melanoma patients. Moreover, we found that DNAJB4 suppresses the invasion of cultured melanoma cells through diminished expression and activities of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). Together, we established, for the first time, a high-throughput targeted proteomics method for profiling quantitatively the human heat shock proteome and discovered DNAJB4 as a suppressor for melanoma metastasis.


The "Reading the Mind in the Eyes" Test: Complete Absence of Typical Sex Difference in ~400 Men and Women with Autism.
The "Reading the Mind in the Eyes" test (Eyes test) is an advanced test of theory of mind. Typical sex difference has been reported (i.e., female advantage). Individuals with autism show more difficulty than do typically developing individuals, yet it remains unclear how this is modulated by sex, as females with autism have been under-represented. Here in a large, non-male-biased sample we test for the effects of sex, diagnosis, and their interaction. The Eyes test (revised version) was administered online to 395 adults with autism (178 males, 217 females) and 320 control adults (152 males, 168 females). Two-way ANOVA showed a significant sex-by-diagnosis interaction in total correct score (F(1,711) = 5.090, p = 0.024, ηp2 = 0.007) arising from a significant sex difference between control males and females (p < 0.001, Cohen's d = 0.47), and an absence of a sex difference between males and females with autism (p = 0.907, d = 0.01); significant case-control differences were observed across sexes, with effect sizes of d = 0.35 in males and d = 0.69 in females. Group-difference patterns fit with the extreme-male-brain (EMB) theory predictions. Eyes test-Empathy Quotient and Eyes test-Autism Spectrum Quotient correlations were significant only in females with autism (r = 0.35, r = -0.32, respectively), but not in the other 3 groups. Support vector machine (SVM) classification based on response pattern across all 36 items classified autism diagnosis with a relatively higher accuracy for females (72.2%) than males (65.8%). Nevertheless, an SVM model trained within one sex generalized equally well when applied to the other sex. Performance on the Eyes test is a sex-independent phenotypic characteristic of adults with autism, reflecting sex-common social difficulties, and provides support for the EMB theory predictions for both males and females. Performance of females with autism differed from same-sex controls more than did that of males with autism. Females with autism also showed stronger coherence between self-reported dispositional traits and Eyes test performance than all other groups.


[Uterine inversion].
The uterine inversion is a rare but serious pathology of the delivery. We describe two cases of uterine inversion of secondary and quaternary degree; the first had a delay diagnosis and the second having a return after the manual replacement, finishing both on surgical resolution. The authors describe the causal factors, the diagnosis and the therapeutic of uterine inversion.


Impact of the Dynamic Change of Metabolic Health Status on the Incident Type 2 Diabetes: A Nationwide Population-Based Cohort Study.
Metabolically healthy obese (MHO) is regarded as a transient concept. We examined the effect of the dynamic change of metabolic health status on the incidence of type 2 diabetes mellitus (T2DM) both in obese and normal weight individuals. We analyzed 3,479,514 metabolically healthy subjects aged over 20 years from the Korean National Health Screening Program, who underwent health examination between 2009 and 2010, with a follow-up after 4 years. The relative risk for T2DM incidence until the December 2017 was compared among the four groups: stable metabolically healthy normal weight (MHNW), unstable MHNW, stable MHO, and unstable MHO. During the 4 years, 11.1% of subjects in the MHNW group, and 31.5% in the MHO group converted to a metabolically unhealthy phenotype. In the multivariate adjusted model, the unstable MHO group showed the highest risk of T2DM (hazard ratio [HR], 4.67; 95% confidence interval [CI], 4.58 to 4.77). The unstable MHNW group had a higher risk of T2DM than stable MHO group ([HR, 3.23; 95% CI, 3.16 to 3.30] vs. [HR, 1.81; 95% CI, 1.76 to 1.85]). The stable MHO group showed a higher risk of T2DM than the stable MHNW group. The influence of the transition into a metabolically unhealthy phenotype on T2DM incidence was greater in subjects with aged <65 years, women, and those with weight gain. Metabolically healthy phenotype was transient both in normal weight and obese individuals. Maintaining metabolic health was critical for the prevention of T2DM, irrespective of their baseline body mass index.


World-centered perception of 3D object motion during visually guided self-motion.
We investigated how human observers estimate an object's three-dimensional (3D) motion trajectory during visually guided self-motion. Observers performed a task in an immersive virtual reality system consisting of front, left, right, and floor screens of a room-sized cube. In one experiment, we found that the presence of an optic flow simulating forward self-motion in the background induces a world-centered frame of reference, instead of an observer-centered frame of reference, for the perceived rotation of a 3D surface from motion. In another experiment, we found that the perceived direction of 3D object motion is biased toward a world-centered frame of reference when an optic flow pattern is presented in the background. In a third experiment, we confirmed that the effect of the optic flow pattern on the perceived direction of 3D object motion was not caused only by local motion detectors responsible for the change of the retinal size of the target. These results suggest that visually guided self-motion from optic flow induces world-centered criteria for estimates of 3D object motion.


Exposure to radiofrequency radiation (900 MHz, GSM signal) does not affect micronucleus frequency and cell proliferation in human peripheral blood lymphocytes: an interlaboratory study.
The objective of this study was to investigate whether 24 h exposure to radiofrequency electromagnetic fields similar to those emitted by mobile phones induces genotoxic effects and/or effects on cell cycle kinetics in cultured human peripheral blood lymphocytes. The effect of 900 MHz exposure (GSM signal) was evaluated at four specific absorption rates (SARs, 0, 1, 5 and 10 W/kg peak values). The exposures were carried out in wire patch cells under strictly controlled conditions of both temperature and dosimetry, and the induction of genotoxic effects was evaluated in lymphocyte cultures from 10 healthy donors by applying the cytokinesis-block micronucleus assay. Positive controls were provided by using mitomycin C. Two research groups were involved in the study, one at ENEA, Rome, and the other at CNR-IREA, Naples. Each laboratory tested five donors, and the resulting slides were scored by both laboratories. Following this experimental scheme, it was also possible to compare the results obtained by cross-scoring of slides. The results obtained provided no evidence for the existence of genotoxic or cytotoxic effects in the range of SARs investigated. These findings were confirmed in the two groups of five donors examined in the two laboratories and when the same slides were scored by two operators.


Long-term effect of cinacalcet hydrochloride on abdominal aortic calcification in patients on hemodialysis with secondary hyperparathyroidism.
Secondary hyperparathyroidism (SHPT) is one of the common complications in dialysis patients, and is associated with increased risk of vascular calcification. The effects of cinacalcet hydrochloride treatment on bone and mineral metabolism have been previously reported, but the benefit of cinacalcet on vascular calcification remains uncertain. The aim of this study was to evaluate the impact of cinacalcet on abdominal aortic calcification in dialysis patients. Patients were on maintenance hemodialysis with insufficiently controlled SHPT (intact parathyroid hormone [PTH] >180 pg/mL) by conventional therapies. All subjects were initially administered 25 mg cinacalcet daily, with concomitant use of calcitriol analogs. Abdominal aortic calcification was annually evaluated by calculating aortic calcification area index (ACAI) using multidetector computed tomography (MDCT), from 12 months before to 36 months after the initiation of cinacalcet therapy. Twenty-three patients were analyzed in this study. The mean age was 59.0±8.7 years, 34.8% were women, and the mean dialysis duration was 163.0±76.0 months. After administration of cinacalcet, serum levels of intact PTH, phosphorus, and calcium significantly decreased, and mean Ca × P values significantly decreased from 67.4±7.9 mg(2)/dL(2) to 52±7.7 mg(2)/dL(2). Although the ACAI value did not decrease during the observation period, the increase in ACAI between 24 months and 36 months after cinacalcet administration was significantly suppressed. Long-term administration of cinacalcet was associated with reduced progression of abdominal aortic calcification, and achieving appropriate calcium and phosphorus levels may reduce the rates of cardiovascular events and mortality in patients on hemodialysis.


Making the best of the early years: the Tambellup way.
Tambellup is a small rural town in the Great Southern region of Western Australia (WA), approximately 300 km south-east of state capital Perth. Tambellup has a much higher Aboriginal population than the national average and achieved very positive results for year one children in 2007 regional Australian Early Development Index testing. In 2009 the Great Southern GP Network (which has a facilitating role in providing early intervention strategies to families with young children at risk of disadvantage) requested that public health staff at Edith Cowan University, Perth, WA undertake an exploratory study to discover the factors protective of children's development in Tambellup. This article describes the subsequent research and its findings. This 2009 qualitative study interviewed both adult members of the local Aboriginal community (Noongar people; n = 23), and non-Aboriginal leaders from a cross-section of organisations, services and the community (n = 14) to determine what made growing up in Tambellup a positive experience. Aboriginal participants were introduced to the researchers by a local cultural consultant. Non-Aboriginal participants were initially sourced from a list provided by the GSGPN and extended by asking those listed to identify other appropriate contacts. Face-to-face interviews were carried out with Aboriginal participants and telephone interviews were undertaken with non-Aboriginal participants. All interviews were conducted using a standard schedule of questions as a guide, supplemented by clarifying and broadening questions from research team members. Data were analysed in a multi-stage process of collation, extraction of common themes and verification of themes with study participants and other stakeholders. Findings were presented to local Aboriginal leaders at a community meeting and a final report was prepared and circulated to community members. There was substantial evidence of widespread trust and positive relationships in this close-knit community, where adults looked out for and supported both their own and others' children. The primary school played a key role in supporting children's development even before children started school. Good relations generally existed between Aboriginal and non-Aboriginal residents, contributing to the stability of the population and providing many role models in successful cross-cultural relationships. Aboriginal people in Tambellup played significant but often under-recognised roles in promoting child and youth wellbeing in the community. The community had the capacity to respond to local needs and challenges. Communication channels were effective and there was a sense of belonging, pride and 'connectedness' in the community that promoted and supported a safe environment for children. High quality services and staff (eg school and community health centre) reinforced children's developmental opportunities. The results suggest that small rural communities offer significant and untapped resources for enhancing the health and wellbeing of children in the critical early years of life.


Aseptic preparation of parenteral medicinal products in healthcare establishments in Europe.
In many cases, parenteral medicines with a marketing authorisation cannot be administered directly to patients, that is, they are not presented in ready-to-administer form. Before administration to patients, these medicines have to be reconstituted. Reconstitution has a special position; it can neither be seen as industrial manufacture nor as 'regular' pharmacy preparation. There are other processes in healthcare establishments (eg, parenteral nutrition), related to the reconstitution process, where the requirements of national quality assurance standards for the safe preparation of sterile products are equally important and have to be fulfilled. In European healthcare establishments, aseptic preparation of parenteral medicinal products is considered to be a process of crucial importance for patient safety because errors in the preparation of these medicines may lead to a product that can cause immediate damage to patients. Aseptic preparation of medicinal products is carried out in hospital pharmacies as well as in clinical areas in healthcare establishments. The Committee of Experts on Quality and Safety Standards for Pharmaceutical Practices and Pharmaceutical Care (Council of Europe; hereafter: Committee of Experts), supported by the European Directorate for the Quality of Medicines & Healthcare, is undertaking work on the topic of aseptic preparation of medicines. The work is carried out in cooperation with the European Association of Hospital Pharmacists on the basis of a Resolution CM/Res AP(2011)1 on Quality and Safety Assurance requirements for Medicinal Products prepared in Pharmacies for the Special Needs of Patients, which was adopted by the Committee of Ministers on 19 January 2011. The Resolution includes some recommendations and an outlook to further work on reconstitution of parenteral medicines. A survey that was sent to the different European countries demonstrated that there is no or just limited regulation concerning reconstitution in Europe. This article describes the risks associated with poor reconstitution practices and the previous work as well as the ongoing activities concerning reconstitution at the European level. The article emphasises the need for regulation in this area, which is missing at present. It is expected that consensus can be reached on a guidance document for reconstitution at the European level.


Ribosomal proteins L7 and L8 function in concert with six A₃ assembly factors to propagate assembly of domains I and II of 25S rRNA in yeast 60S ribosomal subunits.
Ribosome biogenesis is a complex multistep process that involves alternating steps of folding and processing of pre-rRNAs in concert with assembly of ribosomal proteins. Recently, there has been increased interest in the roles of ribosomal proteins in eukaryotic ribosome biogenesis in vivo, focusing primarily on their function in pre-rRNA processing. However, much less is known about participation of ribosomal proteins in the formation and rearrangement of preribosomal particles as they mature to functional subunits. We have studied ribosomal proteins L7 and L8, which are required for the same early steps in pre-rRNA processing during assembly of 60S subunits but are located in different domains within ribosomes. Depletion of either leads to defects in processing of 27SA(3) to 27SB pre-rRNA and turnover of pre-rRNAs destined for large ribosomal subunits. A specific subset of proteins is diminished from these residual assembly intermediates: six assembly factors required for processing of 27SA(3) pre-rRNA and four ribosomal proteins bound to domain I of 25S and 5.8S rRNAs surrounding the polypeptide exit tunnel. In addition, specific sets of ribosomal proteins are affected in each mutant: In the absence of L7, proteins bound to domain II, L6, L14, L20, and L33 are greatly diminished, while proteins L13, L15, and L36 that bind to domain I are affected in the absence of L8. Thus, L7 and L8 might establish RNP structures within assembling ribosomes necessary for the stable association and function of the A(3) assembly factors and for proper assembly of the neighborhoods containing domains I and II.


Estrogen promotes stress sensitivity in a prefrontal cortex-amygdala pathway.
We have recently reported in male rats that medial prefrontal cortex (mPFC) neurons that project to the basolateral nucleus of the amygdala (BLA) are resilient to stress-induced dendritic remodeling. The present study investigated whether this also occurs in female rats. This pathway was identified using the retrograde tracer Fast Blue injected into the BLA of ovariectomized female rats with estrogen replacement (OVX + E) and without (OVX + veh). Animals were exposed for 10 days either to 2-h immobilization stress or to home cage rest, after which layer III mPFC neurons that were either retrogradely labeled by Fast Blue or unlabeled were filled with Lucifer Yellow and analyzed for apical dendritic length and spine density. No dendritic remodeling occurred in unlabeled neurons from OVX + veh or OVX + E animals. In BLA-projecting neurons, however, stress had no effect on length in OVX + veh animals, but stressed OVX + E females showed greater dendritic length than controls at intermediate branches. Stress also caused an increase in spine density in all neurons in OVX + veh animals and a spine density increase in BLA-projecting neurons in OVX + E females. Estrogen also increased spine density on BLA-projecting neurons in unstressed animals. These data demonstrate both independent effects of estrogen on pyramidal cell morphology and effects that are interactive with stress, with the BLA-projecting neurons being sensitive to both kinds of effects.


Local field potential oscillations as a cortical soliloquy.
Synchronized network activity can be recorded as fluctuations in the local field potential (LFP). In this issue of Neuron, Fröhlich and McCormick suggest that cortical LFPs themselves contribute to synchronization of the very network that generates them. Thus, in monitoring these brain waves, we may be listening to the cortex talking to itself.


A randomised multicentre trial of acupuncture in patients with seasonal allergic rhinitis--trial intervention including physician and treatment characteristics.
In a large randomised trial in patients with seasonal allergic rhinitis (SAR), acupuncture was superior compared to sham acupuncture and rescue medication. The aim of this paper is to describe the characteristics of the trial's participating physicians and to describe the trial intervention in accordance with the STRICTA (Standards for Reporting Interventions in Controlled Trials of Acupuncture) guidelines, to make details of the trial intervention more transparent to researchers and physicians. ACUSAR (ACUpuncture in Seasonal Allergic Rhinitis) was a three-armed, randomised, controlled multicentre trial. 422 SAR patients were randomised to semi-standardised acupuncture plus rescue medication (RM, cetirizine), sham acupuncture plus RM or RM alone. We sent a questionnaire to trial physicians in order to evaluate their characteristics regarding their education about and experience in providing acupuncture. During the trial, acupuncturists were asked to diagnose all of their patients according to Chinese Medicine (CM) as a basis for the semi-standardised, individualized intervention in the acupuncture group. Every acupuncture point used in this trial had to be documented after each session Acupuncture was administered in outpatient clinics by 46 (mean age 47 ± 10 years; 24 female/ 22 male) conventionally-trained medical doctors (67% with postgraduate specialization such as internal or family medicine) with additional extensive acupuncture training (median 500 hours (1st quartile 350, 3rd quartile 1000 hours with 73% presenting a B-diploma in acupuncture training (350 hours)) and experience (mean 14 years in practice). The most reported traditional CM diagnosis was 'wind-cold invading the lung' (37%) and 'wind-heat invading the lung' (37%), followed by 'lung and spleen qi deficiency' (9%). The total number of needles used was higher in the acupuncture group compared to the sham acupuncture group (15.7 ± 2.5 vs. 10.0 ± 1.6). The trial interventions were provided by well educated and experienced acupuncturists. The different number of needles in both intervention groups could be possibly a reason for the better clinical effect in SAR patients. For future trials it might be more appropriate to ensure that acupuncture and sham acupuncture groups should each be treated by a similar number of needles. ClinicalTrials.gov: NCT00610584.


Importance of Standardized DXA Protocol for Assessing Physique Changes in Athletes.
The implications of undertaking DXA scans using best practice protocols (subjects fasted and rested) or a less precise but more practical protocol in assessing chronic changes in body composition following training and a specialized recovery technique were investigated. Twenty-one male cyclists completed an overload training program, in which they were randomized to four sessions per week of either cold water immersion therapy or control groups. Whole-body DXA scans were undertaken with best practice protocol (Best) or random activity protocol (Random) at baseline, after 3 weeks of overload training, and after a 2-week taper. Magnitudes of changes in total, lean and fat mass from baseline-overload, overload-taper and baseline-taper were assessed by standardization (Δmean/SD). The standard deviations of change scores for total and fat-free soft tissue mass (FFST) from Random scans (2-3%) were approximately double those observed in the Best (1-2%), owing to extra random errors associated with Random scans at baseline. There was little difference in change scores for fat mass. The effect of cold water immersion therapy on baseline-taper changes in FFST was possibly harmful (-0.7%; 90% confidence limits ±1.2%) with Best scans but unclear with Random scans (0.9%; ±2.0%). Both protocols gave similar possibly harmful effects of cold water immersion therapy on changes in fat mass (6.9%; ±13.5% and 5.5%; ±14.3%, respectively). An interesting effect of cold water immersion therapy on training-induced changes in body composition might have been missed with a less precise scanning protocol. DXA scans should be undertaken with Best.


Pharmacokinetic and Safety Evaluation of Various Oral Doses of a Novel 1:20 THC:CBD Cannabis Herbal Extract in Dogs.
Objective: To determine the pharmacokinetics (PK) and safety of various oral doses of a Cannabis herbal extract (CHE) containing a 1:20 ratio of Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) in 13 healthy Beagle-cross dogs. Methods: Single-dose PK was assessed after oral administration of CHE at low, medium, or high doses [2, 5, or 10 mg CBD and 0.1, 0.25, or 0.5 mg THC per kg of body weight (bw), respectively; n = 6 per group]. Dogs were monitored for adverse events for up to 48 h post-dose. Evaluations of neurological signs, clinical laboratory abnormalities, and other adverse events were performed in two separate study phases: a multiple-dose phase with 12 dogs receiving five medium doses (5 mg CBD/kg bw) at 12 h intervals, and a single low-dose (2 mg CBD/kg bw), randomized, blinded, negative controlled study with 13 dogs. Results: Cannabinoids CBD, THC, CBC, and metabolites 6-OH-CBD, 7-OH-CBD, 11-OH-THC, and THC-COOH were quantified in plasma. CBD and THC were rapidly absorbed (mean T max of 1.9-2.3 h) and initially depleted rapidly (mean CBD T 1/2β of 2.3-2.6 h). A prolonged elimination phase (mean CBD T 1/2λ of 13.3-24.4 h) was observed. CBD and THC concentrations increased in a dose-dependent (non-linear) manner, with disproportionally greater cannabinoid exposure relative to the dose increase. Neurological signs (hyperesthesia or proprioceptive deficits) were noted in five of six dogs in the high-dose group, but only occasionally or rarely in the medium- and low-dose groups, respectively. Presence and severity of clinical signs correlated with plasma cannabinoid concentrations. Dogs appeared to develop a tolerance to cannabinoid effects after multiple CHE doses, with fewer neurological signs noted after the final (fifth) vs. first dose. No clinically meaningful changes in blood count or chemistry values occurred after multiple CHE doses. Clinical Significance: Dogs tolerated the 1:20 THC:CBD formulation well at low and medium doses, but clinically meaningful neurological signs were observed at high doses. Because of non-proportional increases in plasma cannabinoid concentrations with increasing doses, as well as potential differences in CHE product composition and bioavailability, the possibility of adverse events and dose regimen consistency should be discussed with dog owners.


Effects of In Utero Exposure to Perfluorooctane Sulfonate on Placental Functions.
Perfluorooctane sulfonate (PFOS) is a metabolic-disrupting chemical. There is a strong association between maternal and cord blood PFOS concentrations, affecting metabolism in early life. However, the underlying effects have not been fully elucidated. In this study, using the maternal-fetal model, we investigated the impact of gestational PFOS exposure on the placental structure and nutrient transport. Pregnant mice were oral gavaged with PFOS (1 or 3 μg PFOS/g body weight) from gestational day (GD) 4.5 until GD 17.5. Our data showed a significant reduction in fetal body weight at high dose exposure. There were no noticeable changes in placental weights and the relative areas of junctional and labyrinth zones among the control and exposed groups. However, a placental nutrient transport assay showed a significant reduction in maternal-fetal transport of the glucose and amino acid analogues. Western blot analysis showed a significant decrease in the expression levels of placental SNAT4 upon PFOS exposure. Moreover, in the high-dose exposed group, placenta and fetal livers were found to have significantly higher corticosterone levels, a negative regulator of fetal growth. The perturbation in the placental transport function and corticosterone levels accounted for the PFOS-induced reduction of fetal body weights.


Scaling-up the Xpert MTB/RIF assay for the detection of tuberculosis and rifampicin resistance in India: An economic analysis.
India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India. Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients. The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US$ 1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert-for-all scenario (US$ 11,099). The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care.


Sleep duration change across breast cancer survivorship: associations with symptoms and health-related quality of life.
Sleep duration among breast cancer survivors correlates with fatigue, depression, and health-related quality of life (HRQOL); however, this has not been studied longitudinally. This study investigated patterns of sleep duration change across the early breast cancer survivorship period, their demographic and clinical predictors, and their relationships with subsequent cancer-related symptoms and HRQOL. Breast cancer survivors (n = 572), were assessed 6 months post-diagnosis (current sleep & retrospective reports of pre-diagnosis sleep), 30 months post-diagnosis (sleep), and 39 months post-diagnosis (symptoms, HRQOL). Sleep duration change was determined by examining sleep at each time point in relation to published norms. Analysis of variance and logistic regression models tested demographic and clinical differences between the sleep change groups; linear regression models tested differences in symptoms and HRQOL. Half of the survivors reported no sleep duration change over time; however, 25% reported sleep changes indicating a temporary (5.6%), late-occurring (14%), or sustained (5.9%) change. Survivors reporting sustained or temporary sleep changes were more likely to have been treated with chemotherapy (OR = 2.62, P < 0.001) or gained weight after diagnosis (OR = 1.82, P = 0.04) than those with no sleep change. Sustained sleep changes were related to greater subsequent severity, affective, and sensory aspects of fatigue (βs = 2.0, 2.3, 1.8; all P < 0.0001) and lower vitality (β = -10.8, P = 0.005). Survivors treated with chemotherapy and those who gain weight after diagnosis may have increased risk for sustained sleep duration changes, which may increase their fatigue. These results point to the need for routine assessment of sleep as part of survivorship care.


Glycated hemoglobin measurement and prediction of cardiovascular disease.
The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk. During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.


DNA replication in thermophiles.
DNA replication enzymes in the thermophilic Archaea have previously attracted attention due to their obvious use in methods such as PCR. The proofreading ability of the Pyrococcus furiosus DNA polymerase has resulted in a commercially successful product (Pfu polymerase). One of the many notable features of the Archaea is the fact that their DNA processing enzymes appear on the whole to be more like those found in eukaryotes than bacteria. These proteins also appear to be simpler versions of those found in eukaryotes. For these reasons, archaeal organisms make potentially interesting model systems to explore the molecular mechanisms of processes such as DNA replication, repair and recombination. Why archaeal DNA-manipulation systems were adopted over bacterial systems by eukaryotic cells remains a most interesting question that we suggest may be linked to thermophily.


Endovascular repair of abdominal aortic aneurysm: an evidence-based analysis.
The Medical Advisory Secretariat conducted a systematic review of the evidence on the effectiveness and cost-effectiveness of endovascular repair of abdominal aortic aneurysm in comparison to open surgical repair. An abdominal aortic aneurysm [AAA] is the enlargement and weakening of the aorta (major blood artery) that may rupture and result in stroke and death. Endovascular abdominal aortic aneurysm repair [EVAR] is a procedure for repairing abdominal aortic aneurysms from within the blood vessel without open surgery. In this procedure, an aneurysm is excluded from blood circulation by an endograft (a device) delivered to the site of the aneurysm via a catheter inserted into an artery in the groin. The Medical Advisory Secretariat conducted a review of the evidence on the effectiveness and cost-effectiveness of this technology. The review included 44 eligible articles out of 489 citations identified through a systematic literature search. Most of the research evidence is based on non-randomized comparative studies and case series. In the short-term, EVAR appears to be safe and comparable to open surgical repair in terms of survival. It is associated with less severe hemodynamic changes, less blood transfusion and shorter stay in the intensive care and hospital. However, there is concern about a high incidence of endoleak, requiring secondary interventions, and in some cases, conversion to open surgical repair. Current evidence does not support the use of EVAR in all patients. EVAR might benefit individuals who are not fit for surgical repair of abdominal aortic aneurysm and whose risk of rupture of the aneurysm outweighs the risk of death from EVAR. The long-term effectiveness and cost-effectiveness of EVAR cannot be determined at this time. Further evaluation of this technology is required. The objective of this health technology policy assessment was to determine the effectiveness and cost-effectiveness of endovascular repair of abdominal aortic aneurysms (EVAR) in comparison to open surgical repair (OSR). An abdominal aortic aneurysm (AAA) is a localized, abnormal dilatation of the aorta greater than 3 cm or 50% of the aortic diameter at the diaphragm. (1) A true AAA involves all 3 layers of the vessel wall. If left untreated, the continuing extension and thinning of the vessel wall may eventually result in rupture of the AAA. The risk of death from ruptured AAA is 80% to 90%. (61) Heller et al. (44) analyzed information from a national hospital database in the United States. They found no significant change in the incidence rate of elective AAA repair or ruptured AAA presented to the nation's hospitals. The investigators concluded that technologic and treatment advances over the past 19 years have not affected the outcomes of patients with AAAs, and the ability to identify and to treat patients with AAAs has not improved. At least 90% of the AAAs are affected by atherosclerosis, and most of these aneurysms are below the level of the renal arteries.(1) An abdominal aortic aneurysm may be symptomatic or asymptomatic. An AAA may be classified according to their sizes:(7) SMALL ANEURYSMS: less than 5 cm in diameter.MEDIUM ANEURYSMS: 5-7cm.LARGE ANEURYSMS: more than 7 cm in diameter.Small aneurysms account for approximately 50% of all clinically recognized aneurysms.(7) Aortic aneurysms may be classified according to their gross appearance as follows (1): Fusiform aneurysms affect the entire circumference of a vessel, resulting in a diffusely dilated lesionSaccular aneurysms involve only a portion of the circumference, resulting in an outpouching (protrusion) in the vessel wall. In community surveys, the prevalence of AAA is reported to be between 1% and 5.4%. (61) The prevalence is related to age and vascular risk factors. It is more common in men and in those with a positive family history. In Canada, Abdominal aortic aneurysms are the 10(th) leading cause of death in men 65 years of age or older. (60) Naylor (60) reported that the rate of AAA repair in Ontario has increased from 38 per 100,000 population in 1981/1982 to 54 per 100,000 population in 1991/1992. For the period of 1989/90 to 1991/92, the rate of AAA repair in Ontarians age 45 years and over was 53 per 100,000. (60) In the United States, about 200,000 new cases are diagnosed each year, and 50,000 to 60,000 surgical AAA repairs are performed. (2) Ruptured AAAs are responsible for about 15,000 deaths in the United States annually. One in 10 men older than 80 years has some aneurysmal change in his aorta. (2) SYMPTOMS OF ABDOMINAL AORTIC ANEURYSMS: AAAs usually do not produce symptoms. However, as they expand, they may become painful. Compression or erosion of adjacent tissue by aneurysms also may cause symptoms. The formation of mural thrombi, a type of blood clots, within the aneurysm may predispose people to peripheral embolization, where blood vessels become blocked. Occasionally, an aneurysm may leak into the vessel wall and the periadventitial area, causing pain and local tenderness. More often, acute rupture occurs without any prior warning, causing acute pain and hypotension. This complication is always life-threatening and requires an emergency operation. An AAA is usually detected on routine examination as a palpable, pulsatile, and non-tender mass. (1) Abdominal radiography may show the calcified outline of the aneurysms; however, about 25% of aneurysms are not calcified and cannot be visualized by plain x-ray. (1) An abdominal ultrasound provides more accurate detection, can delineate the traverse and longitudinal dimensions of the aneurysm, and is useful for serial documentation of aneurysm size. Computed tomography and magnetic resonance have also been used for follow-up of aortic aneurysms. These technologies, particularly contrast-enhanced computer tomography, provide higher resolution than ultrasound. Abdominal aortography remains the gold standard to evaluate patients with aneurysms for surgery. This technique helps document the extent of the aneurysms, especially their upper and lower limits. It also helps show the extent of associated athereosclerotic vascular disease. However, the procedure carries a small risk of complications, such as bleeding, allergic reactions, and atheroembolism. (1) PROGNOSIS OF ABDOMINAL AORTIC ANEURYSMS: The risk of rupture of an untreated AAA is a continuous function of aneurysm size as represented by the maximal diameter of the AAA. The annual rupture rate is near zero for aneurysms less than 4 cm in diameter. The risk is about 1% per year for aneurysms 4 to 4.9 cm, 11% per year for aneurysms 5 to 5.9 cm, and 25% per year or more for aneurysms greater than 6 cm. (7) The 1-year mortality rate of patients with AAAs who do not undergo surgical treatment is about 25% if the aneurysms are 4 to 6 cm in diameter. This increases to 50% for aneurysms exceeding 6 cm. Other major causes of mortality for people with AAAs include coronary heart disease and stroke. Treatment of an aneurysm is indicated under any one of the following conditions: The AAA is greater than 6 cm in diameter.The patient is symptomatic.The AAA is rapidly expanding irrespective of the absolute diameter.Open surgical repair of AAA is still the gold standard. It is a major operation involving the excision of dilated area and placement of a sutured woven graft. The surgery may be performed under emergent situation following the rupture of an AAA, or it may be performed electively. Elective OSR is generally considered appropriate for healthy patients with aneurysms 5 to 6 cm in diameter. (7) Coronary artery disease is the major underlying illness contributing to morbidity and mortality in OSR. Other medical comorbidities, such as chronic renal failure, chronic lung disease, and liver cirrhosis with portal hypertension, may double or triple the usual risk of OSR. Serial noninvasive follow-up of small aneurysms (less than 5 cm) is an alternative to immediate surgery. Endovascular repair of AAA is the third treatment option and is the topic of this review.


A lignocellulosic ethanol strategy via nonenzymatic sugar production: process synthesis and analysis.
The work develops a strategy for the production of ethanol from lignocellulosic biomass. In this strategy, the cellulose and hemicellulose fractions are simultaneously converted to sugars using a γ-valerolactone (GVL) solvent containing a dilute acid catalyst. To effectively recover GVL for reuse as solvent and biomass-derived lignin for heat and power generation, separation subsystems, including a novel CO2-based extraction for the separation of sugars from GVL, lignin and humins have been designed. The sugars are co-fermented by yeast to produce ethanol. Furthermore, heat integration to reduce utility requirements is performed. It is shown that this strategy leads to high ethanol yields and the total energy requirements could be satisfied by burning the lignin. The integrated strategy using corn stover feedstock leads to a minimum selling price of $5 per gallon of gasoline equivalent, which suggests that it is a promising alternative to current biofuels production approaches.