Pediatric liver transplant with Campath 1H induction--Preliminary report.
Since Campath 1H (C1H) has been successfully used in adult liver transplant recipients since 2001 in our program, we started to use it in children. C1H induction was employed in 10 children with autoimmune hepatitis (AIH) (n = 6), primary sclerosing cholangitis (PSC) (n = 1), biliary atresia (n = 1), glycogen storage disease (n = 1), and Wilson's disease. Eight were primary transplants, and two retransplants. Patients ages ranged from 5 to 17 years. C1H was administered at a dose of 0.3 mg/kg on days 0, 4, and 7. Tacrolimus level was maintained at 5 to 10 ng/mL. No patient received maintenance steroids posttransplantation except two who were on steroid therapy at the time transplant. They were prescribed small doses of maintenance steroids. Median follow-up of C1H recipients was 679 days (range 115-1143). Postoperative courses were mostly uneventful except for one retransplant recipient who required prolonged hospitalization (40 days) for rehabilitation. Median hospital stay was 12 days (range 7-40 days). All 10 patients in the C1H group are currently alive and well with stable graft function. No opportunistic infection was observed in these patients to date. We compared six patients with AIH who received C1H to the historic control of 10 recipients with AIH who received conventional immunosuppression (tacrolimus + steroid). The patients treated with C1H showed significantly prolonged rejection-free survival. In our preliminary experience, C1H induction was well tolerated in pediatric liver recipients. Rejections-free survival was prolonged among recipients with AIH despite a low level of maintenance immunosuppression.


Oocytes recovered after ovarian tissue slow freezing have impaired H2AX phosphorylation and functional competence.
It has been shown that oocytes isolated from ovarian tissue cryopreservation acquire DNA damage during the process of freeze-thawing. Using a mouse model, here we have investigated the functional competence and phosphorylation of H2AX (γ-H2AX) in germinal vesicle (GV) and parthenogenetically activated oocytes derived from conventional ovarian tissue slow freezing and vitrification techniques. The number of GV-stage oocytes with γ-H2AX foci was not significantly different between the slow-freezing and vitrification groups. Although the in vitro maturation (IVM) potential of GV oocytes in the slow-freezing group showed a significant delay (P<0.0001) in the process of germinal vesicle breakdown, no difference in the maturation rate was observed between the two protocols. Nevertheless, parthenogenetic activation of IVM oocytes using strontium chloride showed a significantly lower activation rate in the slow-freezing group compared with the vitrification (P<0.05) and control (P<0.01) groups. Importantly, H2AX phosphorylation was significantly perturbed in the slow-freezing group in comparison to the control (P<0.05). Therefore, we conclude that impaired sensing of DNA strand breaks and repair processes are associated with the reduced functional competence of the oocytes recovered from the slow-freezing group, which may have a significant impact on the reproductive outcome.


Distributed representations of rule identity and rule order in human frontal cortex and striatum.
Humans are able to flexibly devise and implement rules to reach their desired goals. For simple situations, we can use single rules, such as "if traffic light is green then cross the street." In most cases, however, more complex rule sets are required, involving the integration of multiple layers of control. Although it has been shown that prefrontal cortex is important for rule representation, it has remained unclear how the brain encodes more complex rule sets. Here, we investigate how the brain represents the order in which different parts of a rule set are evaluated. Participants had to follow compound rule sets that involved the concurrent application of two single rules in a specific order, where one of the rules always had to be evaluated first. The rules and their assigned order were independently manipulated. By applying multivariate decoding to fMRI data, we found that the identity of the current rule was encoded in a frontostriatal network involving right ventrolateral prefrontal cortex, right superior frontal gyrus, and dorsal striatum. In contrast, rule order could be decoded in the dorsal striatum and in the right premotor cortex. The nonhomogeneous distribution of information across brain areas was confirmed by follow-up analyses focused on relevant regions of interest. We argue that the brain encodes complex rule sets by "decomposing" them in their constituent features, which are represented in different brain areas, according to the aspect of information to be maintained.


Alternate finger tapping test in patients with migraine.
Migraine patients are thought to show some cognitive dysfunction and slight structural abnormalities in the white matter of the brain, whereas most patients with multiple sclerosis (MS) are known to have numerous white matter lesions, often affecting the corpus callosum. To demonstrate psychomotor dysfunction, an alternate finger tapping task (a-FTT) on a PC was administered to controls (n = 41), migraine patients (n = 25), and multiple sclerosis patients (n = 22). Five MS patients with secondary callosal atrophy detected by MRI were also investigated as a separate group. Significant slowing was demonstrated in migraine (P = 0.0005) and MS (P<0.0001). The poorest test results were found in patients with callosal atrophy. In summary, a-FTT on a PC is able to detect minimal psychomotor dysfunction in migraine.


European surveillance for enterovirus D68 during the emerging North-American outbreak in 2014.
In August and September 2014, unexpected clusters of enterovirus-D68 (EV-D68) infections associated with severe respiratory disease emerged from North-America. In September, the European Centre for Disease Prevention and Control (ECDC) asked European countries to strengthen respiratory sample screening for enterovirus detection and typing in cases with severe respiratory presentations. To provide a detailed picture of EV-D68 epidemiology in Europe by conducting a retrospective and prospective laboratory analysis of clinical specimens. An initiative supported by the European Society for Clinical Virology (ESCV) and ECDC was launched to screen for EV-D68 in respiratory specimens between July 1st and December 1st 2014 in Europe and to sequence the VP1 region of detected viruses for phylogenetic analytic purposes. Forty-two institutes, representing 51 laboratories from 17 European countries, analyzed 17,248 specimens yielding 389 EV-D68 positive samples (2.26%) in 14 countries. The proportion of positive samples ranged between 0 and 25% per country. These infections resulted primarily in mild respiratory disease, mainly detected in young children presenting with wheezing and in immuno-compromised adults. The viruses detected in Europe are genetically very similar to those of the North-American epidemic and the majority (83%) could be assigned to clade B. Except for 3 acute flaccid paralysis (AFP) cases, one death and limited ICU admissions, no severe cases were reported. The European study showed that EV-D68 circulated in Europe during summer and fall of 2014 with a moderate disease burden and different pathogenic profile compared to the North-American epidemic.


Reference ranges for bone mineral density and prevalence of osteoporosis in Vietnamese men and women.
The aim of this study was to examine the effect of different reference ranges in bone mineral density on the diagnosis of osteoporosis. This cross-sectional study involved 357 men and 870 women aged between 18 and 89 years, who were randomly sampled from various districts within Ho Chi Minh City, Vietnam. BMD at the femoral neck, lumbar spine and whole body was measured by DXA (Hologic QDR4500). Polynomial regression models and bootstraps method were used to determine peak BMD and standard deviation (SD). Based on the two parameters, we computed T-scores (denoted by TVN) for each individual in the study. A similar diagnosis was also done based on T-scores provided by the densitometer (TDXA), which is based on the US White population (NHANES III). We then compared the concordance between TVN and TDXA in the classification of osteoporosis. Osteoporosis was defined according to the World Health Organization criteria. In post-menopausal women, the prevalence of osteoporosis based on femoral neck TVN was 29%, but when the diagnosis was based on TDXA, the prevalence was 44%. In men aged 50+ years, the TVN-based prevalence of osteoporosis was 10%, which was lower than TDXA-based prevalence (30%). Among 177 women who were diagnosed with osteoporosis by TDXA, 35% were actually osteopenia by TVN. The kappa-statistic was 0.54 for women and 0.41 for men. These data suggest that the T-scores provided by the Hologic QDR4500 over-diagnosed osteoporosis in Vietnamese men and women. This over-diagnosis could lead to over-treatment and influence the decision of recruitment of participants in clinical trials.


Cross-Talk between Staphylococcus aureus and Other Staphylococcal Species via the agr Quorum Sensing System.
Staphylococci are associated with both humans and animals. While most are non-pathogenic colonizers, Staphylococcus aureus is an opportunistic pathogen capable of causing severe infections. S. aureus virulence is controlled by the agr quorum sensing system responding to secreted auto-inducing peptides (AIPs) sensed by AgrC, a two component histidine kinase. agr loci are found also in other staphylococcal species and for Staphylococcus epidermidis, the encoded AIP represses expression of agr regulated virulence genes in S. aureus. In this study we aimed to better understand the interaction between staphylococci and S. aureus, and show that this interaction may eventually lead to the identification of new anti-virulence candidates to target S. aureus infections. Here we show that culture supernatants of 37 out of 52 staphylococcal isolates representing 17 different species inhibit S. aureus agr. The dog pathogen, Staphylococcus schleiferi, expressed the most potent inhibitory activity and was active against all four agr classes found in S. aureus. By employing a S. aureus strain encoding a constitutively active AIP receptor we show that the activity is mediated via agr. Subsequent cloning and heterologous expression of the S. schleiferi AIP in S. aureus demonstrated that this molecule was likely responsible for the inhibitory activity, and further proof was provided when pure synthetic S. schleiferi AIP was able to completely abolish agr induction of an S. aureus reporter strain. To assess impact on S. aureus virulence, we co-inoculated S. aureus and S. schleiferi in vivo in the Galleria mellonella wax moth larva, and found that expression of key S. aureus virulence factors was abrogated. Our data show that the S. aureus agr locus is highly responsive to other staphylococcal species suggesting that agr is an inter-species communication system. Based on these results we speculate that interactions between S. aureus and other colonizing staphylococci will significantly influence the ability of S. aureus to cause infection, and we propose that other staphylococci are potential sources of compounds that can be applied as anti-virulence therapy for combating S. aureus infections.


Monitoring annoyance and stress effects of wind turbines on nearby residents: A comparison of U.S. and European samples.
As wind turbines and the number of wind projects scale throughout the world, a growing number of individuals might be affected by these structures. For some people, wind turbine sounds and their effects on the landscape can be annoying and could even prompt stress reactions. This comparative study analyzed a combined sample of survey respondents from the U.S., Germany and Switzerland. It utilized a newly developed assessment scale (AS-Scale) to reliably characterize these stress-impacted individuals living within populations near turbines. Findings indicate low prevalence of annoyance, stress symptoms and coping strategies. Noise annoyance stress (NAS-Scale) was negatively correlated with the perceptions of a lack of fairness of the wind project's planning and development process, among other subjective variables. Objective indicators, such as the distance from the nearest turbine and sound pressure level modeled for each respondent, were not found to be correlated to noise annoyance. Similar result patterns were found across the European and U.S. samples.


Gambling disorder and other behavioral addictions: recognition and treatment.
Addiction professionals and the public are recognizing that certain nonsubstance behaviors--such as gambling, Internet use, video-game playing, sex, eating, and shopping--bear resemblance to alcohol and drug dependence. Growing evidence suggests that these behaviors warrant consideration as nonsubstance or "behavioral" addictions and has led to the newly introduced diagnostic category "Substance-Related and Addictive Disorders" in DSM-5. At present, only gambling disorder has been placed in this category, with insufficient data for other proposed behavioral addictions to justify their inclusion. This review summarizes recent advances in our understanding of behavioral addictions, describes treatment considerations, and addresses future directions. Current evidence points to overlaps between behavioral and substance-related addictions in phenomenology, epidemiology, comorbidity, neurobiological mechanisms, genetic contributions, responses to treatments, and prevention efforts. Differences also exist. Recognizing behavioral addictions and developing appropriate diagnostic criteria are important in order to increase awareness of these disorders and to further prevention and treatment strategies.


A facile and fully automated on-fiber derivatization protocol for direct analysis of short-chain aliphatic amines using a matrix compatible solid-phase microextraction coating.
Solid-phase microextraction (SPME) analysis of short-chain aliphatic amines (C3-C6) in aqueous solutions was investigated using pentafluorobenzaldehyde (PFBAY) as on-fiber derivatization reagent. A standard gas generating vial agent was used for on-fiber loading of the derivatization agent so as to avoid the need for its regeneration at each derivatization cycle. Several parameters such as loading time, reaction temperature, and reaction/extraction time were optimized for headspace and direct sampling in aqueous solutions. Three different coating chemistries were tested and their performances compared in order to achieve the best compromise between sensitivity and analysis throughput. The newly developed PDMS/DVB/PDMS coating showed superior performance in terms of extraction efficiency while the capability to prevent on-fiber degradation of the derivatizing products. The optimized method was used for quantitation of short-chain aliphatic amines in aqueous samples and provided detection limits in the low ppb range for all the amines tested with accuracy values between 79 and 120%. The method was applied towards the analysis of environmental water samples and the accuracy of the results was evaluated by different calibration approaches.


Management of incision design in symphysis graft procedures: a review of the literature.
Symphysis graft procedures are being performed in clinical practice more frequently than ever before. Convenient surgical access, proximity of donor and recipient sites, low morbidity, availability of larger quantities of bone over other donor sites, minimal resorption, no hospitalization, and minimal discomfort are some advantages of this procedure over other intraoral sites. Three types of horizontal incisions can be performed during this procedure: the sulcular, the marginal, and the alveolar mucosal. Most studies regarding the chin graft technique are more concerned with the bone graft aspect than soft tissue management. Moreover, the criteria for the selected flap design appear to be based primarily on clinical experience or the same surgical approach regardless of interfacing factors. The periodontal status, amount of bone loss, periodontal risk of root fenestration, amount of keratinized gingiva, restorations in the gingival margin, and local musculature are some of the clinical findings that should be assessed to indicate the best incision design. In this review article, the advantages, disadvantages, indications, and contraindications of each incision design will be discussed.


Sound and vibration: effects on infants' heart rate and heart rate variability during neonatal transport.
To measure the effect of sound and whole-body vibration on infants' heart rate and heart rate variability during ground and air ambulance transport. Sixteen infants were transported by air ambulance with ground ambulance transport to and from the airports. Whole-body vibration and sound levels were recorded and heart parameters were obtained by ECG signal. Sound and whole-body vibration levels exceeded the recommended limits. Mean whole-body vibration and sound levels were 0.19 m/s(2) and 73 dBA, respectively. Higher whole-body vibration was associated with a lower heart rate (p < 0.05), and higher sound level was linked to a higher heart rate (p = 0.05). The heart rate variability was significantly higher at the end of the transport than at the beginning (p < 0.01). Poorer physiological status was associated with lower heart rate variability (p < 0.001) and a lower heart rate (p < 0.01). Infants wearing earmuffs had a lower heart rate (p < 0.05). Sound and whole-body vibration during neonatal transport exceed recommended levels for adults, and sound seem to have a more stressful effect on the infant than vibrations. Infants should wear earmuffs during neonatal transport because of the stress-reducing effect.


Persistence Mindset among Adolescents: Who Benefits from the Message that Academic Struggles are Normal and Temporary?
Research proposing that mindset interventions promote student achievement has been conducted at a frenetic pace nationwide in the United States, with many studies yielding mixed results. The present study explores the hypothesis that mindset interventions are beneficial for students only under specific circumstances. Using a randomized controlled trial with student-level random assignment within two public schools (School 1: n = 198 seventh-graders, 73% Black, 27% White, 53% male; School 2: n = 400 ninth-graders, 98% White, 2% Black, 52% male), this trial conceptually integrated elements from three evidence-based mindset interventions. It then examined two theoretically driven moderators of student performance following the transition to middle or high school: students' racial backgrounds and students' educational expectations. Results indicated that the intervention was effective for a particular subset of students-Black students with high educational expectations-resulting in higher grades over the course of the year. Among students with low educational expectations (regardless of race), the intervention did not impact grades. For White students with high educational expectations, the control activities actually benefitted grades more than the mindset intervention. Both theoretical and practical implications for mindset research are discussed.


Isolation and in vitro translation of human placental lactogen messenger RNA from human term placenta.
A messenger activity for HPL was identified in normal human term placentas. The mRNA was translated in rabbit reticulocyte cell-free system. The HPL synthesized was quantified by a specific immunoprecipitation and further identified by electrophoresis on sodium dodecyl sulfate polyacrylamide gel. The HPL synthesized in the reticulocyte lysate exhibited a molecular weight between 20,000 and 22,000 daltons similar to the active hormone. The messenger RNA activity for HPL corresponded to a sedimentation coefficient of 11-12 S. Furthermore the messenger activity for HPL was preferentially associated with membrane bound polyribosomes than with free polyribosomes.


Paroxysmal hemicrania responding to topiramate.
Chronic paroxysmal hemicrania (CPH) is a rare primary headache syndrome, which is classified along with cluster headache and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) as a trigeminal autonomic cephalalgia. CPH is exquisitely responsive to indomethacin, so much so that the response is one of the current diagnostic criteria. The case of a patient with CPH, who had marked epigastric symptoms with indomethacin treatment and responded well to topiramate 150 mg daily, is reported. Cessation of topiramate caused return of episodes, and the response has persisted for 2 years. Topiramate may be a treatment option in CPH.


Modelling the fate of persistent organic pollutants in Europe: parameterisation of a gridded distribution model.
A regionally segmented multimedia fate model for the European continent is described together with an illustrative steady-state case study examining the fate of gamma-HCH (lindane) based on 1998 emission data. The study builds on the regionally segmented BETR North America model structure and describes the regional segmentation and parameterisation for Europe. The European continent is described by a 5 degrees x5 degrees grid, leading to 50 regions together with four perimetric boxes representing regions buffering the European environment. Each zone comprises seven compartments including; upper and lower atmosphere, soil, vegetation, fresh water and sediment and coastal water. Inter-regions flows of air and water are described, exploiting information originating from GIS databases and other georeferenced data. The model is primarily designed to describe the fate of Persistent Organic Pollutants (POPs) within the European environment by examining chemical partitioning and degradation in each region, and inter-region transport either under steady-state conditions or fully dynamically. A test case scenario is presented which examines the fate of estimated spatially resolved atmospheric emissions of lindane throughout Europe within the lower atmosphere and surface soil compartments. In accordance with the predominant wind direction in Europe, the model predicts high concentrations close to the major sources as well as towards Central and Northeast regions. Elevated soil concentrations in Scandinavian soils provide further evidence of the potential of increased scavenging by forests and subsequent accumulation by organic-rich terrestrial surfaces. Initial model predictions have revealed a factor of 5-10 underestimation of lindane concentrations in the atmosphere. This is explained by an underestimation of source strength and/or an underestimation of European background levels. The model presented can further be used to predict deposition fluxes and chemical inventories, and it can also be adapted to provide characteristic travel distances and overall environmental persistence, which can be compared with other long-range transport prediction methods.


Asymmetry of neuronal activity during extracellular microelectrode recording from left and right human temporal lobe neocortex during rhyming and line-matching.
Recordings of neuronal activity in humans have identified few correlates of the known hemispheric asymmetries of functional lateralization. Here, we examine single-unit activity recorded from both hemispheres during two delayed match-to-sample tasks that show strong hemispheric lateralization based on lesion effects; a line-matching (LM) task related to the right hemisphere, and a rhyming (RHY) task related to the left. Nineteen neuronal populations were recorded with extracellular microelectrodes from the left temporal neocortex of 11 awake patients, and 18 from the right in 9 patients during anterior temporal lobectomy for complex partial seizures under local anesthesia. All subjects were left hemisphere dominant for language. Twelve (32%) populations exhibited statistically significant changes in activity at p <.05. Although changes in firing frequency were recorded from both hemispheres during both tasks, the RHY task elicited changes in activity several hundred milliseconds earlier on the left side than on the right. The LM task, on the other hand, induced changes earlier on the right side than on the left. Both hemispheres contained units active during verbal responses regardless of which behavior elicited the response. Our results indicate that cerebral dominance is reflected in earlier neuronal activity in the anterior temporal lobe during tasks lateralized to that hemisphere.


Construction of stable fluorescent laboratory control strains for several food safety relevant Enterobacteriaceae.
Using naturally-occurring bacterial strains as positive controls in testing protocols is typically feared due to the risk of cross-contaminating samples. We have developed a collection of strains which express Green Fluorescent Protein (GFP) at high-level, permitting rapid screening of the following species on selective or non-selective plates: Escherichia coli O157:H7, Shigella sonnei, S. flexneri, Salmonella enterica subsp. Enterica serovar Gaminera, S. Mbandaka, S. Tennesse, S. Minnesota, S. Senftenberg and S. Typhimurium. These new strains fluoresce when irradiated with UV light and maintain this phenotype in absence of antibiotic selection. Recombinants were phenotypically equivalent to the parent strain, except for S. Tennessee Sal66 that appeared Lac- on Xylose Lysine Deoxycholate (XLD) agar plates and Lac+ on Mac Conkey and Hektoen Enteric agar plates. Analysis of closed whole genome sequences revealed that Sal66 had lost one lactose operon; slower rates of lactose metabolism may affect lactose fermentation on XLD agar. These fluorescent enteric control strains were challenging to develop and should provide an easy and effective means of identifying cross-contamination.


Klinefelter syndrome and testosterone treatment: a national cohort study on thrombosis risk.
Klinefelter syndrome (KS), 47,XXY, can be viewed as a disease model for investigating the risk of thrombosis in male hypogonadism and the subsequent risk related to testosterone treatment. We describe rates of thrombotic risk factors, thrombosis and thrombosis mortality in KS and the association with testosterone treatment. National registry-based matched cohort study with follow-up from 1995 to 2016 set in Denmark. For the study, 1155 men with KS were each matched by year and month of birth to 100 men from the background population. First thrombotic events and thrombosis mortality was evaluated by event rates and hazard ratios (HRs) and by applying testosterone treatment as a time-dependent covariate. The KS cohort had higher incidence of venous thromboembolism relative to the comparison cohort (HR, 3.95; 95% CI, 2.83-5.52). Total thrombotic deaths were increased in KS (HR, 1.76; 95% CI, 1.18-2.62), and all-cause mortality was increased in KS following arterial thrombosis (HR 1.73; 95% CI 1.22-2.47). Only 48.7% of men with KS redeemed prescriptions for testosterone. Untreated men with KS were on average born 12 years before those treated, and the majority of untreated men with KS with available biochemistry were hypogonadal. Testosterone treatment in KS was associated with a non-significant decrease in venous thromboembolism and thrombotic deaths. Thrombosis and thrombotic deaths are increased in KS. Only half of the men with KS ever received testosterone treatment, despite overt hypogonadism in the non-treated. Testosterone treatment in Klinefelter syndrome was insignificantly associated with lower incidence rates of venous thrombosis and thrombotic deaths.


Monte-Carlo sure: a black-box optimization of regularization parameters for general denoising algorithms.
We consider the problem of optimizing the parameters of a given denoising algorithm for restoration of a signal corrupted by white Gaussian noise. To achieve this, we propose to minimize Stein's unbiased risk estimate (SURE) which provides a means of assessing the true mean-squared error (MSE) purely from the measured data without need for any knowledge about the noise-free signal. Specifically, we present a novel Monte-Carlo technique which enables the user to calculate SURE for an arbitrary denoising algorithm characterized by some specific parameter setting. Our method is a black-box approach which solely uses the response of the denoising operator to additional input noise and does not ask for any information about its functional form. This, therefore, permits the use of SURE for optimization of a wide variety of denoising algorithms. We justify our claims by presenting experimental results for SURE-based optimization of a series of popular image-denoising algorithms such as total-variation denoising, wavelet soft-thresholding, and Wiener filtering/smoothing splines. In the process, we also compare the performance of these methods. We demonstrate numerically that SURE computed using the new approach accurately predicts the true MSE for all the considered algorithms. We also show that SURE uncovers the optimal values of the parameters in all cases.


Feasibility and validation of a computer-automated Columbia-Suicide Severity Rating Scale using interactive voice response technology.
To evaluate a computer-automated version of the Columbia-Suicide Severity Rating Scale (C-SSRS) using interactive voice response technology (eC-SSRS™). The eC-SSRS assesses "Lifetime" ideations and behaviors at baseline and monitors suicidality prospectively thereafter. Ten control volunteers and ten psychiatric inpatients participated and were administered the C-SSRS at baseline and 4-8 days later by two experienced clinical trial raters. Study participants also completed the eC-SSRS using touch-tone telephones. Kappa measures of agreement compared inter-rater reliability of the C-SSRS administrations and the C-SSRS administrations with the eC-SSRS. Convergent validity with the Beck Scale for Suicide Ideation BSS and patient feedback forms were also evaluated. Twenty baseline and nineteen follow-up assessments were completed. In general, agreement between the eC-SSRS and each rater was comparable or superior to the agreement between both raters. Subject feedback and personal preferences varied across individuals, but were generally supportive of the feasibility and validity of the eC-SSRS. The reliability and validity of the C-SSRS and eC-SSRS for assessing suicidal ideation and behaviors were comparable in this first study comparing the methods. These data were obtained from relatively small patient samples recruited from a single investigational site over a relatively short follow-up period. They support the feasibility and validity of the eC-SSRS for prospective monitoring of suicidality for use in clinical trials or clinical care, but further research with larger samples, other patient populations, and longer follow-up periods is needed.


Navigating the fine line between benefit and risk in chronic atrial fibrillation: rationale and design of the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY).
Health outcomes associated with atrial fibrillation (AF) continue to be poor and standard management often does not provide clinical stability. The Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY) compares the efficacy of a post-discharge, nurse-led, multi-disciplinary programme to optimise AF management with usual care. SAFETY is a prospective, multi-centre, randomised controlled trial with blinded-endpoint adjudication. A target of 320 hospitalised patients with a chronic form of AF will be randomised (stratified by "rate" versus "rhythm" control) to usual post-discharge care or the SAFETY Intervention (SI). The SI involves home-based assessment, extensive clinical profiling and the application of optimal gold-standard pharmacology which is individually tailored according to a "traffic light" framework based on clinical stability, risk profile and therapeutic management. The primary endpoint is event-free survival from all-cause death or unplanned readmission during 18-36 months follow-up. Secondary endpoints include rate of recurrent hospital stay, treatment success (i.e. maintenance of rhythm or rate control and/or application of anti-thrombotic therapy without a bleeding event) and cost-efficacy. With study recruitment to be completed in early 2012, the results of this study will be available in early 2014. If positive, SAFETY will represent a potentially cost-effective and readily applicable strategy to improve health outcomes in high risk individuals discharged from hospital with chronic AF.


Fluoride Levels in Saliva and Plaque following the Use of High Fluoride and Conventional Dentifrices- a Triple Blinded Randomised Parallel Group Trial.
The comparison of fluoride levels in saliva and plaque following the use of conventional, 2800 and 5000 ppm dentifrices for different time intervals up to 24 hours has not been explored. The aim of the present study was to assess salivary and plaque fluoride levels at different time intervals following the use of high fluoride dentifrices. This randomised control trial was conducted on sixty adolescents between the age group of 16 and 18 years divided into three groups A, B, and C. Subjects were asked to brush the occlusal surfaces of posterior teeth with one of the dentifrices for 2 min. Unstimulated whole saliva and plaque samples were collected at different time intervals. Fluoride levels were determined using SPADNS method. Data was collected and statistically analyzed using SPSS 20 Inc. by mixed repeated measure ANOVA. A significant difference in fluoride levels was observed at different time intervals in both saliva (p=0.048) and plaque (p=0.03). The variance was low with time and concentration of the dentifrice used in saliva, whereas the magnitude of treatment was large for time (>0.25) but small for (<0.09) concentration in plaque. A significant difference in fluoride levels was observed at different time intervals in both saliva and plaque among the three groups. There was a positive correlation between fluoride levels in saliva and plaque. Both high fluoride dentifrices were effective in maintaining higher intraoral fluoride levels up to 12 hours and 5000 ppm up to 24 hours compared to conventional dentifrice.


Optical data storage potential of six materials.
Measurements of writing sensitivity and theoretical projections of readout signal-to-noise ratio achievable for several magnetooptical materials and an amorphous semiconductor material are used to assess their storage density and data rate potential in a discrete bit recording system. Dynamic read/write experiments utilizing infrared GaAs lasers presently indicate a density limit of 10(7) bits/cm(2) on MnAlGe and MnGaGe due to grain noise and on GdCo due to domain stability. Wavelength limited resolution appears obtainable on MnBi and TeGeAs although reversibility limitations exist. PtCo seems capable of exceeding 10(8) bits/cm(2) at data rates of 50 M bits/sec.


Exome and genome sequencing: a revolution for the discovery and diagnosis of monogenic disorders.
Massively parallel DNA sequencing has revolutionized analyses of human genetic variation. From having been out of reach for individual research groups and even more so for clinical diagnostic laboratories until recently, it is now possible to analyse complete human genomes within reasonable time frames and at a reasonable cost using technologies that are becoming increasingly available. This represents a huge advance in our ability to provide correct diagnoses for patients with rare inherited disorders and their families. This paradigm shift is especially dramatic within the area of monogenic disorders. Not only can rapid and safe diagnostics of virtually all known single-gene defects now be established, but novel causes of disease in previously unsolved cases can also be identified, illuminating novel pathways important for normal physiology. This greatly increases the capability not only to improve management of rare disorders, but also to improve understanding of pathogenetic mechanisms relevant for common, complex diseases.


Nonmelanoma skin cancer and the risk of second primary cancers: a systematic review.
Based on empirical evidence, a personal history of nonmelanoma skin cancer (NMSC) has been hypothesized to be a risk factor for other cancers. Others hypothesize that NMSC may be a marker of high cutaneous vitamin D synthesis and therefore inversely associated with risk of other malignancies. To reconcile these divergent views, we carried out a systematic review to determine the association between NMSC and subsequent risk of other cancers. Bibliographic databases were searched through March 2009. Studies were included if sufficient information was presented to estimate the risk of developing other cancers following NMSC. Studies were reviewed and data were abstracted independently in duplicate with disagreements resolved by consensus. Of the 21 included studies, 15 reported the association between NMSC and risk of all other cancers combined. NMSC was significantly associated with increased risk of another malignancy among cohort studies based on cancer registries summary random-effects relative risk (SRR), 1.12; 95% confidence interval (CI), 1.07-1.17; n = 12 studies) and those with individual-level data (SRR, 1.49; 95% CI, 1.12-1.98; n = 3). In stratified analyses of registry studies, this association held true for both squamous (SRR, 1.17; 95% CI, 1.12-1.23; n = 7) and basal cell carcinoma (SRR, 1.09; 95% CI, 1.01-1.17; n = 7), and both men (SRR, 1.14; 95% CI, 1.09-1.20; n = 12) and women (SRR, 1.10; 95% CI, 1.04-1.15; n = 12). Strong, consistent evidence indicates that a personal history of NMSC is associated with increased risk of developing other malignancies. For unknown reasons, NMSC may be a risk factor for other cancers.


Goblet cell carcinoids of the appendix.
Goblet cell carcinoid (GCC) tumors are a rare subgroup of neuroendocrine tumors almost exclusively originating in the appendix. The tumor most often presents in the fifth or sixth decade with a clinical picture of appendicitis or in advanced cases an abdominal mass associated with abdominal pain. Histologically tumors are most often positive for chromogranin A and synaptophysin, however, less homogenous than for classic appendix carcinoids. The malignant potential is higher than that for the classic appendix carcinoids due to local spread and distant metastases at diagnosis and the proliferation markers (Ki67 index) may determine prognosis. Octreotide receptor scintigraphy is usually negative while CT/MRI scans may be useful. Chromogranin A is usually negative and other biomarkers related to the mucinous component or the tumor (CEA, CA-19-9, and CA-125) may be used. Surgery is the main treatment with appendectomy and right hemicolectomy while patients with disseminated disease should be treated with chemotherapy. Overall 5-year survival is approximately 75%. The diagnosis and treatment of GCC tumors should be restricted to high volume NET centers in order to accumulate knowledge and improve survival in GCC NET patients. The aim of this paper is to update on epidemiology, clinical presentation, and diagnostic markers including Ki67 index, treatment, and survival.


Simultaneous Detection and Survey of Three Rice Viruses in China.
Rice black-streaked dwarf virus, Rice stripe virus, and Southern rice black-streaked dwarf virus (SRBSDV) have been epidemic in large areas of China where rice is grown, causing significant losses of rice yield in recent years. These viral diseases sometimes occur in the same regions, and even in the same fields, making it difficult to detect and diagnose the viral pathogens. A set of primers specific to the genes encoding the capsid proteins of the three viruses were designed, and a multiple one-step reverse-transcription polymerase chain reaction protocol was developed. The method proved to be simple, rapid, and sensitive. It was used to detect the viruses in samples of rice, maize, small brown planthoppers, and white-backed planthoppers collected from different regions of China, showing that it is suitable for routine diagnosis. A simultaneous survey of the three viruses was further conducted by this method throughout Zhejiang Province, Eastern China. The results showed that both RBSDV and RSV had continued to spread and that the newly emerging virus, SRBSDV, was present in at least 27 counties or cities, suggesting that more effort is needed to monitor and control the threat from these three viral diseases.


Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE).
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with multiple susceptibility genes. We have previously reported suggestive linkage to the chromosomal region 14q21-q23 in Finnish SLE families. Genetic fine mapping of this region in the same family material, together with a large collection of parent affected trios from UK and two independent case-control cohorts from Finland and Sweden, indicated that a novel uncharacterized gene, MAMDC1 (MAM domain containing glycosylphosphatidylinositol anchor 2, also known as MDGA2, MIM 611128), represents a putative susceptibility gene for SLE. In a combined analysis of the whole dataset, significant evidence of association was detected for the MAMDC1 intronic single nucleotide polymorphisms (SNP) rs961616 (P -value = 0.001, Odds Ratio (OR) = 1.292, 95% CI 1.103-1.513) and rs2297926 (P -value = 0.003, OR = 1.349, 95% CI 1.109-1.640). By Northern blot, real-time PCR (qRT-PCR) and immunohistochemical (IHC) analyses, we show that MAMDC1 is expressed in several tissues and cell types, and that the corresponding mRNA is up-regulated by the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) in THP-1 monocytes. Based on its homology to known proteins with similar structure, MAMDC1 appears to be a novel member of the adhesion molecules of the immunoglobulin superfamily (IgCAM), which is involved in cell adhesion, migration, and recruitment to inflammatory sites. Remarkably, some IgCAMs have been shown to interact with ITGAM, the product of another SLE susceptibility gene recently discovered in two independent genome wide association (GWA) scans. Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE.


Efficiency of photosynthesis in a Chl d-utilizing cyanobacterium is comparable to or higher than that in Chl a-utilizing oxygenic species.
The cyanobacterium Acaryochloris marina uses chlorophyll d to carry out oxygenic photosynthesis in environments depleted in visible and enhanced in lower-energy, far-red light. However, the extent to which low photon energies limit the efficiency of oxygenic photochemistry in A. marina is not known. Here, we report the first direct measurements of the energy-storage efficiency of the photosynthetic light reactions in A. marina whole cells, and find it is comparable to or higher than that in typical, chlorophyll a-utilizing oxygenic species. This finding indicates that oxygenic photosynthesis is not fundamentally limited at the photon energies employed by A. marina, and therefore is potentially viable in even longer-wavelength light environments.


Substrate- and isoform-specific dioxygen complexes of nitric oxide synthase.
Nitric oxide synthase (NOS) catalyzes the formation of NO via a consecutive two-step reaction. In the first step, L-arginine (Arg) is converted to N-hydroxy-L-arginine (NOHA). In the second step, NOHA is further converted to citrulline and nitric oxide (NO). To assess the mechanistic differences between the two steps of the reaction, we have used resonance Raman spectroscopy combined with a homemade continuous-flow rapid solution mixer to study the structural properties of the metastable dioxygen-bound complexes of the oxygenase domain of inducible NOS (iNOSoxy). We identified the O-O stretching frequency of the substrate-free enzyme at 1133 cm-1. This frequency is insensitive to the presence of tetrahydrobiopterin, but it shifts to 1126 cm-1 upon binding of Arg, which we attribute to H-bonding interactions to the terminal oxygen atom of the heme iron-bound dioxygen. In contrast, the addition of NOHA to the enzyme did not bring about a shift in the frequency of the O-O stretching mode, because, unlike Arg, there is no H-bond associated with the terminal oxygen atom of the dioxygen. The substrate-specific H-bonding interactions play a critical role in determining the fate of the key peroxy intermediate. In the first step of the reaction, the H-bonds facilitate the rupture of the O-O bond, leading to the formation of the active ferryl species, which is essential for the oxidation of the Arg. On the other hand, in the second step of the reaction, the absence of the H-bonds prevents the premature O-O bond cleavage, such that the peroxy intermediate can perform a nucleophilic addition reaction to the substrate, NOHA.


Diversity of human tRNA genes from the 1000-genomes project.
The sequence diversity of individual human genomes has been extensively analyzed for variations and phenotypic implications for mRNA, miRNA, and long non-coding RNA genes. TRNA (tRNA) also exhibits large sequence diversity in the human genome, but tRNA gene sequence variation and potential functional implications in individual human genomes have not been investigated. Here we capitalize on the sequencing data from the 1000-genomes project to examine the diversity of tRNA genes in the human population. Previous analysis of the reference human genome indicated an unexpected large number of diverse tRNA genes beyond the necessity of translation, suggesting that some tRNA transcripts may perform non-canonical functions. We found 24 new tRNA sequences in>1% and 76 new tRNA sequences in>0.2% of all individuals, indicating that tRNA genes are also subject to evolutionary changes in the human population. Unexpectedly, two abundant new tRNA genes contain base-pair mismatches in the anticodon stem. We experimentally determined that these two new tRNAs have altered structures in vitro; however, one new tRNA is not aminoacylated but extremely stable in HeLa cells, suggesting that this new tRNA can be used for non-canonical function. Our results show that at the scale of human population, tRNA genes are more diverse than conventionally understood, and some new tRNAs may perform non-canonical, extra-translational functions that may be linked to human health and disease.


Increased polymorphism near low-complexity sequences across the genomes of Plasmodium falciparum isolates.
Low-complexity regions (LCRs) within proteins sequences are often considered to evolve neutrally even though recent studies reported evidence for selection acting on some of them. Because of their widespread distribution among eukaryotes genomes and the potential deleterious effect of expansion/contraction of some of them in humans, low-complexity sequences are of major interest and numerous studies have attempted to describe their dynamic between genomes as well as the factors correlated to their variation and to assess their selective value. However, due to the scarcity of individual genomes within a species, most of the analyses so far have been performed at the species level with the implicit assumption that the variation both in composition and size within species is too small relative to the between-species divergence to affect the conclusions of the analysis. Here we used the available genomes of 14 Plasmodium falciparum isolates to assess the relationship between low-complexity sequence variation and factors such as nucleotide polymorphism across strains, sequence composition, and protein expression. We report that more than half of the 7,711 low-complexity sequences found within aligned coding sequences are variable in size among strains. Across strains, we observed an increasing density of polymorphic sites toward the LCR boundaries. This observation strongly suggests the joint effects of lowered selective constraints on low-complexity sequences and a mutagenic effect of these simple sequences.


Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1.
An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin. In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks. Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events. In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.).


Formation of the Inclusive Environments and Metrics in Biology Education and Research (iEMBER) Network: Building a Culture of Diversity, Equity, and Inclusion.
The Inclusive Environments and Metrics in Biology Education and Research (iEMBER) network is a newly forming national community of practice that engages diversity, equity, and inclusion stakeholders in interdisciplinary collaborative projects. iEMBER was initiated with incubator funding from the National Science Foundation program for Research Coordination Networks in Undergraduate Biology Education. In June 2017, biology education researchers, social scientists, biologists, and program and policy administrators, all with interests in diversity, equity, and inclusion, met to lay the foundation for the iEMBER network. iEMBER provides a distinct forum to coordinate efforts through networking, professional development, and the initiation of collaborative research. iEMBER advances science, technology, engineering, and mathematics reform focused on diversity, equity, and inclusion through the initiation of research teams at the iEMBER biennial conference and outreach efforts at discipline-specific meetings and conferences. The focus of iEMBER is on understanding how to create inclusive, supportive, and engaging environments to foster the success of all biology students and trainees. This report focuses on the structure of the iEMBER network, two takeaways that emerged from the 2017 conference (interdisciplinary networking/collaboration and intradisciplinary broadening participation strategies), and ways for prospective members to engage in ongoing dialogue and future events. Learn more at http://iember.org .


What does Brexit mean for UK tobacco control?
In January 2020 the UK left the European Union (EU), although a transition period extends EU rules/regulations until the end of 2020 while a longer-term relationship agreement is negotiated. After almost 50 years of membership the UK economy is tightly integrated into that of the EU single market, and many UK laws and regulations have their origins in the EU, including those concerning tobacco. This paper provides an overview of potential implications of Brexit for UK tobacco control. We examine the key areas of the supply, cost, taxation, and regulation of tobacco products, and the impact of commitments in regards to the border between Ireland and Northern Ireland (NI). We find that Brexit provides an opportunity for improved tobacco control with potential for particular enhancements in the areas of taxation and product regulation. However, commitments in regards to NI mean these benefits either won't extend to NI (which will continue to follow EU rules), or could lead to the whole UK having to follow most EU rules/regulations despite no longer being involved in the decision making process. The details of any future deal will be important, especially since virtually all UK tobacco products come from the EU, and hence would be subject to disruption/considerable new tariffs (i.e. taxation on imports) without a trade deal. We conclude that political will by the UK government to secure conditions which protect the UK's world leading tobacco control measures will be key to whether Brexit helps or hinders tobacco control in the UK. In this regards the signs are mixed.


Cap 'n' collar C regulates genes responsible for imidacloprid resistance in the Colorado potato beetle, Leptinotarsa decemlineata.
The Colorado potato beetle (CPB), Leptinotarsa decemlineata developed resistance to imidacloprid after exposure to this insecticide for multiple generations. Our previous studies showed that xenobiotic transcription factor, cap 'n' collar isoform C (CncC) regulates the expression of multiple cytochrome P450 genes, which play essential roles in resistance to plant allelochemicals and insecticides. In this study, we sought to obtain a comprehensive picture of the genes regulated by CncC in imidacloprid-resistant CPB. We performed sequencing of RNA isolated from imidacloprid-resistant CPB treated with dsRNA targeting CncC or gene coding for green fluorescent protein (control). Comparative transcriptome analysis showed that CncC regulated the expression of 1798 genes, out of which 1499 genes were downregulated in CncC knockdown beetles. Interestingly, expression of 79% of imidacloprid induced P450 genes requires CncC. We performed quantitative real-time PCR to verify the reduction in the expression of 20 genes including those coding for detoxification enzymes (P450s, glutathione S-transferases, and esterases) and ABC transporters. The genes coding for ABC transporters are induced in insecticide resistant CPB and require CncC for their expression. Knockdown of genes coding for ABC transporters simultaneously or individually caused an increase in imidacloprid-induced mortality in resistant beetles confirming their contribution to insecticide resistance. These studies identified CncC as a transcription factor involved in regulation of genes responsible for imidacloprid resistance. Small molecule inhibitors of CncC or suppression of CncC by RNAi could provide effective synergists for pest control or management of insecticide resistance.


Adaptive introgression underlies polymorphic seasonal camouflage in snowshoe hares.
Snowshoe hares (Lepus americanus) maintain seasonal camouflage by molting to a white winter coat, but some hares remain brown during the winter in regions with low snow cover. We show that cis-regulatory variation controlling seasonal expression of the Agouti gene underlies this adaptive winter camouflage polymorphism. Genetic variation at Agouti clustered by winter coat color across multiple hare and jackrabbit species, revealing a history of recurrent interspecific gene flow. Brown winter coats in snowshoe hares likely originated from an introgressed black-tailed jackrabbit allele that has swept to high frequency in mild winter environments. These discoveries show that introgression of genetic variants that underlie key ecological traits can seed past and ongoing adaptation to rapidly changing environments.


Effective communication in eliciting and responding to suicidal thoughts: a systematic review protocol.
In the UK, over 6500 people die by suicide each year. In England alone, this is one person every 2 h. Professionals assess risk of suicide in face-to-face contacts with people potentially at risk. The National Confidential Inquiry into Suicide found that most people who took their life were classified as 'low risk' in their final contact with mental health services. Training for front-line staff in reducing suicide is a NHS priority. While there is considerable evidence on what to assess when exploring suicidal ideation, there is little evidence on how to ask sensitive questions to effectively identify suicide risk and how to respond in the treatment encounter to reduce patient distress and suicidal ideation. This is critical for identifying risk and putting appropriate care in place. An electronic search will be conducted using MEDLINE, CINAHL, Cochrane Library, EMBASE and PsycINFO databases. Controlled studies of effectiveness will be identified using a predefined search strategy. The focus will be on suicidal thoughts/feelings rather than self-harm without intent to die. Two authors will independently screen articles using predefined inclusion and exclusion criteria and relevant data will be extracted using the Cochrane Collaboration data extraction form for randomised controlled trials (RCTs). Discrepancies between the two authors will be resolved by consensus or by consulting a third author at all levels of screening. We will assess the quality of evidence as well as risk of bias. A meta-analysis will be conducted if participants, interventions and comparisons are sufficiently similar, and we will perform the meta-analysis using Stata data analysis and statistical software. The results of this systematic review will be used to guide training and practice for health care professionals. PROSPERO CRD42015025867.


The Impact of Adding an Eccentric-Exercise Component to the Rehabilitation Program of Patients With Shoulder Impingement: A Critically Appraised Topic.
Shoulder pain is a common musculoskeletal complaint and is often associated with shoulder impingement. The annual incidence of shoulder pain is estimated to be 7% of all injuries, and is the third-most-common type of musculoskeletal pain. Initial treatment of shoulder impingement follows a conservative plan and emphasizes rehabilitation programs as opposed to surgical interventions. Shoulder rehabilitation programs commonly focus on strengthening the muscles of the shoulder complex and, more specifically, the rotator cuff. The rotator cuff is a primary dynamic stabilizer of the glenohumeral joint, using both eccentric and concentric contractions. The posterior rotator cuff, including teres minor and infraspinatus, works eccentrically to decelerate the arm during overhead throwing. Exercises to strengthen the rotator cuff and the surrounding dynamic stabilizers of the shoulder girdle vary and include activities such as internal and external rotation, full-can lifts, and rhythmic stabilizations. Traditionally, shoulder rehabilitation programs have focused on isotonic concentric contractions. Common strengthening exercises typically involve movements that result in shortening the muscle length while simultaneously loading the muscles. However, recent attention has been given to eccentric exercises, which involve lengthening of the muscle during loading, for the treatment of a variety of different tendinopathies including those of the Achilles and patellar tendons. The eccentric, or lengthening, motion is thought to be beneficial for people who are involved in activities that place eccentric stress on their shoulder, such as overhead throwers. Based on studies related to the Achilles tendon, eccentric exercise may positively influence the tendon structure by increasing collagen production and decreasing neovascularization. The changes that occur as a result of eccentric exercises may improve function, strength, and performance and decrease pain more than concentric programs, producing better patient outcomes. Although eccentric strength training has been shown to provide strength gains, there are no clear guidelines as to the inclusion of this form of exercise training in shoulder rehabilitation programs for the purposes of improving function and decreasing pain. Focused Clinical Question: Does adding an eccentric-exercise component to the rehabilitation program of patients with shoulder impingement improve shoulder function and/or decrease pain?


Description, evaluation and scale-up potential of a model for rapid access to early intervention for psychosis.
This paper aims to describe the entry protocol of the Prevention and Early Intervention for Psychosis Program (PEPP)-Montreal, an early intervention program for psychosis. The protocol is designed to fulfil a key objective of the early intervention movement-reducing delays to accessing high-quality care. The paper also aims to describe how this rapid entry protocol can be deployed in other services interested in reducing delays in initiating treatment. PEPP provides rapid, easy access to quality care by placing a single, well-trained professional, the intake clinician, at the point of entry. Anyone can refer a youth directly and without formalities to the intake clinician who responds promptly and sensitively to all help-seeking, whether by a youth, a family member, a school counsellor or anyone acting on behalf of a youth in need. To promote accessibility, PEPP guarantees an initial assessment within 72 hours; maintains relationships with referral sources; and conducts awareness-enhancing outreach activities. Since 2003, PEPP has received 1750 referrals, which have all been responded to within 72 hours. Families have been involved in the intake process in 60% of the cases and hospitalization may have been averted in over half of the referrals originating from emergency-room services. Another indicator of success is the very low turnover in the intake clinician's position. Overall, the PEPP model has succeeded in providing rapid, engaging, easy and youth-friendly access to high-quality care. The success of this protocol at PEPP has inspired the entry protocols at other first-episode psychosis services. Its ability to provide rapid, engaging access to high-quality services may allow this protocol to become a model for other early intervention services for psychosis and other mental illnesses.


Higher order mode suppression in high-Q anomalous dispersion SiN microresonators for temporal dissipative Kerr soliton formation.
High-Q silicon nitride (SiN) microresonators enable optical Kerr frequency comb generation on a photonic chip and have recently been shown to support fully coherent combs based on temporal dissipative Kerr soliton formation. For bright soliton formation, it is necessary to operate SiN waveguides in the multimode regime in order to produce waveguide induced anomalous group velocity dispersion. However, this regime can lead to local disturbances of the dispersion due to avoided crossings caused by coupling between different mode families and, therefore, prevent the soliton formation. Here, we demonstrate that a single-mode "filtering" section inside high-Q resonators enables efficiently suppression of avoided crossings, while preserving high quality factors (Q∼10(6)). We verify the approach by demonstrating single soliton formation in SiN resonators with a filtering section.


Selectivity profiling of DegP substrates and inhibitors.
Protein quality control factors are involved in many key physiological processes and severe human diseases that are based on misfolding or amyloid formation. Prokaryotic representatives are often virulence factors of pathogenic bacteria. Therefore, protein quality control factors represent a novel class of drug targets. The bacterial serine protease DegP, belonging to the widely conserved family of HtrA proteases, exhibits unusual structural and functional plasticity that could be exploited by small molecule modulators. However, only one weak synthetic peptide substrate and no inhibitors are available to date. We report the identification of a potent heptameric pNA-substrate and chloromethyl ketone based inhibitors of DegP. In addition, specificity profiling resulted in the identification of one strong inhibitor and a potent substrate for subtilisin as well as a number of specific elastase substrates and inhibitors.


Improving signal strength in serial crystallography with DIALS geometry refinement.
The DIALS diffraction-modeling software package has been applied to serial crystallography data. Diffraction modeling is an exercise in determining the experimental parameters, such as incident beam wavelength, crystal unit cell and orientation, and detector geometry, that are most consistent with the observed positions of Bragg spots. These parameters can be refined by nonlinear least-squares fitting. In previous work, it has been challenging to refine both the positions of the sensors (metrology) on multipanel imaging detectors such as the CSPAD and the orientations of all of the crystals studied. Since the optimal models for metrology and crystal orientation are interdependent, alternate cycles of panel refinement and crystal refinement have been required. To simplify the process, a sparse linear algebra technique for solving the normal equations was implemented, allowing the detector panels to be refined simultaneously against the diffraction from thousands of crystals with excellent computational performance. Separately, it is shown how to refine the metrology of a second CSPAD detector, positioned at a distance of 2.5 m from the crystal, used for recording low-angle reflections. With the ability to jointly refine the detector position against the ensemble of all crystals used for structure determination, it is shown that ensemble refinement greatly reduces the apparent nonisomorphism that is often observed in the unit-cell distributions from still-shot serial crystallography. In addition, it is shown that batching the images by timestamp and re-refining the detector position can realistically model small, time-dependent variations in detector position relative to the sample, and thereby improve the integrated structure-factor intensity signal and heavy-atom anomalous peak heights.


Effect of green tea and lycopene on the insulin-like growth factor system: the ProDiet randomized controlled trial.
Whether prostate cancer (PCa) may be preventable by dietary interventions can be assessed in randomized trials using intermediate biomarkers of cancer risk or progression. We investigated whether lycopene or green tea modify circulating insulin-like growth factor (IGF) peptides in men at increased risk of PCa. Participants (aged 50-69 years) in one centre in the UK wide PCa testing and treatment trial (ProtecT) with prostate specific antigen between 2.0 and 2.95 ng/ml or negative biopsies, were randomized to daily lycopene (n = 44 assigned 15 mg capsules/day; 44 assigned a lycopene-rich diet; 45 assigned placebo) and green tea (n = 45 assigned 600 mg/day epigallocatechin gallate; 45 assigned green tea drink; 43 assigned placebo) for 6 months. The interventions significantly elevated the primary outcomes, serum epigallocatechin gallate and lycopene at 6 months of follow-up. We report here an exploratory analysis in which serum IGF-I, IGF-II, IGF binding protein (BP)-2 and IGFBP-3 were measured at baseline and 6 months of postintervention. A total of 133 men were randomized (34% of eligible men approached) and 130 had follow-up IGF peptides (98%). In intention-to-treat analyses, there was only weak evidence that lycopene or green tea influenced some aspects of serum IGF-I, IGF-II, IGFBP-2 or IGFBP-3. In men randomized to lycopene supplements, IGFBP-2 was nonsignificantly (50.9 ng/ml; 95% confidence interval: -51.2-152.9, P = 0.3) higher in comparison to placebo, whereas in men randomized to green tea supplements, IGFBP-3 was nonsignificantly (205.2 ng/ml; 95% confidence interval: -583.3-172.9, P = 0.3) lower than with placebo. In this small, pilot randomized controlled trial, there was little evidence that lycopene or green tea interventions influenced serum levels of IGF-I, IGF-II, IGFBBP-3 and IGFBP-2. However, the effects were imprecisely estimates and some observed trends may justify larger trials.


Genome-wide transcriptome profiling reveals functional networks involving the Plasmodium falciparum drug resistance transporters PfCRT and PfMDR1.
The acquisition of multidrug resistance by Plasmodium falciparum underscores the need to understand the underlying molecular mechanisms so as to counter their impact on malaria control. For the many antimalarials whose mode of action relates to inhibition of heme detoxification inside infected erythrocytes, the digestive vacuole transporters PfCRT and PfMDR1 constitute primary resistance determinants. Using gene expression microarrays over the course of the parasite intra-erythrocytic developmental cycle, we compared the transcriptomic profiles between P. falciparum strains displaying mutant or wild-type pfcrt or varying in pfcrt or pfmdr1 expression levels. To account for differences in the time of sampling, we developed a computational method termed Hypergeometric Analysis of Time Series, which combines Fast Fourier Transform with a modified Gene Set Enrichment Analysis. Our analysis revealed coordinated changes in genes involved in protein catabolism, translation initiation and DNA/RNA metabolism. We also observed differential expression of genes with a role in transport or coding for components of the digestive vacuole. Interestingly, a global comparison of all profiled transcriptomes uncovered a tight correlation between the transcript levels of pfcrt and pfmdr1, extending to dozens of other genes, suggesting an intricate regulatory balance in order to maintain optimal physiological processes. This study provides insight into the mechanisms by which P. falciparum adjusts to the acquisition of mutations or gene amplification in key transporter loci that mediate drug resistance. Our results implicate several biological pathways that may be differentially regulated to compensate for impaired transporter function and alterations in parasite vacuole physiology.


The effects of non-insulin-dependent diabetes mellitus on the kinetics of onset of insulin action in hepatic and extrahepatic tissues.
The mechanism(s) of insulin resistance in non-insulin-dependent diabetes mellitus remains ill defined. The current studies sought to determine whether non-insulin-dependent diabetes mellitus is associated with (a) a delay in the rate of onset of insulin action, (b) impaired hepatic and extrahepatic kinetic responses to insulin, and (c) an alteration in the contribution of gluconeogenesis to hepatic glucose release. To answer these questions, glucose disappearance, glucose release, and the rate of incorporation of 14CO2 into glucose were measured during 0.5 and 1.0 mU/kg-1 per min-1 insulin infusions while glucose was clamped at approximately 95 mg/dl in diabetic and nondiabetic subjects. The absolute rate of disappearance was lower (P < 0.05) and the rate of increase slower (P < 0.05) in diabetic than nondiabetic subjects during both insulin infusions. In contrast, the rate of suppression of glucose release in response to a change in insulin did not differ in the diabetic and nondiabetic subjects during either the low (slope 30-240 min:0.02 +/- 0.01 vs 0.02 +/- 0.01) or high (0.02 +/- 0.00 vs 0.02 +/- 0.00) insulin infusions. However, the hepatic response to insulin was not entirely normal in the diabetic subjects. Both glucose release and the proportion of systemic glucose being derived from 14CO2 (an index of gluconeogenesis) was inappropriately high for the prevailing insulin concentration in the diabetic subjects. Thus non-insulin-dependent diabetes mellitus slows the rate-limiting step in insulin action in muscle but not liver and alters the relative contribution of gluconeogenesis and glycogenolysis to hepatic glucose release.


[Validation of tools for assessing the intelligence and the functional impairment of Papiamento speaking suspects].
Although Antillean suspects in the Netherlands are often diagnosed as being intellectually impaired, there are no validated tests available Papiamento (the native language) for assessing intelligence or functional impairment. To validate the use of the GIT 2 (Groninger Intelligentie Test 2) and the Barkley Functioning Impairment Scale (BFIS) for Antillean defendants detained by the Judicial Service of the Caribbean Netherlands in Bonaire. With the approval of the publishers, the GIT 2 and the BFIS were translated in Papiamento by two independent experts. The two translations were then re-translated into Dutch by two other independent experts. Defendants with both parents born in Bonaire who had been detained for at least 18 days by the Judicial Detention Centre of the Caribbean Netherlands (JICN) in Bonaire during the period 1 January 2013 until 1 July 2014 were examined with both tests. The Papiamento GIT 2 and BFIS tests were taken by 23 Bonairian defendants who had been detained in the JICN in Bonaire. The internal consistency and inter-item correlation of the tests were found to be satisfactory. The IQ of 95% of the participants was reproduced as a score between 79.2 and 96.8 points. In the BFIS the question about self-care was a particularly sensitive item. The use of drugs was associated with increased functional impairment. This study seems to be a promising first step towards the validation of the GIT 2 and the BFIS. Apparently, it has now become acceptable to use written Papiamento in assessment tools.


Understanding the Value of Patientview for Enabling Self-Care Practice in Chronic Kidney Disease.
Individual responsibility and self-care are seen as ways to overcome some of the challenges for long-term health care provision. Patients are being encouraged to take an active role in their health care. Access to health information via a web-based, patient-facing portal is an innovative way to engage in self-care. PatientView is one such portal, which was developed to allow patients with kidney disease access to parts of their health record. It was thought that the use of PatientView would improve self-care activity but there was little evidence to support this claim. To gain an understanding of how patients with kidney disease use PatientView in their self-care practice. Six users and four non-users of PatientView. Qualitative, semi-structured interviews and participant observation. A practice-based approach was used to collect qualitative data to better understand how patients use PatientView in daily life to enable self-care. Participants were invited to "show the researcher" how they use PatientView and to describe how they translated the information into actions of self-care. Inductive analysis was used to identify themes. The analysis identified four key themes, which were non-linear inter-related. Patients engage with PatientView because it supports ways of knowing that are of direct importance to self-care activity. Patients interact with PatientView and translate the information they gain from using it into actions that support self-care. A consequence of engaging with PatientView is that patients can involve their family more in their care and this helps to reduce the burden on health care professionals. Patient interactions with PatientView are inter-related, multi-dimensional and differ according to the individual's positioning within a continuum of care. Nonetheless, these interactions can be captured and doing so provides a basis for understanding of how patients create and sustain opportunities for care through information technology.


Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors.
Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages. To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed. The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms. During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3-4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome.


Biocompatibility and biodistribution of surface-enhanced Raman scattering nanoprobes in zebrafish embryos: in vivo and multiplex imaging.
Nanoparticles are increasingly being used to investigate biological processes in various animal models due to their versatile chemical, unique optical, and multifunctional properties. In this report we address the biocompatibility and biodistribution of nanoparticle sensors used for Raman chemical imaging in live zebrafish (Danio rerio) embryos. Surface-enhanced Raman scattering (SERS) nanoprobes (NPs) comprising gold nanoparticles (AuNPs) as enhancing substrate and nonfluorescent Raman labels were synthesized and microinjected into zebrafish embryos at the one-cell stage. Raman mapping was performed to assess their distribution in various cell-types and tissues of developing embryo at five different stages between 6 and 96 hpf (hours post-fertilization). Biocompatibility and toxicity studies indicate that the NPs are not toxic and the embryos were found to exhibit normal morphological and gene expression in addition to the proper form and function of major organs such as the heart and vasculature (of 7 day old NPs injected zebrafish embryos). A multiplex in vivo detection protocol was developed by SERS imaging to demonstrate that multiple labels can be detected by Raman mapping in undifferentiated cells as they develop into distinct cell- and tissue-types. The present work is the first to report on multiplex Raman imaging of zebrafish embryos with potential implications in tracking tissue development and biological processes at single molecule sensitivity using appropriate target molecules in vivo.


T-cell reactivity to insulin peptide A1-12 in children with recently diagnosed type 1 diabetes or multiple beta-cell autoantibodies.
Insulin-specific immune responses appear early in preclinical type 1 diabetes (T1D), and bovine insulin in cow's milk-based infant formulas has been suggested to be of importance in induction of the primary response to insulin in humans. To characterize insulin-specific T-cell reactivity we studied T-cell responses to 10 insulin peptides derived from bovine (BI) and human insulin (HI) in 42 children with recently diagnosed T1D, 47 children with multiple autoantibodies and 111 autoantibody-negative control children with risk-associated HLA alleles. Proliferation responses detected in antigen-stimulated peripheral blood mononuclear cells did not differ between the three groups when the comparison was performed without considering HLA genotypes. However, significant differences were observed, when children with the high-risk genotype HLA (DRB1*03)-DQA1*05-DQB1*02/DRB1*0401-DQA1*03-DQB1*0302 were analyzed separately. The responses to the peptides including amino acids A1-12 derived from B1 and H1 were significantly higher in children with T1D (P=0.008, P=0.004, for B1 and H1, respectively) and in children with diabetes-associated autoantibodies (P=0.002 and P=0.001, respectively) than in control children. Positive responses (stimulation indices SI> or =3) were seen more frequently in T1D children than in controls (4/7 vs 2/19; P=0.03 and 4/7 vs 1/19; P=0.01 for B1 and H1, respectively). T-cell response to the insulin peptide A1-12 is enhanced in clinical and preclinical T1D associated with the high-risk HLA-genotype emphasizing the importance of this epitope.


Oral mucositis: the new paradigms.
Mucositis has long been viewed as an unavoidable consequence of high-dose chemotherapy and/or radiation. Management has been directed to supportive care including oral pain control, nutritional support, infection treatment and control of diarrhea. Whereas these interventions have been valuable for clinical management, they have not been collectively directed to molecularly targeted prevention and treatment. This review addresses recent advances regarding mucosal injury in cancer patients, with emphasis on symptom clusters, genetically based tissue susceptibility and risk prediction, imaging technology, and computational biology. Modeling of symptom clusters in cancer patients continues to mature. Although integration of mucositis into the paradigm is at an early stage, recent studies suggest that important molecular and clinical insights will emerge in this regard. Initial studies of genetic-based tissue risk are also providing a research basis that may lead to clinical risk prediction models. These advances are in part being engineered via new imaging and computational biology technologies, drawing upon literature in nonmucositis systems. Just as the past decade has been hallmarked by linkage of pathobiology with clinical expression of mucosal toxicity, the next decade promises to identify new molecular interactions and risk prediction models based on novel application of the analytic technologies. Recent research has culminated in convergence of molecular pathobiology with models of symptom clusters, genetic-based risk, and imaging and computational biology. The field is poised to further delineate this paradigm, with the goal of development of molecularly targeted drugs and devices for mucositis management.


Outer brain barriers in rat and human development.
Complex barriers at the brain's surface, particularly in development, are poorly defined. In the adult, arachnoid blood-cerebrospinal fluid (CSF) barrier separates the fenestrated dural vessels from the CSF by means of a cell layer joined by tight junctions. Outer CSF-brain barrier provides diffusion restriction between brain and subarachnoid CSF through an initial radial glial end feet layer covered with a pial surface layer. To further characterize these interfaces we examined embryonic rat brains from E10 to P0 and forebrains from human embryos and fetuses (6-21st weeks post-conception) and adults using immunohistochemistry and confocal microscopy. Antibodies against claudin-11, BLBP, collagen 1, SSEA-4, MAP2, YKL-40, and its receptor IL-13Rα2 and EAAT1 were used to describe morphological characteristics and functional aspects of the outer brain barriers. Claudin-11 was a reliable marker of the arachnoid blood-CSF barrier. Collagen 1 delineated the subarachnoid space and stained pial surface layer. BLBP defined radial glial end feet layer and SSEA-4 and YKL-40 were present in both leptomeningeal cells and end feet layer, which transformed into glial limitans. IL-13Rα2 and EAAT1 were present in the end feet layer illustrating transporter/receptor presence in the outer CSF-brain barrier. MAP2 immunostaining in adult brain outlined the lower border of glia limitans; remnants of end feet were YKL-40 positive in some areas. We propose that outer brain barriers are composed of at least 3 interfaces: blood-CSF barrier across arachnoid barrier cell layer, blood-CSF barrier across pial microvessels, and outer CSF-brain barrier comprising glial end feet layer/pial surface layer.


Photochromic control of photoinduced electron transfer. Molecular double-throw switch.
A molecular double-throw switch that employs a photochromic moiety to direct photoinduced electron transfer from an excited state donor down either of two pathways has been prepared. The molecular triad consists of a free base porphyrin (P) linked to both a C(60) electron acceptor and a dihydroindolizine (DHI) photochrome. Excitation of the porphyrin moiety of DHI-P-C(60) results in photoinduced electron transfer with a time constant of 2.3 ns to give the DHI-P(*)(+)-C(60)(*)(-) charge-separated state with a quantum yield of 82%. UV (366 nm) light photoisomerizes the DHI moiety to the betaine (BT) form, which has a higher reduction potential than DHI. Excitation of the porphyrin of BT-P-C(60) is followed by photoinduced electron transfer with a time constant of 56 ps to produce BT(*)(-)-P(*)(+)-C(60) in 99% yield. Isomerization of BT-P-C(60) back to DHI-P-C(60) may be achieved with visible light, or thermally. Thus, photoinduced charge separation originating from the porphyrin is reversibly directed down either of two different pathways by photoisomerization of the dihydroindolizine. The switch may be cycled many times.


Fertilization and nicotinic acid adenine dinucleotide phosphate induce pH changes in acidic Ca(2+) stores in sea urchin eggs.
The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) releases Ca(2+) from the acidic Ca(2+) stores of many organisms, including those of the sea urchin egg. We investigated whether the pH within the lumen of these acidic organelles changes in response to stimuli. Fertilization activates the egg by Ca(2+) release dependent upon NAADP, and accordingly, we report that fertilization also alters organellar pH in a spatio-temporally complex manner. Upon sperm fusion, vesicles deep in the egg center slowly acidify, whereas cortical vesicles undergo a rapid alkalinization. The cortical vesicle alkalinization is independent of exocytosis and cytosolic pH but coincides with the NAADP-dependent fertilization Ca(2+) wave. Microinjection of NAADP mimicked the fertilization cortical response, suggesting that it occurred within NAADP-sensitive acidic Ca(2+) stores. Our data show that NAADP and physiological stimuli alter the pH within intracellular organelles and suggest that NAADP signals through pH as well as Ca(2+).


Localization of sparse and coherent sources by orthogonal least squares.
This paper proposes an efficient method for the joint localization of sources and estimation of the covariance of their signals. In practice, such an estimation is useful to study correlated sources existing, for instance, in the presence of spatially distributed sources or reflections, but is confronted with the challenge of computational complexity due to a large number of required estimates. The proposed method is called covariance matrix fitting by orthogonal least squares. It is based on a greedy dictionary based approach exploiting the orthogonal least squares algorithm in order to reduce the computational complexity of the estimation. Compared to existing methods for sources correlation matrix estimation, its lower computational complexity allows one to deal with high dimensional problems (i.e., fine discretization of the source space) and to explore large regions of possible sources positions. As shown by numerical results, it is more accurate than existing methods and does not require the tuning of any regularization parameter. Experiments in an anechoic chamber involving correlated sources or reflectors show the ability of the method to locate and identify physical and mirror sources as well.


"Health in all policies" in practice: guidance and tools to quantifying the health effects of cycling and walking.
There is growing interest in "Health in All Policies" approaches, aiming at promoting health through policies which are under the control of nonhealth sectors. While economic appraisal is an established practice in transport planning, health effects are rarely taken into account. An international project was carried out to develop guidance and tools for practitioners for quantifying the health effects of cycling and walking, supporting their full appraisal. A systematic review of existing approaches was carried out. Then, the products were developed with an international expert panel through an extensive consensus finding process. Methodological guidance was developed which addresses the main challenges practitioners encounter in the quantification of health effects from cycling and walking. A "Health Economic Assessment Tool (HEAT) for cycling" was developed which is being used in several countries. There is a need for a more consistent approach to the quantification of health benefits from cycling and walking. This project is providing guidance and an illustrative tool for cycling for practical application. Results show that substantial savings can be expected. Such tools illustrate the importance of considering health in transport policy and infrastructure planning, putting "Health in All Policies" into practice.


Nontransitivity of paternity in a bird.
In many animals reproductive success is determined after insemination by the interaction of male and female processes. While sperm competition is reasonably well understood in some taxa, other processes, such as cryptic female choice and differential early embryo mortality resulting from genetic incompatibilities, are less well understood. The relative importance of these different factors contributing to reproductive success is difficult to assess. Here we control for male-mediated effects (which are often considerable and can mask more subtle processes) through the artificial insemination of known numbers of sperm in the domestic fowl to reveal that male reproductive success is nontransitive across females: the success of a particular male depends on the background against which his sperm compete for fertilization. Two potential processes could account for this effect: cryptic female choice (sperm choice) or differential early embryo mortality. Regardless of the mechanism, nontransitivity of male reproductive success has important evolutionary consequences, including the maintenance of variation in male fitness.


Linear free energy relationship and kinetic isotope effects as measures for the transition state variation. A computational study.
Linear free energy relationship (LFER) and kinetic isotope effects (KIEs) are frequently used experimental means to study reaction mechanisms, in particular the nature of transition states (TSs). Density functional theory (B3LYP/6-311+G**) calculations were carried out on a model reaction, acid-catalyzed ionization of phenylethyl alcohol, to analyze how experimentally observable properties, such as nonlinearity in the Hammett and Brønsted relations and variation in KIE, are related to a variation of the transition state structure and the mechanism. Several conclusions and insights were obtained: (1) Linear Hammett plots with a dual parameter treatment may not be evidence for an invariable TS structure for a series of reactions. (2) Variations of KIEs indeed reflect the variations of TS structures. (3) Nonlinear Brønsted plots cannot always be taken as evidence for a stepwise mechanism. (4) A TS structure in the gas phase may change much more easily than a TS structure in solution.


Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Forty-six consecutive patients with symptomatic exercise limitation (peak Vo(2) <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to -0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak Vo(2)) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL · kg(-1) · min(-1); P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo). In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy.


Randomized trial of early developmental intervention on outcomes in children after birth asphyxia in developing countries.
To determine if early developmental intervention (EDI) improves developmental abilities in resuscitated children. This was a parallel group, randomized controlled trial of infants unresponsive to stimulation who received bag and mask ventilation as part of their resuscitation at birth and infants who did not require any resuscitation born in rural communities in India, Pakistan, and Zambia. Intervention infants received a parent-implemented EDI delivered with home visits by parent trainers every other week for 3 years starting the first month after birth. Parents in both intervention and control groups received health and safety counseling during home visits on the same schedule. The main outcome measure was the Mental Development Index (MDI) of the Bayley Scales of Infant Development, 2nd edition, assessed at 36 months by evaluators unaware of treatment group and resuscitation history. MDI was higher in the EDI (102.6 ± 9.8) compared with the control resuscitated children (98.0 ± 14.6, 1-sided P = .0202), but there was no difference between groups in the nonresuscitated children (100.1 ± 10.7 vs 97.7 ± 10.4, P = .1392). The Psychomotor Development Index was higher in the EDI group for both the resuscitated (P = .0430) and nonresuscitated children (P = .0164). This trial of home-based, parent provided EDI in children resuscitated at birth provides evidence of treatment benefits on cognitive and psychomotor outcomes. MDI and Psychomotor Development Index scores of both nonresuscitated and resuscitated infants were within normal range, independent of early intervention.