Elements of the polycomb repressor SU(Z)12 needed for histone H3-K27 methylation, the interface with E(Z), and in vivo function.
Polycomb repressive complex 2 (PRC2) is an essential chromatin-modifying enzyme that implements gene silencing. PRC2 methylates histone H3 on lysine-27 and is conserved from plants to flies to humans. In Drosophila melanogaster, PRC2 contains four core subunits: E(Z), SU(Z)12, ESC, and NURF55. E(Z) bears a SET domain that houses the enzyme active site. However, PRC2 activity depends upon critical inputs from SU(Z)12 and ESC. The stimulatory mechanisms are not understood. We present here functional dissection of the SU(Z)12 subunit. SU(Z)12 contains two highly conserved domains: an ∼140-amino-acid VEFS domain and a Cys2-His2 zinc finger (ZnF). Analysis of recombinant PRC2 bearing VEFS domain alterations, including some modeled after leukemia mutations, identifies distinct elements needed for SU(Z)12 assembly with E(Z) and stimulation of histone methyltransferase. The results define an extensive VEFS subdomain that organizes the SU(Z)12-E(Z) interface. Although the SU(Z)12 ZnF is not needed for methyltransferase in vitro, genetic rescue assays show that the ZnF is required in vivo. Chromatin immunoprecipitations reveal that this ZnF facilitates PRC2 binding to a genomic target. This study defines functionally critical SU(Z)12 elements, including key determinants of SU(Z)12-E(Z) communication. Together with recent findings, this illuminates PRC2 modulation by conserved inputs from its noncatalytic subunits.


Ligand exchange based paraoxon imprınted QCM sensor.
In the present work, a paraoxon imprinted QCM sensor has been developed for the determination of paraoxon based on the modification of paraoxon imprinted film onto a quartz crystal combining the advantages of high selectivity of the piezoelectric microgravimetry using MIP film technique and high sensitivity of QCM detection. The paraoxon selective memories have formed on QCM electrode surface by using a new metal-chelate interaction based on pre-organized monomer and the paraoxon recognition activity of these molecular memories was investigated. Molecular imprinted polymer (MIP) film for the detection of paraoxon was developed and the analytical performance of paraoxon imprinted sensor was studied. The molecular imprinted polymer were characterized by FTIR measurements. Paraoxon imprinted sensor was characterized with AFM and ellipsometer. The study also includes the measurement of binding interaction of paraoxon imprinted quartz crystal microbalance (QCM) sensor, selectivity experiments and analytical performance of QCM electrode. The detection limit and the affinity constant (K(affinity)) were found to be 0.06 μM and 2.25 × 10(4) M(-1) for paraoxon [MAAP-Cu(II)-paraoxon] based thin film, respectively. Also, it has been observed that the selectivity of the prepared paraoxon imprinted sensor is high compared to a similar chemical structure which is parathion.


Mechanism of decrease in heart rate by peripheral dopaminergic D2-receptors.
We performed this study in order to verify the heart rate decrease caused by the D2-receptor on cardiac sympathetic nerve endings and its relation to the concentration of norepinephrine in synaptic clefts. Sprague-Dawley rats were pithed and the heart rate was increased either by electrical stimulation of the cardiac accelerator nerve or by intravenous infusion of norepinephrine, tyramine, or isoproterenol. Increased heart rate by electrical stimulation of cardiac accelerator nerve was dose-dependently lowered by lisuride and its effect was blocked by pretreatment with sulpiride but not with yohimbine and SCH 23390. Also, the heart rate was decreased in a dose-dependent manner by clonidine and this effect was blocked by pretreatment with yohimbine, but not with sulpiride. For increased heart rate by infusion of norepinephrine, tyramine, or isoproterenol, the heart rate lowering effect of lisuride was more marked in the norepinephrine-and tyramine-infusion groups, in which the intrasynaptic concentration of norepinephrine was elevated, compared to the isoproterenol-infusion group, in which intrasynaptic concentration of norepinephrine was not elevated. In conclusion, there is a D2-receptor on the cardiac sympathetic nerve endings which decreases the heart rate and is different from the presynaptic alpha 2-receptor. Also, the heart rate lowering effect via stimulation of the D2-receptor by lisuride was more marked with increased concentration of norepinephrine in the synaptic cleft.


Antenatal bowel dilatation in gastroschisis: a bad sign?
Foetal bowel dilatation in gastroschisis is traditionally taken to be an indicator of poor prognosis and parents are counselled accordingly. Increased bowel distension is often a factor in the decision for early delivery. The aim of this study was to establish whether a correlation exists between antenatally detected bowel dilatation and the postnatal outcome for babies with gastroschisis. Antenatal ultrasound scans and subsequent postnatal notes were reviewed for cases of isolated gastroschisis from 2004 to 2008. Bowel dilatation was defined as >10 mm diameter. The type (intra- and/or extra-abdominal dilatation), maximum bowel diameter and gestation at which bowel dilatation was first seen was recorded. Outcome measures included number of days of TPN, type of closure (primary or delayed) and postnatal complications. There were 60 antenatal cases of gastroschisis over 5 years. Postnatal notes of 47 were obtained. 38 (81%) had antenatal bowel dilatation, 9 did not. Of those with bowel dilatation, 24 underwent primary closure, 9 required silos, 2 a patch and 3 stomas. Seven (15%) had bowel atresia or necrosis. Three died: NEC, septicaemia and CMV hepatitis. The average time on TPN for those without major complications was 22 days. Of those with no bowel dilatation, 4 had primary closure, 3 a silo, 1 a patch and 1 a stoma. Two had complications requiring further surgery, including one atresia resulting in short gut syndrome. There were no deaths. The mean number of days on TPN was 23. The results also demonstrated no significant correlation between gestation when dilatation was first seen, or degree of dilatation, or both these factors combined, and time of TPN requirement. These results do not support the current practice of using antenatal bowel dilatation as a prognostic indicator.


Characterization of fatty acid esters of okadaic acid and related toxins in blue mussels (Mytilus edulis) from Norway.
Marine algal toxins of the okadaic acid group can occur as fatty acid esters in blue mussels, and are commonly determined indirectly by transformation to their parent toxins by alkaline hydrolysis. Some data are available regarding the identity of the fatty acid esters, mainly of palmitic acid (16:0) derivatives of okadaic acid (OA), dinophysistoxin-1 (DTX1) and dinophysistoxin-2 (DTX2). Other fatty acid derivatives have been described, but with limited mass spectral data. In this paper, the mass spectral characterization of the [M-H](-) and [M+Na](+) ions of 16 fatty acid derivatives of each of OA, DTX1 and DTX2 is presented. The characteristic fragmentation of [M+Na](+) ions of OA analogues provided a useful tool for identifying these, and has not been described previously. In addition, a set of negative ion multiple reaction monitoring (MRM) methods was developed for direct determination of 16 fatty acid esters of OA, 16 fatty acid esters of DTX1 and 16 fatty acid esters of DTX2 in shellfish extracts. The MRM methods were employed to study the profiles of fatty acid esters of OA analogues in blue mussels and to compare these with fatty acid ester profiles reported for other groups of marine algal toxins.


Vision: keeping the world still when the eyes move.
A long-standing problem for visual science is how the world remains so apparently stable in the face of continual rapid eye movements. New experimental evidence, and computational models are helping to solve this mystery.


Cognitive rehabilitation training in patients with brain tumor-related epilepsy and cognitive deficits: a pilot study.
The aim of this pilot observational study was to evaluate effect of cognitive rehabilitation training (RehabTr) on cognitive performances in patients with brain tumor-related epilepsy (BTRE) and cognitive disturbances. Medical inclusion criteria: patients (M/F) ≥ 18 years ≤ 75 with symptomatic seizures due to primary brain tumors or brain metastases in stable treatment with antiepileptic drugs; previous surgical resection or biopsy; >70 Karnofsky Performance Status; stable oncological disease. Eligible patients recruited from 100 consecutive patients with BTRE at first visit to our Center from 2011 to 2012. All recruited patients were administered battery of neuropsychological tests exploring various cognitive domains. Patients considered to have a neuropsychological deficit were those with at least one test score for a given domain indicative of impairment. Thirty patients out of 100 showed cognitive deficits, and were offered participation in RehabTr, of which 16 accepted (5 low grade glioma, 4 high grade glioma, 2 glioblastoma, 2 meningioma and 3 metastases) and 14 declined for various reasons. The RehabTr consisted of one weekly individual session of 1 h, for a total of 10 weeks, carried out by a trained psychologist. The functions trained were: memory, attention, visuo-spatial functions, language and reasoning by means of Training NeuroPsicologico (TNP(®)) software. To evaluate the effect of the RehabTr, the same battery of tests was administered directly after cognitive rehabilitation (T1), and at six-month follow-up (T2). Statistical analysis with Student T test for paired data showed that short-term verbal memory, episodic memory, fluency and long term visuo-spatial memory improved immediately after the T1 and remained stable at T2. At final follow-up all patients showed an improvement in at least one domain that had been lower than normal at baseline. Our results demonstrated a positive effect of rehabilitative training at different times, and, for these reasons, should encourage future research in this area with large, randomized clinical trials that evaluate the impact of a cognitive rehabilitation in patients with BTRE and cognitive deficits.


Effects of right atrial distension on the activity of magnocellular neurons in the supraoptic nucleus.
A small balloon placed at the junction of the superior vena cava and right atrium was used to stimulate cardiac volume receptors in pentobarbital sodium-anesthetized male rats. Extracellular recordings were obtained from antidromically identified vasopressinergic and oxytocinergic neurosecretory cells of the supraoptic nucleus. Cells were considered sensitive to the stimulus if balloon inflation resulted in a 30% change in firing frequency. Balloon inflation that did not stretch the caval-atrial junction had no significant effect on vasopressin neurons (n = 51, P > 0.05). Stretch of the caval-atrial junction decreased the firing activity in 64 of 83 putative vasopressin neurons (P < 0.01 compared with control). Stretch of the caval-atrial junction influenced the firing activity of only 3 of 26 antidromically activated oxytocinergic neurons, an effect not statistically different from control (P > 0. 05). When bilateral vagotomy was performed while recording from vasopressin neurons (n = 5), sensitivity to stretch of the caval-atrial junction was eliminated. Cardiac receptors located at the junction of the superior vena cava and right atrium may be important in regulating the activity of vasopressinergic but not oxytocinergic neurons of the supraoptic nucleus.


Demequina aestuarii gen. nov., sp. nov., a novel actinomycete of the suborder Micrococcineae, and reclassification of Cellulomonas fermentans Bagnara et al. 1985 as Actinotalea fermentans gen. nov., comb. nov.
An actinobacterial strain containing demethylmenaquinone DMK-9(H(4)) as the diagnostic isoprenoid quinone was isolated from a tidal flat sediment sample, from South Korea. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain JC2054(T) represents a distinct phyletic line within the suborder Micrococcineae of the order Actinomycetales. The closest phylogenetic neighbour was Cellulomonas fermentans, with 94.7 % 16S rRNA gene sequence similarity. The novel isolate was strictly aerobic and slightly halophilic, with optimum growth occurring in 2-4 % (w/v) NaCl. Cells were non-motile, non-sporulating and rod-shaped. The peptidoglycan type was of the A-type of cross-linkage. l-ornithine was the diamino acid and d-glutamate represented the N-terminus of the interpeptide bridge. The predominant fatty acids were anteiso-branched and straight-chain fatty acids. The major polar lipids were phosphatidylinositol, diphosphatidylglycerol and an unknown phospholipid. The menaquinone composition of C. fermentans was determined to be MK-10(H(4)), MK-9(H(4)) and MK-8(H(4)) in the ratio 56 : 2 : 1. On the basis of the polyphasic evidence presented in this study, it is proposed that strain JC2054(T) should be classified as representing a novel genus and species of the suborder Micrococcineae, with the name Demequina aestuarii gen. nov., sp. nov. The type strain is JC2054(T) (=IMSNU 14027(T)=KCTC 9919(T)=JCM 12123(T)). In addition, it was clear from the phylogenetic analysis and chemotaxonomic data that C. fermentans does not belong to the genus Cellulomonas or any other recognized genera. Therefore, C. fermentans should be reclassified as representing a novel genus, for which the name Actinotalea fermentans gen. nov., comb. nov. is proposed, with strain DSM 3133(T) (=ATCC 43279(T)=CFBP 4259(T)=CIP 103003(T)=NBRC 15517(T)=JCM 9966(T)=LMG 16154(T)) as the type strain.


A new plane grating monochromator with off-axis paraboloids and curved slits.
A design for a new plane grating monochromator is described. The system employs a symmetrical configuration of off-axis paraboloids for both the collimator and camera mirrors. The entrance and exit slits are mounted on the same side of the grating and are curved in order to eliminate wavelength errors due to spectral line curvature. There is, in fact, a remarkable coincidence between the curvature which is required to avoid wavelength errors and the curvature which is required to obtain equal curvatures in the object and image planes. Ray tracing calculations for a symmetrical configuration of off-axis paraboloids show that the image of a curved slit with a length equal to 0.05 times the focal length of an f/5 mirror is diffraction limited for wavelengths lambda > 0.2 . micro.


Acute Obstructive Hydrocephalus due to a Giant Posterior Cerebral Artery Aneurysm in a Pediatric Patient.
Intracranial aneurysms are very rare in children. Although subarachnoidal hemorrhage (SAH) is by far the most common presentation of aneurysms in the majority of the pediatric case series, it is not rare for an unruptured aneurysm to present with a mass effect. Acute hydrocephalus is a common finding following aneurysmal SAH. However, this malady may develop even in the absence of SAH but secondary to direct obstruction by a giant aneurysm. This situation is extremely rare in children, with only a few known case reports in the literature. We report the case of a 10-year-old girl who presented with signs and symptoms of acute hydrocephalus; further radiological evaluation revealed obstructive hydrocephalus and a giant posterior cerebral artery aneurysm. Following endovascular treatment of the aneurysm, hydrocephalus was completely resolved, and the patient was symptom free. Although they are very rare, giant intracranial aneurysms must be kept in mind during the differential diagnosis of pediatric acute hydrocephalus cases. Hydrocephalus may resolve spontaneously after the successful treatment of these aneurysms.


Ex Vivo Perfusion With Methylprednisolone Attenuates Brain Death-induced Lung Injury in Rats.
The onset of brain death (BD) leads to the deterioration of potential donor lungs. Methylprednisolone is considered to increase lung oxygenation capacity and enhance the procurement yield of donor lungs, when applied in situ, during donor management. However, whether BD-induced lung damage is ameliorated upon treatment with methylprednisolone during acellular ex vivo lung perfusion (EVLP), remains unknown. We aimed to investigate whether the quality of lungs from brain-dead donors improves upon methylprednisolone treatment during EVLP. Rat lungs were randomly assigned to 1 of 3 experimental groups (n = 8/group): (1) healthy, directly procured lungs subjected to EVLP; (2) lungs from brain-dead rats subjected to cold storage and EVLP; and (3) lungs from brain-dead rats subjected to cold storage and EVLP with 40 mg methylprednisolone added to the perfusate. Ventilation and perfusion parameters, histology, edema formation, metabolic profile, and inflammatory status of lungs were investigated. Methylprednisolone treated lungs from brain-dead donors improved positive inspiratory pressures needed to maintain tidal volumes of 7 mL/kg of body weight, which was 25.6 ± 5.8 cm H2O in untreated lungs and 18.0 ± 3.0 cm H2O in methylprednisolone treated lungs, after 6 h EVLP. Furthermore, dynamic lung compliance increased upon methylprednisolone treatment, with values of 0.11 ± 0.05 mL/cm H2O versus 0.18 ± 0.04 mL/cm H2O after 6 h of EVLP. Methylprednisolone treatment ameliorated the amount of lung edema, as corroborated by a reduction of 0.7 in the wet/dry ratio. Although glucose consumption levels were comparable, the BD-induced cumulative lactate production decreased from 0.44 ± 0.26 to 0.11 ± 0.16 mmol/L upon methylprednisolone treatment. Finally, BD-induced inflammatory status was reduced upon methylprednisolone treatment compared to untreated lungs from brain-dead donors, as reflected by lower proinflammatory gene expression levels of IL-1β, IL-6 and MCP-1, and IL-6 perfusate levels. We showed that methylprednisolone treatment during EVLP attenuates BD-induced lung injury.


Public knowledge, beliefs, and treatment preferences concerning attention-deficit hyperactivity disorder.
This study aimed to understand the level of public knowledge about attention-deficit hyperactivity disorder (ADHD), treatment preferences for the disorder, and their sociodemographic correlates. A short battery of questions about ADHD was included in the 2002 General Social Survey (N=1,139). In face-to-face interviews, respondents answered questions about whether they had heard of ADHD, what they knew about ADHD, their beliefs about whether ADHD is a "real" disease, and opinions about whether children with ADHD should be offered counseling or medication. Just under two-thirds of respondents (64%) had heard of ADHD; most could not provide detailed information about the disorder. Women and those with higher levels of education were more likely to have heard of ADHD; African Americans, members of other nonwhite racial and ethnic groups, and older respondents were less likely to have heard of ADHD. Among respondents who had heard of ADHD, 78% said they believed ADHD to be a real disease; women, white respondents, and persons with higher income most often endorsed that belief. Most respondents (65%) endorsed the use of both counseling and medication, although counseling was endorsed as a sole treatment more often than medication. There were few sociodemographic differences in treatment preferences. The public is not well informed about ADHD. Future media and educational efforts should seek to provide accurate information about ADHD, with a special effort to reach specific populations such as men, nonwhite minority groups, and older Americans.


Surgical site infection in women undergoing surgery for gynecologic cancer.
The objectives of this study were to describe the rate and predictors of surgical site infection (SSI) after gynecologic cancer surgery and identify any association between SSI and postoperative outcome. Patients with endometrial, cervical, or ovarian cancers from 2005 to 2011 were identified from the American College of Surgeons National Surgical Quality Improvement Program. The extent of surgical intervention was categorized into modified surgical complexity scoring (MSCS) system. Univariate and multivariate logistic regression analyses were used. Odds ratios were adjusted for patient demographics, comorbidities, preoperative laboratory values, and operative factors. Of 6854 patients, 369 (5.4%) were diagnosed with SSI. Surgical site infection after laparotomy was 3.5 times higher compared with minimally invasive surgery (7% vs 2%; P < 0.001). Among laparotomy group, independent predictors of SSI included endometrial cancer diagnosis, obesity, ascites, preoperative anemia, American Society of Anesthesiologists class greater than or equal to 3, MSCS greater than or equal to 3, and perioperative blood transfusion. Among laparoscopic cases, independent predictors of SSI included only preoperative leukocytosis and overweight. For patients with deep or organ space SSI, significant predictors included hypoalbuminemia, preoperative weight loss, respiratory comorbidities, MSCS greater than 4, and perioperative blood transfusion for laparotomy and only preoperative leukocytosis for minimally invasive surgery. Surgical site infection was associated with longer mean hospital stay and higher rate of reoperation, sepsis, and wound dehiscence. Surgical site infection was not associated with increased risk of acute renal failure or 30-day mortality. These findings were consistent in subset of patients with deep or organ space SSI. Seven percent of patients undergoing laparotomy for gynecologic malignancy developed SSI. Surgical site infection is associated with longer hospital stay and more than 5-fold increased risk of reoperation. In this study, we identified several risk factors for developing SSI among gynecologic cancer patients. These findings may contribute toward identification of patients at risk for SSI and the development of strategies to reduce SSI rate and potentially reduce the cost of care in gynecologic cancer surgery.


Core temperature up to 41.5ºC during the UCI Road Cycling World Championships in the heat.
To characterise the core temperature response and power output profile of elite male and female cyclists during the 2016 UCI Road World Championships. This may contribute to formulating environmental heat stress policies. Core temperature was recorded via an ingestible capsule in 10, 15 and 15 cyclists during the team time trial (TTT), individual time trial (ITT) and road race (RR), respectively. Power output and heart rate were extracted from individual cycling computers. Ambient conditions in direct sunlight were hot (37°C±3°C) but dry (25%±16% relative humidity), corresponding to a wet-bulb globe temperature of 27°C±2°C. Core temperature increased during all races (p<0.001), reaching higher peak values in TTT (39.8°C±0.9°C) and ITT (39.8°C±0.4°C), relative to RR (39.2°C±0.4°C, p<0.001). The highest temperature recorded was 41.5°C (TTT). Power output was significantly higher during TTT (4.7±0.3 W/kg) and ITT (4.9±0.5 W/kg) than RR (2.7±0.4 W/kg, p<0.001). Heart rate increased during the TTs (p<0.001) while power output decreased (p<0.001). 85% of the cyclists participating in the study (ie, 34 of 40) reached a core temperature of at least 39°C with 25% (ie, 10 of 40) exceeding 40°C. Higher core temperatures were reached during the time trials than the RR.


Indoor, outdoor, and night work and blood concentrations of vitamin D and parathyroid hormone.
Objectives The aim of this study was to examine blood concentrations of 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) among indoor, outdoor, permanent and rotating night workers and the association with hours spent outdoors on and off work days. Methods Blood samples were collected from 425 workers (162 indoor, 112 outdoor, 118 rotating night and 33 permanent night workers) throughout all seasons. Serum concentrations of 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were analyzed by isotope dilution liquid chromatography-tandem mass spectrometry (LC MS/MS) and an automated immune analyzer, respectively. Personal light exposure levels were continuously recorded and used to estimate hours spent outdoors (all workers). Results Permanent night workers had 25.3% (95% CI 11.9-36.6) lower 25OHD concentration, 4.55 (95% CI 1.39-14.94) higher odds of vitamin D insufficiency (<50 nmol/L) and 14.5% [95% confidence interval (CI) 0.1-31.1] higher PTH concentration than indoor workers. Outdoor workers had similar 25OHD concentrations but 7.5% (95% CI -0.5-14.9) lower PTH concentration compared to indoor workers. Rotating night workers 25OHD and PTH concentrations did not differ from indoor workers. Concentration of 25OHD increased by 5.2% (95% CI 1.1-9.5) per hour spent outdoor at workdays in the summer. Conclusion Clinicians should be aware that vitamin D insufficiency may be more prevalent among permanent night workers and human resources should consider the positive effect of allowing workers to spend time outdoor during work hours.


A Practical Method to Implement Strain-Level Metagenomics-Based Foodborne Outbreak Investigation and Source Tracking in Routine.
The management of a foodborne outbreak depends on the rapid and accurate identification of the responsible food source. Conventional methods based on isolation of the pathogen from the food matrix and target-specific real-time polymerase chain reactions (qPCRs) are used in routine. In recent years, the use of whole genome sequencing (WGS) of bacterial isolates has proven its value to collect relevant information for strain characterization as well as tracing the origin of the contamination by linking the food isolate with the patient's isolate with high resolution. However, the isolation of a bacterial pathogen from food matrices is often time-consuming and not always successful. Therefore, we aimed to improve outbreak investigation by developing a method that can be implemented in reference laboratories to characterize the pathogen in the food vehicle without its prior isolation and link it back to human cases. We tested and validated a shotgun metagenomics approach by spiking food pathogens in specific food matrices using the Shiga toxin-producing Escherichia coli (STEC) as a case study. Different DNA extraction kits and enrichment procedures were investigated to obtain the most practical workflow. We demonstrated the feasibility of shotgun metagenomics to obtain the same information as in ISO/TS 13136:2012 and WGS of the isolate in parallel by inferring the genome of the contaminant and characterizing it in a shorter timeframe. This was achieved in food samples containing different E. coli strains, including a combination of different STEC strains. For the first time, we also managed to link individual strains from a food product to isolates from human cases, demonstrating the power of shotgun metagenomics for rapid outbreak investigation and source tracking.


Web-centred training in psychological treatments: a study of therapist preferences.
One barrier to the dissemination of evidence-based psychological treatments is the fact that few clinicians have received training in how to implement them. A potential solution is "web-centred training". For any training programme to be successful it must match the perceived needs of the trainee as otherwise there is likely to be poor compliance. As part of the groundwork for developing a web-centred training program, a questionnaire on training preferences was sent to 373 therapists who had expressed interest in the website, of whom 183 responded. Their top priorities were a clinically relevant website that demonstrated in detail how to implement the treatment. The overall characteristics and functioning of the website were also a major concern. There was little interest in being put in touch with others learning the treatment. These findings demonstrate the importance of surveying users' views in advance of and during the website development process.


Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis.
Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP. We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants. In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001). Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.


Multicenter experience with endovascular treatment of aortic coarctation in adults.
The objective of this study was to evaluate outcomes of endovascular treatment of aortic coarctation in adults. Clinical data and imaging studies of 93 consecutive patients treated at nine institutions from 1999 to 2015 were reviewed. We included newly diagnosed aortic coarctation (NCO), recurrent coarctation, and aneurysmal/pseudoaneurysmal degeneration (ANE) after prior open surgical repair (OSR) of coarctation. Primary end points were morbidity and mortality. Secondary end points were stent patency and freedom from reintervention. There were 54 (58%) male and 39 (42%) female patients with a mean age of 44 ± 17 years. Thirty-two patients had NCO (mean age, 48 ± 16 years) and 61 had endovascular reinterventions after prior OSR during childhood (mean, 30 ± 17 years after initial repair), including 50 patients (54%) with recurrent coarctation and 11 (12%) with ANE. Clinical presentation included asymptomatic in 31 patients (33%), difficult to control hypertension in 42 (45%), and lower extremity claudication in 20 (22%). Endovascular treatment was performed using balloon-expandable covered stents in 47 (51%) patients, stent grafts in 36 (39%) patients, balloon-expandable uncovered stents in 9 (10%) patients, and primary angioplasty in 1 (1%) patient. Mean lesion length and diameter were 64.5 ± 50.6 mm and 19.5 ± 6.7 mm, respectively. Mean systolic pressure gradient decreased from 24.0 ± 17.5 mm Hg to 4.4 ± 7.4 mm Hg after treatment (P < .001). Complications occurred in nine (10%) patients, including aortic dissections in three (3%) patients and intraoperative ruptures in two patients; type IA endoleak, renal embolus, spinal headache, and access site hemorrhage occurred in one patient each. The aortic dissections and ruptures were treated successfully by deploying an additional covered stent proximal to the site of dissection or rupture. Two patients died within 30 days of the index procedure. After a mean follow-up of 3.2 ± 3.1 years, nearly all patients (98%) were clinically improved and all stents were patent. Reintervention was needed in 10 (11%) patients. Freedom from reintervention at 5 years was 85%. Two additional patients died during follow-up of coarctation-related causes, including rupture of an infected graft and visceral ischemia. Patient survival at 5 years was 89%. Endovascular repair is effective with an acceptable safety profile in the treatment of NCO and postsurgical complications of coarctation after initial OSR. Aortic rupture is an infrequent (2%) but devastating complication with high mortality. Balloon-expandable covered stents are preferred for NCO, whereas stent grafts are used for ANE. The rate of reinterventions is acceptable, with high procedural and long-term clinical success.


Prenatal Developmental Toxicity Study of Glycosides-based Standardized Fenugreek Seed Extract in Rats.
Glycoside-based standardized fenugreek seed extract (SFSE-G) demonstrated promising efficacy in animal models of immune-inflammatory conditions. The present study was aimed at embryo-fetal development toxicity evaluation of SFSE-G in Wistar rats as per guideline No. 414 of the Organization for Economic Co-operation and Development (OECD). Mated female rats were randomized into four groups of 30 each and received oral doses of either SFSE-G at 250, 500, and 1000 mg/kg or vehicle (water) during the period of gestation (postconception) from gestational day 5 (GD5, an implantation day) until 1 day before cesarean sections (GD19). Maternal food consumption, body weights, and clinical signs were monitored throughout gestation. Cesarean sections were performed on GD20 and fetal observations (gravid uterine weight, implantation sites, early and late resorptions, live and dead fetuses) were recorded. Live fetuses were weighed and examined for external, visceral, and skeletal variations and malformations. None of the SFSE-G-treated groups showed maternal and embryo-fetal toxicity. Occasional and incidental skeletal and visceral malformations were observed and found to be spontaneous and unrelated to the treatment. Oral exposure of SFSE-G during the prenatal period did not show significant maternal and embryo-fetal toxicity up to a dose of 1000 mg/kg in rats. Therefore, the no-observed-adverse-effect level for SFSE-G for prenatal oral exposure was considered to be 1000 mg/kg. Prenatal toxicity of glycoside-based standardized fenugreek seed extract (SFSE-G) was evaluated.SFSE-G was orally gavaged to rats on gestational days 5-19 with a limit dose of 1000 mg/kg.SFSE-G did not show maternal or developmental toxicity.SFSE-G showed NOAEL of 1000 mg/kg for prenatal exposure in female rats. Abbreviations used: CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; GD: Gestational day; GRAS: Generally recognized as safe; HED: Human equivalent dose; NOAEL: No-observed adverse effect levels; OECD: Organization for Economic Co-operation and Development; SFSE-G: glycoside-based standardized fenugreek seed extract.


New relevant pesticide transformation products in groundwater detected using target and suspect screening for agricultural and urban micropollutants with LC-HRMS.
Groundwater is a major drinking water resource, but its quality is threatened by a broad variety of anthropogenic micropollutants (MPs), originating from agriculture, industry, or households, and undergoing various transformation processes during subsurface passage. To determine a worst-case impact of pesticide application in agriculture on groundwater quality, a target and suspect screening for more than 300 pesticides and more than 1100 pesticide transformation products (TPs) was performed in 31 Swiss groundwater samples which predominantly originated from areas with intensive agriculture. To assess additional urban contamination sources, more than 250 common urban MPs were quantified. Most of the screened pesticide TPs were experimentally observed by the pesticide producers within the European pesticide registration. To cover very polar pesticide TPs, vacuum-assisted evaporative concentration was used for enrichment, followed by liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). Based on intensity, isotope pattern, retention time, and in silico fragmentation, the suspect hits were prioritised and verified. We identified 22 suspects unequivocally and five tentatively; 13 TPs are reported here for the first time to be detected in groundwater. In 13 out of 31 groundwater samples, the total concentration of the 20 identified and quantified suspects (1 pesticide and 19 pesticide TPs) exceeded the total concentration of the 519 targets (236 pesticides and TPs; 283 urban MPs) for which we screened. Pesticide TPs had higher concentrations than the parent pesticides, illustrating their importance for groundwater quality. The newly identified very polar chlorothalonil TP R471811 was the only compound detected in all samples with concentrations ranging from 3 to 2700 ng/L. Agricultural MP concentration and detection frequency correlated with agricultural land use in the catchment, except for aquifers, where protective top layers reduced MP transport from the surface. In contrast to agricultural MPs, urban MPs displayed almost no correlation with land use. The dominating entry pathway of urban MPs was river bank filtration.


Non-destructive analysis of sucrose, caffeine and trigonelline on single green coffee beans by hyperspectral imaging.
Hyperspectral imaging (HSI) is a novel technology for the food sector that enables rapid non-contact analysis of food materials. HSI was applied for the first time to whole green coffee beans, at a single seed level, for quantitative prediction of sucrose, caffeine and trigonelline content. In addition, the intra-bean distribution of coffee constituents was analysed in Arabica and Robusta coffees on a large sample set from 12 countries, using a total of 260 samples. Individual green coffee beans were scanned by reflectance HSI (980-2500nm) and then the concentration of sucrose, caffeine and trigonelline analysed with a reference method (HPLC-MS). Quantitative prediction models were subsequently built using Partial Least Squares (PLS) regression. Large variations in sucrose, caffeine and trigonelline were found between different species and origin, but also within beans from the same batch. It was shown that estimation of sucrose content is possible for screening purposes (R2=0.65; prediction error of ~0.7% w/w coffee, with observed range of ~6.5%), while the performance of the PLS model was better for caffeine and trigonelline prediction (R2=0.85 and R2=0.82, respectively; prediction errors of 0.2 and 0.1%, on a range of 2.3 and 1.1% w/w coffee, respectively). The prediction error is acceptable mainly for laboratory applications, with the potential application to breeding programmes and for screening purposes for the food industry. The spatial distribution of coffee constituents was also successfully visualised for single beans and this enabled mapping of the analytes across the bean structure at single pixel level.


Complexes of focal adhesion kinase (FAK) and Crk-associated substrate (p130(Cas)) are elevated in cytoskeleton-associated fractions following adhesion and Src transformation. Requirements for Src kinase activity and FAK proline-rich motifs.
The focal adhesion kinase (FAK) and Crk-associated substrate, p130(Cas) (Cas), have been implicated in diverse signaling pathways including those mediated by integrins, G-protein-coupled receptors, tyrosine kinase receptors, and the v-src and v-crk oncogenes. The recent identification of a direct interaction between FAK and Cas prompted the examination of potential regulation of FAK.Cas complexes by factors that result in concomitant increase in their phosphotyrosine content, namely cell adhesion and transformation by Src. Both conditions resulted in elevated FAK.Cas complex levels in nonionic detergent-insoluble fractions, indicating increased association with the cytoskeleton. For activated Src, this effect requires an active Src catalytic domain but not its Src homology 2 (SH2) or Src homology 3 (SH3) domains. FAK kinase domain tyrosines 576 and 577 are also required, suggesting that direct phosphorylation of these sites by Src may influence the solubility and/or stability of the complex. FAK-Cas association was only observed in the context of Cas binding to at least one of two distinct proline-rich sites on FAK. These findings firmly establish a direct interaction between FAK and Cas and demonstrate that Src can influence the subcellular localization of the complex by a tyrosine phosphorylation-dependent mechanism.


Asthma and growth--cause for concern? Asthma & Growth in Tayside Children.
This project aimed to investigate the height and weight of children with asthma in the community. The Tayside Childhood Asthma Project examined medical records of 3143 children drawn from 12 general practices, for details of asthma morbidity and management. Concurrently, but independent from it, the Tayside Growth Study measured heights and weights of children aged 3-5, 5, 7, 9, 11 and 14 years. This paper reports on a cross-sectional analysis of 699 children who were known to be receiving some form of asthma medication during the school years 1990-91 and 1991-92 when a growth measurement was recorded. A standard deviation score (SDS) was calculated from height measurements for this cohort of children and from weight and body mass index (BMI = weight/height2) measurements for 559 of these children. The mean and standard deviation of these SDS values were calculated, and the distribution of the scores plotted. The results showed no difference in height, weight or BMI between the general population and the cohort receiving asthma medication. However, further analysis showed the distribution of height for children with severe asthma receiving high doses of inhaled corticosteroids (mean -0.38, SD 0.95) was significantly different from the general population (mean 0, SD 1). This group of children appeared to be shorter, by as much as 2 cm on average for a 5-year-old boy. In general, children receiving treatment for asthma within the community have a similar distribution of height and weight to normal children. Children receiving high-dose inhaled corticosteroids are shorter than their contemporaries, and deserve long-term follow-up.


Using the multiphase optimization strategy (MOST) to optimize an HIV care continuum intervention for vulnerable populations: a study protocol.
More than half of persons living with HIV (PLWH) in the United States are insufficiently engaged in HIV primary care and not taking antiretroviral therapy (ART), mainly African Americans/Blacks and Hispanics. In the proposed project, a potent and innovative research methodology, the multiphase optimization strategy (MOST), will be employed to develop a highly efficacious, efficient, scalable, and cost-effective intervention to increase engagement along the HIV care continuum. Whereas randomized controlled trials are valuable for evaluating the efficacy of multi-component interventions as a package, they are not designed to evaluate which specific components contribute to efficacy. MOST, a pioneering, engineering-inspired framework, addresses this problem through highly efficient randomized experimentation to assess the performance of individual intervention components and their interactions. We propose to use MOST to engineer an intervention to increase engagement along the HIV care continuum for African American/Black and Hispanic PLWH not well engaged in care and not taking ART. Further, the intervention will be optimized for cost-effectiveness. A similar set of multi-level factors impede both HIV care and ART initiation for African American/Black and Hispanic PLWH, primary among them individual- (e.g., substance use, distrust, fear), social- (e.g., stigma), and structural-level barriers (e.g., difficulties accessing ancillary services). Guided by a multi-level social cognitive theory, and using the motivational interviewing approach, the study will evaluate five distinct culturally based intervention components (i.e., counseling sessions, pre-adherence preparation, support groups, peer mentorship, and patient navigation), each designed to address a specific barrier to HIV care and ART initiation. These components are well-grounded in the empirical literature and were found acceptable, feasible, and promising with respect to efficacy in a preliminary study. Study aims are: 1) using a highly efficient fractional factorial experimental design, identify which of five intervention components contribute meaningfully to improvement in HIV viral suppression, and secondary outcomes of ART adherence and engagement in HIV primary care; 2) identify mediators and moderators of intervention component efficacy; and 3) using a mathematical modeling approach, build the most cost-effective and efficient intervention package from the efficacious components. A heterogeneous sample of African American/Black and Hispanic PLWH (with respect to age, substance use, and sexual minority status) will be recruited with a proven hybrid sampling method using targeted sampling in community settings and peer recruitment (N = 512). This is the first study to apply the MOST framework in the field of HIV prevention and treatment. This innovative study will produce a culturally based HIV care continuum intervention for the nation's most vulnerable PLWH, optimized for cost-effectiveness, and with exceptional levels of efficacy, efficiency, and scalability. ClinicalTrials.gov, NCT02801747 , Registered June 8, 2016.


High levels of caregiver burden in Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder that is characterized by hyperphagia, developmental delay, incomplete sexual development, mild-to-moderate intellectual disability, and a variety of challenging behavioral and psychiatric symptoms. The characteristics of PWS can be difficult for caregivers to cope with and are likely to cause significant and long- term caregiver burden. The current study examined burden in 142 caregivers of children and adults with PWS living in the US using the Zarit Burden Interview (ZBI). The study aimed to measure the level of burden in caregivers of individuals with PWS, to explore the impact of PWS on caregiver quality of life, and to assess ZBI as an indicator of that impact. Caregivers participating in this study were predominantly mothers, 30-59 years old, non-Hispanic Whites, married or in a relationship, with an annual household income slightly distributed towards higher income. Nearly 90% of the caregiver`s children with PWS lived at home. Caregivers experienced high caregiver burden with an average ZBI score of 44.4 ± 15.4. ZBI scores were highest for caregivers of teenage and young adult individuals with PWS (49.2 ± 14.6 and 49.2 ± 14.1, respectively), while those caring for older adults (>30) and the youngest age group had lower scores (38.6 ±10.5 and 34.8 ±12.5, respectively). Caregivers reported that caring for a person with PWS negatively impacted their romantic relationship, ability to work, sleep, and mood. Whereas we did not find strong correlations between family income or level of help the caregiver receives and ZBI scores, the results showed significant correlations and a linear relationship between ZBI scores and caregiver depressed mood, feelings of anxiety, negative romantic relationship impact, as well as sleep and work disruption. Our study reveals that PWS incurs high caregiver burden and impacts many aspects of the lives of caregiver. We identified the ZBI as a good predictor of that impact. Our findings draw attention to the critical unmet need for support for caregivers of individuals with PWS.


Water level management and contaminant exposure to tree swallows nesting on the Upper Mississippi River.
The U.S. Army Corps of Engineers conducted a water drawdown on Navigation Pool 8 of the Upper Mississippi River during the summers of 2001 and 2002 to increase aquatic vegetation production and thereby improve fish and wildlife habitat. Flooding of previously dried wetlands, however, may increase the rate of mercury methylation and make mercury more available to terrestrial vertebrates that feed in aquatic environments. Our objective was to determine if mercury, other elements, and organochlorine contaminants were more available to vertebrates following the 2001 drawdown. Tree swallow (Tachycineta bicolor) eggs and nestlings were collected at two sites on Pool 8 and a nearby Reference site in 2000 (pre-2001 drawdown), 2001 (pre-2001 drawdown) and 2002 (post-2001 drawdown) and tissues were analyzed for mercury, other elements, and organochlorine contaminants. Bioindicator measurements of genetic damage, oxidative stress, ethoxyresorufin-O-dealkylase activity, and the ratio of liver to nestling mass were also measured in nestlings at all sites and all years. Based on a multivariate analysis, the 2001 drawdown of Pool 8 did not influence element concentrations, organochlorine concentrations, or bioindicator response. Concentrations of inorganic and organochlorine contaminants in tree swallow eggs and nestlings were not at toxic levels. Hatching success did not differ among years and was comparable to the nationwide average.


Developmental toxicity evaluation of isopropanol by gavage in rats and rabbits.
Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosed orally with aqueous isopropanol (IPA; CAS No. 67-63-0) solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on Gestational Days (GD) 6 through 15 at a dosing volume of 5 ml/kg. Artificially inseminated New Zealand white rabbits, 15/group, were dosed orally with IPA at 0, 120, 240, or 480 mg/kg/day once daily on GD 6 through 18 at 2 ml/kg. Maternal body weights, clinical observations, and food consumption were recorded throughout gestation for both species. At scheduled euthanization for both species (GD 20, rats; GD 30, rabbits), fetuses were weighed, sexed, and examined for external, visceral (including craniofacial) and skeletal alterations. For both species, the pregnancy rate was high and equivalent across all groups; no dams or does aborted, delivered early, or were removed from study. In rats, two dams (8%) died at 1200 mg/kg/day and one dam (4%) died at 800 mg/kg/day. Maternal body weights and weight gain were equivalent across all groups, except for statistically significantly reduced gestational weight gain (GD 0-20; 89.9% of control value), associated with statistically significantly reduced gravid uterine weight at 1200 mg/kg/day (89.2% of control value). There were no treatment-related clinical signs or effects on maternal food consumption. All gestational parameters evaluated were equivalent across groups, including pre- and postimplantation loss, fetal sex ratios, and litter size. Twenty-two to 25 litters were examined per group. Fetal body weights per litter were statistically significantly reduced at the two highest doses (97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and 92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for all fetuses and males and females separately). No evidence of increased teratogenicity was observed at any dose tested in rats. In rabbits, four does (26.7%) died at 480 mg/kg/day. Maternal body weights were statistically significantly reduced during treatment (GD 6-18) at 480 mg/kg/day (45.4% of control value) with a nonsignificant reduction in gestational weight change (GD 0-30; 77.3% of control value) at this dose. Profound clinical signs of toxicity and statistically significantly reduced maternal food consumption were observed at 480 mg/kg/day. All gestational parameters were equivalent across all doses administered. Thirteen to 15 litters were evaluated per group except for the 480 mg/kg/day group with 11 litters (due to maternal deaths). There were no treatment-related effects on pre- or postimplantation loss, fetal sex ratio, litter size, or fetal body weight/litter. Moreover, no evidence was found of increased teratogenicity at any dose tested in rabbits. Therefore, IPA was not teratogenic to CD rats or to NZW rabbits. The NOAELS for both maternal and developmental toxicity were 400 mg/kg/day in rats, and were 240 and 480 mg/kg/day, respectively, in rabbits.


Reproduction potentiated in nematodes (Caenorhabditis elegans) and guppy fish (Poecilia reticulata) by adding a synthetic peptide to their aqueous environment.
Ambient exposure to a short synthetic peptide has enhanced fecundity (number of offspring) in invertebrates and vertebrates, ostensibly by disinhibiting reproduction. In separate experiments, nematodes (Caenorhabditis elegans) and guppy fish (Poecilia reticulata) were exposed via their aqueous environment to a dissolved synthetic hexamer (6mer) peptide, IEPVFT (EPL036), at a concentration of 1 μmol l(-1). In the case of the worms, peptide was added to their aqueous buffer daily throughout the experiment (14 days); for the guppies, peptide administration was on the first 15 alternate days in a 50 week experiment. Fecundity rose by 79% among the worms. The number of descendants of the treated guppies was more than four times that of controls by week 26 (103 versus 25, including 72 juveniles versus 6), with 15.4% more estimated biomass in the test tank in total (i.e. including founders). It was deduced that treated females bred earlier, at a smaller size, and had larger brood sizes. The total number of fish in the control tank had caught up by termination, but biomass continued to lag the test tank. There were no overt signs of toxicity among either the worms or the fish. Bioinformatics has been unilluminating in explaining these results in terms, for example, of mimicry of an endogenous regulator. A mass spectrometric campaign to identify a receptor, using murine brain for expediency, proved inconclusive. Molecular modelling in silico indicated unexpectedly that the hexamer EPL036 might be acting as an antagonist, to pro-fecundity effect; that is, as a blocker of an inhibitor. This suggests that there awaits discovery an evolutionarily conserved reproductive inhibitor and its (anti-fecundity) receptor.


Identifying genetic relationships among tarsier populations in the islands of Bunaken National Park and mainland Sulawesi.
Eastern tarsiers (Tarsius tarsier complex) are small nocturnal primates endemic to Sulawesi Island and small adjacent islands of Indonesia. In 2004, the hybrid biogeography hypothesis predicted this species complex might contain 16 or more taxa, each corresponding to a region of endemism, based on: 1) geological evidence of the development of the archipelago, 2) biological evidence in the form of concordant distributions of monkeys and toads, and 3) the distribution of tarsier acoustic groups. Since then, 11 tarsier species have been recognized, potentially leaving more to be described. Efforts to identify these cryptic species are urgently needed so that habitat conversion, pet trade, and cultural activities will not render some species extinct before they are recognized. We gathered data to test the hypothesis of cryptic tarsier species on three volcanic islands in Bunaken National Park, North Sulawesi, namely Bunaken, Manadotua, and Mantehage, during May-August 2018. We sequenced individuals at 5 nuclear genes (ABCA1, ADORA3, AXIN1, RAG, and TTR) and made comparisons to existing genotypes at 14 mainland sites. Bayesian phylogenetic analyses revealed that island populations are genetically identical in all 5 genes, and formed a clade separated from the mainland ones. The eastern tarsiers first diverged from the western tarsiers approximately 2.5 MYA. The three island populations diverged from mainland tarsiers approximately 2,000-150,000 YA, due to either human activities or natural rafting. This study provides information for tarsier conservation, advances the understanding of biogeography of Sulawesi, and contributes to Indonesian awareness of biodiversity. Further quantitative genetics research on tarsiers, especially the island populations, will offer significant insights to establish more efficient and strategic tarsier conservation actions.


Identification of regulatory elements within the minimal promoter region of the human endogenous ERV9 proviruses: accurate transcription initiation is controlled by an Inr-like element.
ERV9 is a low repeated family of human endogenous retroviral elements whose expression is mainly detectable in undifferentiated embryonal carcinoma NT2/D1 cells. In this report we have analyzed the minimal promoter region located within the ERV9 LTR. Using the transient CAT expression assay we have identified the minimal promoter region, which includes sequences spanning from -70 to +6 relative to the major transcription start site. Deletion analysis, primer extension mapping of the transcription start sites and DNA-protein interactions assays have allowed us to define two important regions within the ERV9 minimal promoter. One region located between -70 to -39 acts as a transcriptional activating sequence and contains an Sp 1 binding site. The second region from -7 to +6, which resembles an initiator element (Inr), was necessary for the correct transcription start site utilization, and binds to a regulatory protein. Cross-competition experiments using various Inr elements have indicated that the protein that binds to the ERV9 Inr element can be competed by the HIV-1 and TdT Inr sequences.


To resurface or not to resurface the patella in total knee arthroplasty.
The management of the patellar articular surface at the time of primary total knee arthroplasty (TKA) is controversial. We used expected-value decision analysis to determine whether the patella should be resurfaced in TKA, and also whether secondary resurfacing on an unresurfaced patella is worthwhile. Outcome probabilities and utility values were derived from randomized controlled trials only. A decision tree was constructed and fold-back analysis was performed to ascertain the best treatment path. Sensitivity analyses were performed to determine the effect on decision-making of varying outcome probabilities and utilities. Our model showed patellar resurfacing is the best management strategy for the patella at the time of primary TKA. This decision is robust to changes in the specific data: the best path would remain the same as long as the incidence of persistent anterior knee pain (AKP) with resurfacing remains less than 29% (current mean, 12%) or the incidence of AKP after nonresurfacing falls below 12% (current mean, 26%). Delayed (ie, secondary) patellar resurfacing for ongoing patellar pain provides inferior results for the majority of patients. Level II, decision analysis. See the Guidelines for Authors for a complete description of levels of evidence.


Active syphilis in HIV infection: a multicentre retrospective survey. The German AIDS Study Group (GASG).
To study syphilis in HIV infection focusing on immunocompromised patients with an atypical or aggressive clinical course of syphilis, inappropriate serological reactions or an unreliable response to therapy. A multicentre retrospective chart review using a standardised questionnaire for all patients with active syphilis. Thirteen dermatological and medical centres throughout Germany, all members of the German AIDS Study Group (GASG). Clinical data of 11,368 HIV infected patients have been analysed for cases of active syphilis requiring treatment. Asymptotic patients with reactive serological parameters indicating latent syphilis without a need for treatment were excluded. Active syphilis was reported in 151 of 11,368 HIV infected patients (1.33%, range per centre 0.3%-5.1%). Most of the 151 syphilis patients were male (93%) and belonged to the homosexual or bisexual exposure category for HIV infection (79%); another 6% were iv drug users. Among the 151 syphilis patients primary syphilis was diagnosed in 17.2%, maculopapular secondary syphilis in 29.1%, ulcerating secondary syphilis in 7.3%, neurosyphilis in 16.6% and latent seropositive syphilis without clinical symptoms but serological abnormalities indicating active syphilis in 25.2%. A history of prior treatments for syphilis was reported in 50%. At the time of syphilis diagnosis 26.5% of the patients were in CDC stage II, 33.8% in stage III and 24.5% in stage IV of HIV disease (CDC classification 1987). CD4 cell count was lowest in those with ulcerating secondary syphilis (mean 307, SD 140/microliters) and neurosyphilis (351, SD 235/ microliters). The highest CD4 count was found in patients with early primary and early secondary syphilis (444, SD 163/microliters and 470, SD 355/microliters). Inappropriate serological response to syphilis infection was found in 81 of 151 patients (54%). Remarkable findings were false negative VDRL titres (11 patients with non primary syphilis), false negative TPHA (1) or 19S-IgM-FTA-ABS-tests (16), and strongly reactive VDRL (> or = 512, 8) or TPHA titres (> or = 10 240, 47). Treatment failures were reported in at least 6 of 151 cases (4%). Atypical clinical and serological courses of syphilis were observed in HIV infected patients. Ulcerating secondary syphilis with general symptoms ("malignant syphilis") was 60 times more frequent than in historic syphilis series. Neurosyphilis was found in one sixth of those with active syphilis. Therefore lumbar puncture should be considered a routine in coinfections with HIV and syphilis. Treatment efficacy should be monitored carefully.


Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19.
Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. ClinicalTrials.gov Identifier: NCT04354701.


SARS-CoV-2 infection in the first trimester and the risk of early miscarriage: a UK population-based prospective cohort study of 3041 pregnancies conceived during the pandemic.
Does maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the first trimester affect the risk of miscarriage before 13 week's gestation? Pregnant women with self-reported diagnosis of SARS-CoV-2 in the first trimester had a higher risk of early miscarriage. Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology. Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity and stillbirth. Data on the impact of first trimester infection on early pregnancy outcomes are scarce. This is the first study, to our knowledge, to investigate the rates of early pregnancy loss during the SARS-CoV-2 outbreak among women with self-reported infection. This was a nationwide prospective cohort study of pregnant women in the community recruited using social media between 21 May and 31 December 2020. We recruited 3545 women who conceived during the SARS-CoV-2 pandemic who were <13 week's gestation at the time of recruitment. The COVID-19 Contraception and Pregnancy Study (CAP-COVID) was an on-line survey study collecting longitudinal data from pregnant women in the UK aged 18 years or older. Women who were pregnant during the pandemic were asked to complete on-line surveys at the end of each trimester. We collected data on current and past pregnancy complications, their medical history and whether they or anyone in their household had symptoms or been diagnosed with SARS-CoV-2 infection during each trimester of their pregnancy. RT-PCR-based SARS-CoV-2 RNA detection from respiratory samples (e.g. nasopharynx) is the standard practice for diagnosis of SARS-CoV-2 in the UK. We compared rate of self-reported miscarriage in three groups: 'presumed infected', i.e. those who reported a diagnosis with SARS-CoV-2 infection in the first trimester; 'uncertain', i.e. those who did not report a diagnosis but had symptoms/household contacts with symptoms/diagnosis; and 'presumed uninfected', i.e. those who did not report any symptoms/diagnosis and had no household contacts with symptoms/diagnosis of SARS-CoV-2. A total of 3545 women registered for the CAP-COVID study at <13 weeks gestation and were eligible for this analysis. Data for the primary outcome were available from 3041 women (86%). In the overall sample, the rate of self-reported miscarriage was 7.8% (238/3041 [95% CI, 7-9]). The median gestational age (GA) at miscarriage was 9 weeks (interquartile range 8-11). Seventy-seven women were in the 'presumed infected' group (77/3041, 2.5% [95% CI 2-3]), 295/3041 were in the uncertain group (9.7% [95% CI 9-11]) and the rest in the 'presumed uninfected' (87.8%, 2669/3041 [95% CI 87-89]). The rate of early miscarriage was 14% in the 'presumed infected' group, 5% in the 'uncertain' and 8% in the 'presumed uninfected' (11/77 [95% CI 6-22] versus 15/295 [95% CI 3-8] versus 212/2669 [95% CI 7-9], P = 0.02). After adjusting for age, BMI, ethnicity, smoking status, GA at registration and the number of previous miscarriages, the risk of early miscarriage appears to be higher in the 'presumed infected' group (relative rate 1.7, 95% CI 1.0-3.0, P = 0.06). We relied on self-reported data on early pregnancy loss and SARS-CoV-2 infection without any means of checking validity. Some women in the 'presumed uninfected' and 'uncertain' groups may have had asymptomatic infections. The number of 'presumed infected' in our study was low and therefore the study was relatively underpowered. This was a national study from the UK, where infection rates were one of the highest in the world. Based on the evidence presented here, women who are infected with SARS-CoV-2 in their first trimester may be at an increased risk of a miscarriage. However, the overall rate of miscarriage in our study population was 8%. This is reassuring and suggests that if there is an effect of SARS-CoV-2 on the risk of miscarriage, this may be limited to those with symptoms substantial enough to lead to a diagnostic test. Further studies are warranted to evaluate a causal association between SARS-CoV-2 infection in early pregnancy and miscarriage risk. Although we did not see an overall increase in the risk of miscarriage, the observed comparative increase in the presumed infected group reinforces the message that pregnant women should continue to exercise social distancing measures and good hygiene throughout their pregnancy to limit their risk of infection. This study was supported by a grant from the Elizabeth Garrett Anderson Hospital Charity (G13-559194). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. J.A.H. is supported by an NIHR Advanced Fellowship. A.L.D. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support to J.A.H. and A.L.D. as above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. N/A.


Sequence analysis of the equine H7 influenza virus haemagglutinin gene.
The nucleotide sequences of ten haemagglutinin genes of representative H7N7 equine influenza viruses isolated between 1956 and 1977 have been determined by primer extension sequencing. Their nucleotide and deduced amino acid sequences demonstrate a high degree of homology. These equine viruses can be divided into two distinct subgroups, the prototype-like, and a group comprising the early American isolates and the remaining equine viruses. The equine H7 haemagglutinins form a quite distinct group compared to H7 haemagglutinins isolated from other species. Each of these equine H7 haemagglutinins possess a tetrabasic amino acid cleavage site separating the HA1 and HA2 domains but, in addition, all ten contain a nine amino acid insertion prior to the tetrabasic sequence. The haemagglutinin glycoproteins of all ten viruses are capable of cleavage activation in virus infected primary chicken embryo fibroblast cells.


Characterization of haloacetaldehyde and trihalomethane formation potentials during drinking water treatment.
Haloacetaldehydes (HAs) are the third prevalent group of disinfection by-products (DBPs) of great health concern. In this study, their formation and speciation during chlorination were investigated for raw and process waters collected at three O3-biological activated carbon (BAC) advanced drinking water treatment plants. The results showed that all HA formation potentials (HAFPs) were highly enhanced whenever ozone was applied before or after conventional treatment. Sand filtration and BAC filtration could substantially reduce HAFPs. Trihalomethanes (THMs) were also measured to better understand the role of HAs in DBPs. Very different from HAFPs, THMFPs kept decreasing with the progress of treatment steps, which was mainly attributed to the different precursors for HAs and THMs. Brominated HAs were detected in bromide-containing waters. Chloral hydrate (CH) contributed from 25% to 48% to the total HAs formed in waters containing 100-150 μg L(-1) bromide, indicating the wide existence of other HAs after chlorination besides CH production. In addition, bromide incorporation factor (BIF) in HAs and THMs increased with the progress of treatment steps and the BIF values of THMs were generally higher than those of HAs. The BAC filtration following ozonation could significantly reduce HA precursors produced from ozonation but without complete removal. The brominated HAFPs in the outflow of BAC were still higher than their levels in the raw water. As a result, O3-BAC combined treatment was effective at controlling the total HAs, whereas it should be cautious for waters with high bromide levels.


The new statistics: why and how.
We need to make substantial changes to how we conduct research. First, in response to heightened concern that our published research literature is incomplete and untrustworthy, we need new requirements to ensure research integrity. These include prespecification of studies whenever possible, avoidance of selection and other inappropriate data-analytic practices, complete reporting, and encouragement of replication. Second, in response to renewed recognition of the severe flaws of null-hypothesis significance testing (NHST), we need to shift from reliance on NHST to estimation and other preferred techniques. The new statistics refers to recommended practices, including estimation based on effect sizes, confidence intervals, and meta-analysis. The techniques are not new, but adopting them widely would be new for many researchers, as well as highly beneficial. This article explains why the new statistics are important and offers guidance for their use. It describes an eight-step new-statistics strategy for research with integrity, which starts with formulation of research questions in estimation terms, has no place for NHST, and is aimed at building a cumulative quantitative discipline.


Societal costs of air pollution-related health hazards: A review of methods and results.
This paper aims to provide a critical and systematic review of the societal costs of air pollution-related ill health (CAP), to explore methodological issues that may be important when assessing or comparing CAP across countries and to suggest ways in which future CAP studies can be made more useful for policy analysis. The methodology includes a systematic search based on the major electronic databases and the websites of a number of major international organizations. Studies are categorized by origin - OECD countries or non-OECD countries - and by publication status. Seventeen studies are included, eight from OECD countries and nine from non-OECD countries. A number of studies based on the ExternE methodology and the USA studies conducted by the Institute of Transportation are also summarized and discussed separately. The present review shows that considerable societal costs are attributable to air pollution-related health hazards. Nevertheless, given the variations in the methodologies used to calculate the estimated costs (e.g. cost estimation methods and cost components included), and inter-country differences in demographic composition and health care systems, it is difficult to compare CAP estimates across studies and countries. To increase awareness concerning the air pollution-related burden of disease, and to build links to health policy analyses, future research efforts should be directed towards theoretically sound and comprehensive CAP estimates with use of rich data. In particular, a more explicit approach should be followed to deal with uncertainties in the estimations. Along with monetary estimates, future research should also report all physical impacts and source-specific cost estimates, and should attempt to estimate 'avoidable cost' using alternative counterfactual scenarios.


The time course of denervation-induced changes is similar in soleus muscles of adult and old rats.
Muscle denervation is accompanied by atrophy and a decline in oxidative capacity. We investigated whether the time course of adaptations following denervation of the soleus muscle differs in adult (5 months old) and older adult (25 months old) rats. We denervated the soleus muscle of the left leg, while the right leg served as an internal control. Two weeks after denervation, muscle mass was decreased both in adult and old animals to, respectively, 57% and 54% (p < 0.001) and capillary to fibre ratio (C:F) decreased to 51% and 50% (p < 0.01) of the control values. Yet, the capillary density was increased in older adult but not in adult muscles, indicating that the regression of the capillary bed during denervation lags behind the decrease in fibre size in the soleus muscle of the older rats. One week after denervation the optical density of sections stained for succinate dehydrogenase was 83% and 79% (p < 0.05) of control adult and older adult muscles, respectively, and then remained stable. This indicates that during the first week of denervation loss of oxidative capacity occurred at a relatively higher rate than that of muscle mass. No major changes occurred between 2 and 4 weeks of denervation, except for an increase in the proportion of hybrid (I/IIa) fibres in 4 week denervated muscles (adult 10% vs. 23%; old 1% vs. 13%; p < 0.05). Except for changes in capillarisation, the time course of atrophy and decrease in oxidative capacity following denervation was similar in soleus muscles from adult and old rats.


The complexities of epidemiology and prevention of gastrointestinal cancers.
Cancer epidemiology and prevention is one of the most well studied fields today. The more we can understand about the incidence and pathogenesis of this disease, the better we will be able to prevent it. Effective prevention strategies can decrease the mortality rate of cancer significantly; this is why it is important to delineate the underlying causes. It has been well recognized that genetic mutations, sporadic or hereditary, may lead to increased chance of tumorigenesis. Detecting genetic mutations can lead to the identification of high-risk individuals with hereditary cancer syndromes, which may assist in devising prevention strategies. Further, environmental factors are known to play important roles in epidemiology and suggest prevention tools that could be implemented to reduce cancer incidence and subsequent cancer-associated morbidity and mortality. Chemoprevention has been tried in colon cancer and is finding new advancements in other carcinomas as well. Out of many environmental cancer preventive agents, the most notable developments are the identification of the role of vitamins E, vitamin D and folic acid. Increased consumption of these vitamins has shown to be inversely correlated with cancer risk. This review will highlight important aspects of cancer epidemiology in the most aggressive carcinomas of the gastrointestinal system focusing on colorectal adenocarcinoma and pancreatic adenocarcinoma. Additionally, some of the well-known and evolving aspects of epidemiology of colorectal and pancreatic cancer along with current and new prevention strategies will also be reviewed.


Major gaps in understanding and treatment of hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a complex dermatological disease characterized by recurrent painful nodules and suppuration in areas such as the axilla and groin. The disease is poorly understood and treatment is not satisfactory. In October 2016, the Canadian and United States Hidradenitis Suppurativa Foundations organized the inaugural Symposium on Hidradenitis Suppurativa Advances (SHSA) in Toronto, Canada. This meeting brought together experts from Canada, the United States, and Europe to discuss the latest advances in HS. After this important event, we considered that it would be helpful to outline current HS knowledge and to identify important gaps in treatment and research in order to move forward more efficiently. This paper briefly summarizes current knowledge in key areas including epidemiology, clinical presentation and morphological classification, natural history and prognosis, genotype-phenotype correlations, clinico-pathological correlation, pathogenesis, optimal treatment and outcome measures. General and initial suggestions for addressing these gaps are presented.


The interplay between activity and filament flexibility determines the emergent properties of active nematics.
Active nematics are microscopically driven liquid crystals that exhibit dynamical steady states characterized by the creation and annihilation of topological defects. Motivated by differences between previous simulations of active nematics based on rigid rods and experimental realizations based on semiflexible biopolymer filaments, we describe a large-scale simulation study of a particle-based computational model that explicitly incorporates filament semiflexibility. We find that energy injected into the system at the particle scale preferentially excites bend deformations, reducing the apparent filament bend modulus. The emergent characteristics of the active nematic depend on activity and flexibility only through this activity-renormalized bend 'modulus', demonstrating that apparent values of material parameters, such as the Frank 'constants', depend on activity. Thus, phenomenological parameters within continuum hydrodynamic descriptions of active nematics must account for this dependence. Further, we present a systematic way to estimate these parameters from observations of deformation fields and defect shapes in experimental or simulation data.


Characterization of novel MSX1 mutations identified in Japanese patients with nonsyndromic tooth agenesis.
Since MSX1 and PAX9 are linked to the pathogenesis of nonsyndromic tooth agenesis, we performed detailed mutational analysis of these two genes sampled from Japanese patients. We identified two novel MSX1 variants with an amino acid substitution within the homeodomain; Thr174Ile (T174I) from a sporadic hypodontia case and Leu205Arg (L205R) from a familial oligodontia case. Both the Thr174 and Leu205 residues in the MSX1 homeodomain are highly conserved among different species. To define possible roles of mutations at these amino acids in the pathogenesis of nonsyndromic tooth agenesis, we performed several functional analyses. It has been demonstrated that MSX1 plays a pivotal role in hard tissue development as a suppressor for mesenchymal cell differentiation. To evaluate the suppression activity of the variants in mesenchymal cells, we used the myoD-promoter, which is one of convenient reporter assay system for MSX1. Although the gene products of these MSX1 variants are stable and capable of normal nuclear localization, they do not suppress myoD-promoter activity in differentiated C2C12 cells. To clarify the molecular mechanisms underlying our results, we performed further analyses including electrophoretic mobility shift assays, and co-immunoprecipitation assays to survey the molecular interactions between the mutant MSX1 proteins and the oligonucleotide DNA with MSX1 consensus binding motif or EZH2 methyltransferase. Since EZH2 is reported to interact with MSX1 and regulate MSX1 mediated gene suppression, we hypothesized that the T174I and L205R substitutions would impair this interaction. We conclude from the results of our experiments that the DNA binding ability of MSX1 is abolished by these two amino acid substitutions. This illustrates a causative role of the T174I and L205R MSX1 homeodomain mutations in tooth agenesis, and suggests that they may influence cell proliferation and differentiation resulting in lesser tooth germ formation in vivo.


Cost-effectiveness of physical activity among women with menopause symptoms: findings from a randomised controlled trial.
Menopause is a period that may predispose one to a decrease in muscle strength, cardiorespiratory fitness, and quality of life. A study was carried out to evaluate the cost-effectiveness of physical activity among women displaying symptoms of menopause. The cost-effectiveness analysis was based on data from a six-month randomised controlled trial (n = 151). The women in the intervention group engaged in an unsupervised session of at least 50 minutes of physical activity four times a week. The control group continued their physical activity as before. An incremental cost-effectiveness ratio (ICER) was calculated in terms of maximal oxygen consumption, lean muscle mass, and quality-adjusted life years (QALYs) gained. A bootstrap technique was utilised to estimate uncertainty around the point estimate for ICER associated with the intervention. The mean total cost in the intervention group was €1,307 (SEM: €311) and in the control group was €1,253 (SEM: €279, p = 0.10) per person. The mean intervention cost was €208 per person. After six months of the behaviour-change intervention, the ICER was €63 for a 1 ml/kg/min improvement in cardiorespiratory fitness, the additional cost per one-gram increase in lean muscle mass was €126, and the cost per QALY gained was €46. According to the findings, physical activity among menopausal women was cost-effective for cardiorespiratory fitness, for lean muscle mass, and for QALYs gained, since the intervention was more effective than the actions within the control group and the additional effects of physical activity were gained at a very low price. From the societal perspective, the intervention used may promote ability to work and thereby save on further costs associated with early retirement or disability pension if the physical-activity level remains at least the same as during the intervention.


Evaluation of amblyopic eyes with optical coherence tomography angiography and electrophysiological tests.
To investigate the structural and functional changes of the retina and optic nerve in amblyopia. Eighteen patients with unilateral anisometropic amblyopia and 27 age-matched healthy controls were involved in this study. All patients underwent optical coherence tomography angiography (OCTA), pattern visual evoked potential (pVEP), and flash electroretinogram (fERG). There was no statistically significant difference in terms of the foveal avascular zone (FAZ), perifoveal superficial density, whole superficial density, parafoveal deep density, perifoveal deep density among the eyes (P > 0 0.05). Significant differences were found only in superficial capillary plexus (SCP) vessel density in whole (P = 0.029) and parafoveal (P = 0.008) image. In electrophysiological tests, while VEP latencies of the amblyopic eyes increased compared to nonamblyopic eyes and controls (P = 0.027), VEP amplitudes decreased in amblyopic and nonamblyopic eyes compared to controls (P = 0.01), amplitudes of the rod (P = 0.027) and cones (P < 0.001) also decreased in amblyopic eyes compared to nonamblyopic and healthy eyes. When we assessed the correlation between the parameters of OCTA and electrophysiological test, only a significant correlation was found between parafoveal SCP vessel density and VEP amplitudes (r = 0.341). We found a significant decrease only in SCP vessel density of the OCTA parameters in amblyopic eyes compared to healthy eyes. We detected a significant relationship between parafoveal SCP vessel density and VEP parameters, which might be associated with the underlying pathophysiology of the amblyopia.


Prevalence and severity of dental caries among American Indian and Alaska Native preschool children.
To describe the Indian Health Service (IHS) oral health surveillance system and the oral health status of American Indian and Alaska Native (AI/AN) children aged 1-5 years. A stratified probability sample of IHS/tribal sites was selected. Children were screened by trained examiners at community-based locations including medical clinics, Head Start, preschools, kindergarten, and Women, Infants, and Children (WIC). Data collection was limited to the primary dentition and included number of teeth present plus number of teeth with cavitated lesions, restorations, and extracted because of decay. Number of molars with sealants and urgency of need for dental care data were also obtained. Statistical analyses were performed with SAS (SAS Institute Inc., Cary, NC, USA). Sample weights were used to produce population estimates based on selection probabilities. A total of 8,461 AI/AN children 12-71 months of age were screened at 63 IHS/tribal sites, approximately 7 percent of the estimated IHS user population of the same age. Overall, 54 percent of the children had decay experience, 39 percent had untreated decay, 7 percent had primary molar sealants, 36 percent needed early or urgent dental care, and 6 percent needed urgent dental care. The mean of decayed, missing, or filled teeth was 3.5 (95 percent confidence interval, 3.1-3.9). The prevalence of decay experience increased with age; 21 percent of 1-year-olds and 75 percent of 5-year-olds had a history of caries. When stratified by IHS area, there were substantial differences in the oral health of preschool children. The results confirm that in the United States, AI/AN children served by IHS/tribal programs are one of the racial/ethnic groups at highest risk of caries.


Water and hydrophobic gates in ion channels and nanopores.
Ion channel proteins form nanopores in biological membranes which allow the passage of ions and water molecules. Hydrophobic constrictions in such pores can form gates, i.e. energetic barriers to water and ion permeation. Molecular dynamics simulations of water in ion channels may be used to assess whether a hydrophobic gate is closed (i.e. impermeable to ions) or open. If there is an energetic barrier to water permeation then it is likely that a gate will also be impermeable to ions. Simulations of water behaviour have been used to probe hydrophobic gates in two recently reported ion channel structures: BEST1 and TMEM175. In each of these channels a narrow region is formed by three consecutive rings of hydrophobic sidechains and in both cases such analysis demonstrates that the crystal structures correspond to a closed state of the channel. In silico mutations of BEST1 have also been used to explore the effect of changes in the hydrophobicity of the gating constriction, demonstrating that substitution of hydrophobic sidechains with more polar sidechains results in an open gate which allows water permeation. A possible open state of the TMEM175 channel was modelled by the in silico expansion of the hydrophobic gate resulting in the wetting of the pore and free permeation of potassium ions through the channel. Finally, a preliminary study suggests that a hydrophobic gate motif can be transplanted in silico from the BEST1 channel into a simple β-barrel pore template. Overall, these results suggest that simulations of the behaviour of water in hydrophobic gates can reveal important design principles for the engineering of gates in novel biomimetic nanopores.


Abandonment and accumulation: embryonic futures in the United States and Ecuador.
When frozen embryos are publically debated in the United States, they are most often positioned as having two possible future trajectories: (1) as individual humans and (2) as contributors to stem cell research. Long-term embryo accumulation threatens both of these futures. An accumulated embryo is stuck in a clinic, held back from having an individual future or from contributing to science. There are other kinds of futures, though. For some patients in the United States and Ecuador, where I conducted ethnographic research, future reckoning involves a vision of responsibility toward embryos embedded within a specific family. For these patients, frozen embryo donation to another family or to science constitutes abandonment. The future at stake is not that of an individual embryo's life, but a group's future who would abandon one of its own. These patients would rather destroy embryos than freeze them for a future away from their relations. [Ecuador, United States, in


High-sensitivity cardiac troponin I in women with a history of early-onset preeclampsia.
Preeclampsia is associated with an elevated risk of cardiovascular disease later in life. Women with a history of preeclampsia are at risk of developing hypertension as well as ischemic heart disease. Identification of women at the highest risk is important to initiate preventive strategies. We investigated whether high-sensitivity cardiac troponin I (hs-cTnI) levels are associated with a history of early-onset preeclampsia, and with hypertension in these high-risk women. Approximately 9-10 years after pregnancy, hs-cTnI levels were measured for 339 women of the Preeclampsia Risk Evaluation in FEMales cohort, consisting of 177 women with a history of early-onset preeclampsia and 162 women with a previous uncomplicated index pregnancy. Associations were analyzed using several statistical tests and linear regression analysis. The median hs-cTnI levels (IQR) were 2.50 ng/l (2.30) in women with a history of early-onset preeclampsia and 2.35 ng/l (2.50) in women without a history of preeclampsia, P = 0.53. Among women with a history of early-onset preeclampsia, the hs-cTnI levels were higher in women who were hypertensive compared with their normotensive counterparts (medians 2.60 versus 2.30; P = 0.03). In addition, blood pressure levels increased with increasing hs-cTnI levels. We did not find a difference in hs-cTnI levels between women with and without a history of early-onset preeclampsia. Nonetheless, hs-cTnI levels were statistically significantly higher in current hypertensive women with a history of preeclampsia compared with their normotensive counterparts. Therefore, hs-cTnI levels might improve risk prediction for women at the highest risk of cardiovascular disease.


The effect of dance mat exergaming systems on physical activity and health-related outcomes in secondary schools: results from a natural experiment.
Exergaming has been proposed as an innovative method for physical activity promotion. However, large effectiveness studies are rare. In January 2011, dance mat systems were introduced in secondary schools in two districts in England with the aim of promoting an innovative opportunity for physical activity. The aim of this natural experiment was to examine the effect of introducing the dance mat exergaming systems on physical activity and health-related outcomes in 11-13 year old students using a non-randomised controlled design and mixed methods. Participants were recruited from five schools in intervention districts (n = 280) and two schools in neighbouring control districts (n = 217). Data on physical activity (accelerometer), anthropometrics (weight, BMI and percentage of body fat), aerobic fitness (20-m multistage shuttle run test), health-related quality of life (Kidscreen questionnaire), self-efficacy (children's physical activity self-efficacy survey), school attendance, focus groups with children and interviews with teachers were collected at baseline and approximately 12 months follow-up. There was a negative intervention effect on total physical activity (-65.4 cpm CI: -12.6 to -4.7), and light and sedentary physical activity when represented as a percentage of wear time (Light: -2.3% CI: -4.5 to 0.2; Sedentary: 3.3% CI: 0.7 to 5.9). However, compliance with accelerometers at follow-up was poor. There was a significant positive intervention effect on weight (-1.7 kg, 95% CI: -2.9 to -0.4), BMI (-0.9 kg/m2, 95% CI: -1.3 to -0.4) and percentage of body fat (-2.2%, 95% CI: -4.2 to -0.2). There was also evidence of improvement in some health-related quality of life parameters: psychological well-being (2.5, 95% CI: 0.1 to 4.8) and autonomy and parent relation (4.2, 95% CI: 1.4 to 7.0). The implementation of a dance mat exergaming scheme was associated with improvement in anthropometric measurements and parameters of health-related quality of life. However, the mechanisms of these benefits are unclear as there was insufficient data from physical activity to draw robust conclusions. Qualitative findings suggest that there was declining support for the initiative over time, meaning that potential benefits may not have been achieved.


Effect of 5-hydroxytryptamine and iproniazid on pregnancy.
The effects of 5-hydroxytryptamine and iproniazid on pregnancy in mice and rabbits were investigated. 5-Hydroxytryptamine can interrupt pregnancy at all stages in mice but is particularly effective early and late in pregnancy. Iproniazid exerts its action essentially in the first half of pregnancy. 5-Hydroxytryptamine produces striking hemorrhage in the placenta.


Protective Role of Propolis on Low and High Dose Furan-induced Hepatotoxicity and Oxidative Stress in Rats.
The aim of this study was to evaluate potential protective effects of propolis on furan-induced hepatic damage by assessing the levels of malondialdehyde (MDA) and reduced glutathione (GSH), antioxidant enzyme activities, and histopathological changes in the liver. Albino Wistar rats were divided into six groups: a control, propolis-treated (100 mg/kg b.w./day), low-dose furan-treated (furan-L group; 2 mg/kg b.w./day), high-dose furan-treated (furan-H group; 16 mg/kg b.w./day), furan-L+propolis treated, and furan-H+propolis treated group. Propolis and furan were applied by gavage; propolis for 8 days, and furan for 20 days in furan-L groups and 10 days in furan-H groups. While MDA levels were elevated in furan-treated groups, levels of GSH and activities of antioxidant enzymes decreased (p < 0.001). The levels of MDA and GSH and activities of antioxidant enzymes were normal in the furan+propolis groups, especially in the furan-L+propolis group (p < 0.001). While the aspartate transaminase, alanine transaminase, alkaline phosphatase, and lactate pdehydrogenase activities were elevated in the furan-H treated group (p < 0.05 and p < 0.001), they were unchanged in the furan-L treated group. Histopathologically, several lesions were observed in the liver tissues of the furan-treated groups, especially in the higher-dose group. It was determined that these changes were milder in both of the furan+propolis groups. The results indicate that propolis exhibits good hepatoprotective and antioxidant potential against furan-induced hepatocellular damage in rats.