Severe propylthiouracil-induced hepatotoxicity in pregnancy managed successfully by liver transplantation: A case report.
Propylthiouracil-induced severe hepatotoxicity is a relatively rare occurrence, with very few cases reported in the literature. The management of this complication in pregnancy can be a challenge because of the effects of the various treatment options on the fetus. We report a rare case of fulminant hepatic failure in a 36-year-old gravida 2 black woman of African descent that occurred at 17 weeks gestation following propylthiouracil treatment for Graves' disease. Her liver failure was managed by liver transplantation and thyroidectomy. Her pregnancy was continued to term, though with not so favorable early childhood sequelae. This case illustrates a very rare complication of treatment with a presumed safe drug during pregnancy followed by adverse neonatal outcomes due to the extensive treatment.


An assessment of tardive dyskinesia in schizophrenic outpatients.
An examination of tardive dyskinesia in 213 schizophrenic outpatients using the Abnormal Involuntary Movement Scale (AIMS) indicates that increasing age is significantly associated with the presence of this disorder while sex is not. Both sexes showed significant linear increases with increasing age. Although males did not evidence the statistically significant curvilinear trend previously reported in an inpatient study using the same methodology, they displayed an attenuated effect at the older age levels. A comparison of prevalence values between the outpatient sample and the inpatient sample previously studied indicated no greater prevalence in the outpatients. However, an examination of differences in AIMS total scores between these samples suggested the presence of many more marginal and mild movements in the outpatients. Reasons for the differences between the inpatient and outpatient studies are discussed.


The complete chloroplast genome sequences of Pogostemon stellatus and Pogostemon yatabeanus (Lamiaceae).
The nucleotide sequences of the two chloroplast (cp) genomes from Pogostemon stellatus and Pogostemon yatabeanus are the first to be completed in genus Pogostemon of family Lamiaceae. The structure of two Pogostemon cp genomes shows similar characteristic to the typical cp genome of angiosperms. The lengths of two cp genomes are 151,825bp and 152,707 bp, respectively. Two cp genomes are divided into LSC region (83,012 bp and 83,791 bp) and SSC region (17,524 bp and 17,568 bp) by two IR regions (25,644 bp and 25,674 bp). Both of two cp genomes contain 114 genes (80 protein-coding genes, 30 tRNA genes and 4 rRNA genes), 10 protein-coding genes and 7 tRNA genes duplicated in the IR regions. Similar to the typical cp genome of angiosperms, 18 of the genes in the Pogostemon cp genome have one or two introns. The overall A-T contents of two genomes are 61.8% which is also similar to general angiosperms. The A-T content in the non-coding (64.4%) is higher than in the coding (59.9%) regions. Sixty-seven and seventy-three simple sequence repeat (SSR) loci were identified in the P. stellatus and P. yatabeanus cp genomes, respectively. In phylogenetic analysis, genus Pogostemon shows closed relationship with Scutellaria baicalensis of Scutellarioideae.


A novel dose regimen of cinacalcet in the treatment of severe hyperparathyroidism in hemodialysis patients.
During the recent years, cinacalcet has markedly improved the management of hyperparathyroidism in patients on hemodialysis. However, to the best of our knowledge, there are no specific studies addressing the dose regimen of cinacalcet. The aim of the study was to evaluate the efficacy of cinacalcet on the achievement of targets in the treatment of hyperparathyroidism in two different dosage schedules. Twenty-seven adult patients who were on hemodialysis for more than four months and with severe secondary hyperparathyroidism (intact parathyroid hormone (iPTH) >88 pmol/L) resistant to conventional treatment were included in this prospective study. We used the targets of K/DOQI-clinical guidelines as optimal target of iPTH, calcium and phosphate. Group 1 received a single daily administration of 30 mg of cinacalcet along with the main meal as the starting dose, and the dose was titrated thereafter monthly. Group 2 received cinacalcet with the main meal twice weekly starting with a dose of 90 mg on the first day of the week and 120 mg at midweek and titrated thereafter monthly. The levels of iPTH decreased significantly (P = 0.0001) from 124.00 ± 44.77 pmol/L to 37.78 ± 12.49 pmol/L and from 109.61 ± 53.13 pmol/L to 33.93 ± 12.03 pmol/L after 12 weeks in groups 1 and 2, respectively. After 12 weeks, alkaline phosphatase declined significantly (P = 0.0001) from 143.42 ± 75.20 IU/L to 87.42 ± 14.46 IU/L in group 1 (P = 0.013), and from 148.00 ± 108.49 IU/L to 101.61 ± 46.62 IU/L in group 2 (P = 0.05). There were no significant differences between the reductions of iPTH, calcium phosphate product and alkaline phosphatase levels in both the groups in the vertical comparison at the end of the study. There was no noteworthy difference in side effects between both the groups. Our results indicate that cinacalcet twice weekly is reasonably safe and effective in suppressing high PTH levels in hemodialysis patients, with fewer side effects.


Identification of polarized macrophage subsets in zebrafish.
While the mammalian macrophage phenotypes have been intensively studied in vitro, the dynamic of their phenotypic polarization has never been investigated in live vertebrates. We used the zebrafish as a live model to identify and trail macrophage subtypes. We generated a transgenic line whose macrophages expressing tumour necrosis factor alpha (tnfa), a key feature of classically activated (M1) macrophages, express fluorescent proteins Tg(mpeg1:mCherryF/tnfa:eGFP-F). Using 4D-confocal microscopy, we showed that both aseptic wounding and Escherichia coli inoculation triggered macrophage recruitment, some of which started to express tnfa. RT-qPCR on Fluorescence Activated Cell Sorting (FACS)-sorted tnfa(+) and tnfa(-) macrophages showed that they, respectively, expressed M1 and alternatively activated (M2) mammalian markers. Fate tracing of tnfa(+) macrophages during the time-course of inflammation demonstrated that pro-inflammatory macrophages converted into M2-like phenotype during the resolution step. Our results reveal the diversity and plasticity of zebrafish macrophage subsets and underline the similarities with mammalian macrophages proposing a new system to study macrophage functional dynamic.


Effects of Heating-Conduction Dry Needling Therapy on Rats with Chronic Myofascial Pain Syndrome.
This study aimed to investigate the effect of dry needling (DN) with 44°C heating on the pressure pain threshold (PPT) of rats with chronic myofascial pain syndrome (MPS) by regulating the transient receptor potential V1 channel. A total of 80 rats were divided into 5 groups: A, B, C, D, and E (16 in each group). The rats in Group A recovered naturally, while those in other groups received the DN treatment. The needles were heated to 40°C for the rats in Groups B and E and 44°C for the rats in Groups C and D. In addition, both Groups D and E received local capsaicin injection. PPTs of the gastrocnemius muscle and tolerance time of the plantar hot plate were measured before modeling, 1 day before the intervention, 24 hours after the intervention, and 7 days after the intervention. PPTs of the gastrocnemius muscle for rats with MPS increased 7 days after DN and heating to 40°C. For the rats receiving DN at 44°C heating, PPTs increased 24 hours and 7 days after the intervention. Further, 44°C heating and capsaicin injection improved PPT. DN and 40°C heating followed by capsaicin injection improved PPT. DN and 44°C heating had therapeutic effects on rats with MPS at 24 hours and at 7 days after the intervention. DN and 40°C heating had therapeutic effects 7 days after the intervention. DN and 44°C heating might exert therapeutic effects by regulating the transient receptor potential V1 channel.


A weighted dictionary learning model for denoising images corrupted by mixed noise.
This paper proposes a general weighted l(2)-l(0) norms energy minimization model to remove mixed noise such as Gaussian-Gaussian mixture, impulse noise, and Gaussian-impulse noise from the images. The approach is built upon maximum likelihood estimation framework and sparse representations over a trained dictionary. Rather than optimizing the likelihood functional derived from a mixture distribution, we present a new weighting data fidelity function, which has the same minimizer as the original likelihood functional but is much easier to optimize. The weighting function in the model can be determined by the algorithm itself, and it plays a role of noise detection in terms of the different estimated noise parameters. By incorporating the sparse regularization of small image patches, the proposed method can efficiently remove a variety of mixed or single noise while preserving the image textures well. In addition, a modified K-SVD algorithm is designed to address the weighted rank-one approximation. The experimental results demonstrate its better performance compared with some existing methods.


Effects of exercise and creatine on myosin heavy chain isoform composition in patients with Charcot-Marie-Tooth disease.
It is not known whether myosin heavy chain (MHC) content changes in response to exercise training or creatine supplementation in subjects with Charcot-Marie-Tooth disease (CMT). Based on previous data, we hypothesized that resistance exercise and creatine would increase the percentage of type I MHC composition in the vastus lateralis muscle and that myosin isoform changes would correlate with improved chair rise-time in CMT subjects. To test this hypothesis, 18 CMT subjects were randomly assigned to either a placebo or creatine group. All subjects performed a 12-week, home-based, moderate-intensity resistance training program. Chair rise-time was measured before and after the training program. Muscle biopsies were obtained from the vastus lateralis before and after the 12-week program. Gel electrophoresis showed a significant decrease (approximately 30%) in MHC type I in CMT subjects given creatine supplementation when compared with placebo. There was a nonsignificant increase in both MHC type IIa (approximately 23%) and MHC type IIx (approximately 7%) in CMT subjects given creatine. Reduced MHC type I content and increased MHC type IIa content correlated with faster chair rise-times (i.e., improved muscle performance). The training-induced change in MHC IIa content was inversely correlated with chair rise-time in CMT subjects given creatine. When the two subject groups were combined, there was a linear, negative relationship between the change in MHC type IIa content and chair rise-time after training and a positive relationship between the training-induced change in MHC type I content and chair rise-time. These data suggest that improved function (chair rise-time) was associated with a lower level of MHC type I and increased MHC type IIa composition. Furthermore, the data are consistent with the hypothesis that creatine supplementation alters MHC composition in CMT patients undergoing resistance training and that MHC changes associated with creatine supplementation can improve muscle function.


Emperor penguins breeding on iceshelves.
We describe a new breeding behaviour discovered in emperor penguins; utilizing satellite and aerial-survey observations four emperor penguin breeding colonies have been recorded as existing on ice-shelves. Emperors have previously been considered as a sea-ice obligate species, with 44 of the 46 colonies located on sea-ice (the other two small colonies are on land). Of the colonies found on ice-shelves, two are newly discovered, and these have been recorded on shelves every season that they have been observed, the other two have been recorded both on ice-shelves and sea-ice in different breeding seasons. We conduct two analyses; the first using synthetic aperture radar data to assess why the largest of the four colonies, for which we have most data, locates sometimes on the shelf and sometimes on the sea-ice, and find that in years where the sea-ice forms late, the colony relocates onto the ice-shelf. The second analysis uses a number of environmental variables to test the habitat marginality of all emperor penguin breeding sites. We find that three of the four colonies reported in this study are in the most northerly, warmest conditions where sea-ice is often sub-optimal. The emperor penguin's reliance on sea-ice as a breeding platform coupled with recent concerns over changed sea-ice patterns consequent on regional warming, has led to their designation as "near threatened" in the IUCN red list. Current climate models predict that future loss of sea-ice around the Antarctic coastline will negatively impact emperor numbers; recent estimates suggest a halving of the population by 2052. The discovery of this new breeding behaviour at marginal sites could mitigate some of the consequences of sea-ice loss; potential benefits and whether these are permanent or temporary need to be considered and understood before further attempts are made to predict the population trajectory of this iconic species.


Effect of carotid endarterectomy on cognitive function in patients with asymptomatic carotid artery stenosis.
This study was conducted to determine if patients with asymptomatic carotid artery stenosis show cognitive function decline, and if they experience any changes in cognitive function after carotid endarterectomy (CEA). Cognitive function was examined in 15 patients (12 males and three females, 70.0 ± 6.5 years) with asymptomatic carotid artery stenosis before and 3 months after CEA. Cognitive function was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), two subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R 2 subtests), and the Japanese version of National Adult Reading Test (JART). The patients' average scores were compared with the normal average by one-sample t-tests, and the before and after scores were compared with paired t-tests. Changes in each patient were calculated from difference before and after CEA using 95 % confidence intervals. Before surgery, patients showed significant cognitive decline in RBANS total scale and immediate memory, language, and attention. At 3 months after CEA, the total scale and the immediate memory were not significantly different from the normal average. The average total scale score, the immediate memory and attention, and the WAIS-R 2 subtests scores were increased after treatment. Changes in each patient were calculated from the scores before and after CEA. At 3 months after CEA, the rate of increase in RBANS scores were 60.0 % of the patients for immediate memory, 26.7 % for visuospatial/constructional, 33.3 % for language and attention, 26.7 % for delayed memory, 47.7 % for total scale and 26.7 % for WAIS-R 2 subtests. Thus, so-called asymptomatic patients exhibit mild cognitive impairment before surgery, but after CEA, patients recover normal memory abilities. Our findings of mild cognitive dysfunction in asymptomatic patients suggest that they might be symptomatic after all.


Clinico-biological characterization and outcome of primary nodal and extranodal diffuse large B-cell lymphoma in the rituximab era.
To study the main clinico-biological characteristics and the outcome of patients with diffuse large B-cell lymphoma (DLBCL) according to the primary site (nodal vs. extranodal), we included 262 patients consecutively diagnosed with DLBCL in a single institution, 5 years before and after immunochemotherapy was considered as the standard treatment. Altogether 116 patients received CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) and 146 rituximab plus CHOP (R-CHOP). The primary site was the lymph node in 140 patients (53%), Waldeyer's ring (WR) in 22, gastrointestinal (GI) in 33, and other extranodal in 67. The addition of rituximab significantly improved the CR rate in nodal, but not in extranodal, lymphomas. Patients receiving R-CHOP showed higher OS than those treated with CHOP alone (5-year OS: 71% vs. 48%). This difference was maintained in primary nodal (5-year OS: 69% vs. 37%, p < 0.0001), but was not observed in primary extranodal (75% vs. 65%, p = 0.45) lymphomas. The IPI, treatment, and primary site were the main variables for OS in multivariate analysis. In nodal cases, IPI and treatment maintained value, whereas only IPI predicted OS in extranodal cases. In conclusion, immunochemotherapy treatment dramatically improved the outcome of patients with nodal DLBCL; however, its effect was less in primary extranodal cases, so the prognosis of patients with nodal and extranodal lymphomas has been equalized in the rituximab era.


Neonatologists less frequently discuss long term complications: A simulation-based study of prenatal consults beyond the threshold of viability.
Guidelines exist for counseling expectant families of infants at periviable gestational ages (22-25 weeks), but it is much more common for neonatologists to counsel families at gestational ages beyond the threshold of viability when several aspects of these guidelines do not apply. We aimed to develop an understanding of what information is shared with mothers at risk of preterm delivery beyond periviability and to evaluate communication skills of our participants. We developed a checklist of elements to include in counseling based on a comprehensive literature review. The checklist was divided into an information sharing section and a connect score. The information sharing list was sub-divided into general information and specific complications. Neonatologists engaged in a simulated prenatal counseling session with a standardized patient. Videotaped encounters were then analyzed for checklist elements. Neonatologists all scored well in communication using our tool and two other validated communication tools - the SEGUE and the analytic global OSCE. There was no difference in scoring based on years of experience or level of training. Information sharing from neonatologists more often discussed general information over specific. Neonatologists also focused more on early outcomes over long-term outcomes. Only 12% of neonatologists quoted the correct survival rate for the case. Neonatologists generally communicate well but share less information specific to prematurity and the long-term sequelae of prematurity. Our tool may be used to test if other interventions improve information sharing or communication.


G-CSF and IL-8 for early diagnosis of sepsis in neonates and critically ill children - safety and cost effectiveness of a new laboratory prediction model: study protocol of a randomized controlled trial [ISRCTN91123847].
Bacterial infection represents a serious risk in neonates and critically ill paediatric patients. Current clinical practice is characterized by frequent antibiotic treatment despite low incidence of true infection. However, some patients escape early diagnosis and progress to septic shock. Many new markers, including cytokines, have been suggested to improve decision making, but the clinical efficacy of these techniques remains uncertain. Therefore, we will test the clinical efficacy of a previously validated diagnostic strategy to reduce antibiotic usage and nosocomial infection related morbidity. All patients admitted to the multidisciplinary neonatal and paediatric intensive care unit of a university children's hospital will be included. Patients will be allocated either to routine sepsis work up or to the intervention strategy with additional cytokine measurements. Physicians will be requested to estimate the pre-test probability of sepsis and pneumonia at initial suspicion. In the treatment arm, physicians will receive raw cytokine results, the likelihood ratio and the updated post-test probability. A high post-test probability will suggest that immediate initiation of antibiotic treatment is appropriate, whereas a low post-test probability will be supportive of watchful waiting or discontinuing prophylactic empirical therapy. Physicians may overrule the suggestions resulting from the post-test probability. This trial will ascertain the clinical efficacy of introducing new diagnostic strategies consisting of pre-test probability estimate, novel laboratory markers, and computer-generated post-test probability in infectious disease work up in critically ill newborns and children.


Everyday life in a Swedish nursing home during the COVID-19 pandemic: a qualitative interview study with persons 85 to 100 years.
To understand and report on the impact of the COVID-19 pandemic on the everyday lives of frail older persons living in nursing homes by exploring their experiences of how the pandemic-related restrictions had influenced them and in what way. Empirical qualitative interview study. A publicly run nursing home in an urban area in Sweden in June 2020. The nursing home had visitor restrictions, cancelled activities and physical distancing requirements since March 2020. A total of 10 persons, 85-100 years, living in a Swedish nursing home during the COVID-19 pandemic, were recruited through nursing home management and interviewed in June 2020 using medically approved visors and physical distancing. Interviews were analysed using thematic analysis, which involves familiarisation, coding and definition of themes. Transcripts were coded into data-driven categories before being organised into categories that described and explained the data. The analysis resulted in the main theme 'It is like living in a bubble', that describes everyday life in the nursing home during the pandemic as a world of its own in which the older persons felt both protected and isolated. This is described in four subthemes: living 1 day at a time, without fear of the virus; feeling taken care of; having limited freedom and missing out on the little extras. Contributing to the growing area of COVID-19-related research, our findings provide novel insights into how pandemic-related restrictions in nursing homes represent a risk of isolating older people from the outside world and diminishing their freedom. Put in relation to the previous research, these findings could be applied beyond the pandemic, to develop research and practice that puts focus on how to support older people to decide for themselves how to spend the rest of their lives.


Conidia but not yeast cells of the fungal pathogen Histoplasma capsulatum trigger a type I interferon innate immune response in murine macrophages.
Histoplasma capsulatum is the most common cause of fungal respiratory infections and can lead to progressive disseminated infections, particularly in immunocompromised patients. Infection occurs upon inhalation of the aerosolized spores, known as conidia. Once inside the host, conidia are phagocytosed by alveolar macrophages. The conidia subsequently germinate and produce a budding yeast-like form that colonizes host macrophages and can disseminate throughout host organs and tissues. Even though conidia are the predominant infectious particle for H. capsulatum and are the first cell type encountered by the host during infection, very little is known at a molecular level about conidia or about their interaction with cells of the host immune system. We examined the interaction between conidia and host cells in a murine bone-marrow-derived macrophage model of infection. We used whole-genome expression profiling and quantitative reverse transcription-PCR (qRT-PCR) to monitor the macrophage signaling pathways that are modulated during infection with conidia. Our analysis revealed that type I interferon (IFN)-responsive genes and the beta type I IFN (IFN-beta) were induced in macrophages during infection with H. capsulatum conidia but not H. capsulatum yeast cells. Further analysis revealed that the type I IFN signature induced in macrophages in response to conidia is independent of Toll-like receptor (TLR) signaling and the cytosolic RNA sensor MAVS but is dependent on the transcription factor interferon regulatory factor 3 (IRF3). Interestingly, H. capsulatum growth was restricted in mice lacking the type I IFN receptor, indicating that an intact host type I IFN response is required for full virulence of H. capsulatum in mice.


Hsp70 oligomerization is mediated by an interaction between the interdomain linker and the substrate-binding domain.
Oligomerization in the heat shock protein (Hsp) 70 family has been extensively documented both in vitro and in vivo, although the mechanism, the identity of the specific protein regions involved and the physiological relevance of this process are still unclear. We have studied the oligomeric properties of a series of human Hsp70 variants by means of nanoelectrospray ionization mass spectrometry, optical spectroscopy and quantitative size exclusion chromatography. Our results show that Hsp70 oligomerization takes place through a specific interaction between the interdomain linker of one molecule and the substrate-binding domain of a different molecule, generating dimers and higher-order oligomers. We have found that substrate binding shifts the oligomerization equilibrium towards the accumulation of functional monomeric protein, probably by sequestering the helical lid sub-domain needed to stabilize the chaperone: substrate complex. Taken together, these findings suggest a possible role of chaperone oligomerization as a mechanism for regulating the availability of the active monomeric form of the chaperone and for the control of substrate binding and release.


Working with sex offenders with intellectual disability: evaluation of an introductory workshop for direct care staff.
Sexual aggression by men with intellectual disability (ID) is a serious problem requiring attention from the relevant agencies. Training for staff working with this problem is often not given sufficient attention and is rarely evaluated. In the present study, an introductory workshop for direct care staff that aimed to increase knowledge and improve attitudes towards work with this client group was evaluated. Sixty-six staff working in inpatient and community settings completed a 2.5-day workshop. Before training began, the participants completed a survey questionnaire concerning their experiences of work with this client group. An assessment of their knowledge and attitudes was carried out prior to and at the end of training in order to evaluate any changes. The participants also rated the effectiveness of the workshop and their level of satisfaction with the training at the end of the workshop. The participants' knowledge and attitudes improved significantly following the workshop. Staff with greater experience over time and those who had worked with fewer sex offender clients responded to different aspects of the training. The participants' ratings indicated that they were highly satisfied with the training and found it to be effective. Brief workshop training is acceptable to and can be effective in improving the knowledge, attitudes and confidence of direct care staff working with sex offenders with ID. However, because the results are based on participant self-report, caution should be exercised concerning their external validity.


Evaluating methods for estimating home ranges using GPS collars: A comparison using proboscis monkeys (Nasalis larvatus).
The development of GPS tags for tracking wildlife has revolutionised the study of home ranges, habitat use and behaviour. Concomitantly, there have been rapid developments in methods for estimating habitat use from GPS data. In combination, these changes can cause challenges in choosing the best methods for estimating home ranges. In primatology, this issue has received little attention, as there have been few GPS collar-based studies to date. However, as advancing technology is making collaring studies more feasible, there is a need for the analysis to advance alongside the technology. Here, using a high quality GPS collaring data set from 10 proboscis monkeys (Nasalis larvatus), we aimed to: 1) compare home range estimates from the most commonly used method in primatology, the grid-cell method, with three recent methods designed for large and/or temporally correlated GPS data sets; 2) evaluate how well these methods identify known physical barriers (e.g. rivers); and 3) test the robustness of the different methods to data containing either less frequent or random losses of GPS fixes. Biased random bridges had the best overall performance, combining a high level of agreement between the raw data and estimated utilisation distribution with a relatively low sensitivity to reduced fixed frequency or loss of data. It estimated the home range of proboscis monkeys to be 24-165 ha (mean 80.89 ha). The grid-cell method and approaches based on local convex hulls had some advantages including simplicity and excellent barrier identification, respectively, but lower overall performance. With the most suitable model, or combination of models, it is possible to understand more fully the patterns, causes, and potential consequences that disturbances could have on an animal, and accordingly be used to assist in the management and restoration of degraded landscapes.


Behavior therapy and callous-unemotional traits: effects of a pilot study examining modified behavioral contingencies on child behavior.
The conduct problems of children with callous-unemotional (CU) traits (i.e., lack of empathy, lack of guilt/lack of caring behaviors) are particularly resistant to current behavioral interventions, and it is possible that differential sensitivities to punishment and reward may underlie this resistance. Children with conduct problems and CU (CPCU) are less responsive to behavioral punishment techniques (e.g., time-out), whereas reward techniques (e.g., earning points for prizes or activities) are effective for reducing conduct problems. This study examined the efficacy of modified behavioral interventions, which de-emphasized punishment (Condition B) and emphasized reward techniques (Condition C), compared with a standard behavioral intervention (Condition A). Interventions were delivered through a summer treatment program over 7 weeks with an A-B-A-C-A-BC-A design to a group of 11 children (7-11 years; 91% male). All children were diagnosed with either oppositional defiant disorder or conduct disorder, in addition to attention-deficit hyperactivity disorder. Results revealed the best treatment response occurred during the low-punishment condition, with rates of negative behavior (e.g., aggression, teasing, stealing) increasing over the 7 weeks. However, there was substantial individual variability in treatment response, and several children demonstrated improvement during the modified intervention conditions. Future research is necessary to disentangle treatment effects from order effects, and implications of group treatment of CPCU children (i.e., deviancy training) are discussed.


Parallel genotypic adaptation: when evolution repeats itself.
Until recently, parallel genotypic adaptation was considered unlikely because phenotypic differences were thought to be controlled by many genes. There is increasing evidence, however, that phenotypic variation sometimes has a simple genetic basis and that parallel adaptation at the genotypic level may be more frequent than previously believed. Here, we review evidence for parallel genotypic adaptation derived from a survey of the experimental evolution, phylogenetic, and quantitative genetic literature. The most convincing evidence of parallel genotypic adaptation comes from artificial selection experiments involving microbial populations. In some experiments, up to half of the nucleotide substitutions found in independent lineages under uniform selection are the same. Phylogenetic studies provide a means for studying parallel genotypic adaptation in non-experimental systems, but conclusive evidence may be difficult to obtain because homoplasy can arise for other reasons. Nonetheless, phylogenetic approaches have provided evidence of parallel genotypic adaptation across all taxonomic levels, not just microbes. Quantitative genetic approaches also suggest parallel genotypic evolution across both closely and distantly related taxa, but it is important to note that this approach cannot distinguish between parallel changes at homologous loci versus convergent changes at closely linked non-homologous loci. The finding that parallel genotypic adaptation appears to be frequent and occurs at all taxonomic levels has important implications for phylogenetic and evolutionary studies. With respect to phylogenetic analyses, parallel genotypic changes, if common, may result in faulty estimates of phylogenetic relationships. From an evolutionary perspective, the occurrence of parallel genotypic adaptation provides increasing support for determinism in evolution and may provide a partial explanation for how species with low levels of gene flow are held together.


The "good" dean's letter.
To determine whether a correlation exists between the term "good" on the summative, comparative assessment of a student's Medical Student Performance Evaluation (MSPE) and his or her actual performance in medical school. The authors reviewed the MSPEs submitted to three residency programs to determine the presence of the term "good" in either the summary paragraph or the appendices. Next, they noted, for institutions using "good," the percentile rankings of those students who received "good" as a descriptor. To examine the consistency among institutions regarding the percentile ranking denoted by "good," they dichotomized the data into students below and above the bottom 25th percentile. They analyzed the data using a nonparametric test because of their nonnormal distribution. The authors collected MSPEs from 122 of the 125 Liaison Committee on Medical Education-accredited medical schools that were graduating students in 2008. Of these 122 institutions, 34 (28%) used the term "good." All 34 institutions used the term to characterize students in the bottom 50% of the graduating class. The authors found a significant difference in the percentile ranking of students described as "good" between institutions using it to describe the bottom 25% and institutions using the term to describe those in the 25th to 50th percentiles (median ranking of 12.5% versus 30%, P < .0001). Overall, the term "good" in the MSPE describes students in the bottom 50% of the class; therefore, the term "good," as used to describe performance in medical school, consistently indicates below-average performance.


Carotid artery stenting vs. endarterectomy.
Randomized clinical trials have demonstrated that carotid endarterectomy (CEA) is superior to medical management for stroke prevention in patients with symptomatic and, to a lesser degree, asymptomatic internal carotid artery stenosis. However, large-scale registries have shown that the adverse event rates following CEA are commonly higher than observed in the trials. In the last decade, carotid artery stenting (CAS) has emerged as a less invasive alternative to surgery. In order to address the efficacy of CAS, we performed a meta-analysis of 10 randomized trials comparing CAS with CEA in 4648 mainly symptomatic patients. The analysis showed that CAS was associated with a statistically significant increased death or stroke rate at 30 days compared with CEA (odds ratio 1.60, 95% confidence interval 1.26-2.02). However, most of the trials had inadequate requirements in terms of endovascular expertise and did not mandate the use of emboli protection devices. Beyond 30 days, long-term follow-up of the trials previously reported suggest that both revascularization techniques are equivalent in terms of stroke prevention. Conversely, large-scale high-quality CAS registries--mostly with independent neurological assessment and clinical event committee adjudication--have reported results in the range of current recommendation for CEA in over 20 000 patients, despite the fact that the majority of patients were at high risk for surgery. Until further data become available, the performance of CAS should be limited to protocols or centres of excellence and targeted especially to patients at high risk for surgery.


Comparing the effectiveness and costs of Bevacizumab to Ranibizumab in patients with Diabetic Macular Edema: a randomized clinical trial (the BRDME study).
The effectiveness of ranibizumab in the treatment of diabetic macular edema has been proven with large clinical trials. For bevacizumab only two clinical trials have been published and a head-to-head comparison is lacking to date. However, if proved non-inferior to ranibizumab, use of the off-label bevacizumab could reduce costs enormously without a loss in visual acuity. A cost-effectiveness study has been designed to substantiate this hypothesis. To compare the effectiveness and costs of 1.25 mg of bevacizumab to 0.5 mg ranibizumab given as monthly intravitreal injections during 6 months in patients with diabetic macular edema. It is hypothesized that bevacizumab is non-inferior to ranibizumab regarding its effectiveness. This is a randomized, controlled, double masked, clinical trial in 246 patients in seven academic trial centres in The Netherlands. The primary outcome measure is the change in best-corrected visual acuity (BCVA) in the study eye from baseline to month 6. Secondary outcomes are the proportions of patients with a gain or loss of 15 letters or more or a BCVA of 20/40 or more at 6 months, the change in leakage on fluorescein angiography and the change in foveal thickness by optical coherence tomography at 6 months, the number of adverse events in 6 months, and the costs per quality adjusted life-year of the two treatments.


Molecular mimicry and autoimmunity.
Molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when similarities between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign-derived antigen in a susceptible individual. However, molecular mimicry is unlikely to be the only underlying mechanism for autoimmune responses; other factors such as breach in central tolerance, non-specific bystander activation, or persistent antigenic stimuli (amongst others) may also contribute to the development of autoimmune diseases. Host genetics, exposure to microbiota and environmental chemicals are additional links to our understanding of molecular mimicry. Our current knowledge of the detailed mechanisms of molecular mimicry is limited by the issues of prolonged periods of latency before the appearance of disease, the lack of enough statistical power in epidemiological studies, the limitations of the potential role of genetics in human studies, the relevance of inbred murine models to the diverse human population and especially the limited technology to systematically dissect the human T-cell repertoire and B-cell responses. Nevertheless, studies on the role of autoreactive T-cells that are generated secondary to molecular mimicry, the diversity of the T-cell receptor repertoires of auto-reactive T-cells, the role of exposure to cryptic antigens, the generation of autoimmune B-cell responses, the interaction of microbiota and chemical adjuvants with the host immune systems all provide clues in advancing our understanding of the molecular mechanisms involved in the evolving concept of molecular mimicry and also may potentially aid in the prevention and treatment of autoimmune diseases.


Children with autism show local precedence in a divided attention task and global precedence in a selective attention task.
Children with a diagnosis of autism and typically developing children were given two variations of the Navon task (Navon, 1977), which required responding to a target that could appear at the global level, the local level, or both levels. In one variation, the divided attention task, no information was given to children regarding the level at which a target would appear on any one trial. In the other, the selective attention task, children were instructed to attend to either the local or the global level. Typically developing children made most errors when the target appeared at the local level whereas children with autism made more errors when the target appeared at the global level in the divided attention task. Both groups of children were quicker to respond to the global target than the local target in the selective attention task. The presence of normal global processing in the children with autism in one task but not in the other is discussed in terms of a deficit in mechanisms that inhibit local information in the absence of overt priming or voluntary selective attention to local information.


Patented techniques for detoxification of mycotoxins in feeds and food matrices.
Mycotoxins are found worldwide in cereal grains, animal feed and human food that are produced from contaminated grains. This presents food safety risks. A variety of methods has been developed to reduce the safety risks by removing mycotoxins from contaminated grain products, eliminate the bioavailability of mycotoxins in the gastrointestinal system, degrade mycotoxins in food and feed, reduce mycotoxins pre- and post-harvest, and prevent (mycotoxin involved) plant disease. These techniques include physical methods such as flotation, extraction and adsorption, chemical reactions such as alkalization, oxidation, heat and irradiation, as well as biological detoxifications using microorganisms, enzymes and resistant plants. Most of the recent patented techniques for detoxification of mycotoxins in feeds and food matrices are discussed for an improved understanding of the patent techniques and insights into detoxification of mycotoxins.


Phenological response of tundra plants to background climate variation tested using the International Tundra Experiment.
The rapidly warming temperatures in high-latitude and alpine regions have the potential to alter the phenology of Arctic and alpine plants, affecting processes ranging from food webs to ecosystem trace gas fluxes. The International Tundra Experiment (ITEX) was initiated in 1990 to evaluate the effects of expected rapid changes in temperature on tundra plant phenology, growth and community changes using experimental warming. Here, we used the ITEX control data to test the phenological responses to background temperature variation across sites spanning latitudinal and moisture gradients. The dataset overall did not show an advance in phenology; instead, temperature variability during the years sampled and an absence of warming at some sites resulted in mixed responses. Phenological transitions of high Arctic plants clearly occurred at lower heat sum thresholds than those of low Arctic and alpine plants. However, sensitivity to temperature change was similar among plants from the different climate zones. Plants of different communities and growth forms differed for some phenological responses. Heat sums associated with flowering and greening appear to have increased over time. These results point to a complex suite of changes in plant communities and ecosystem function in high latitudes and elevations as the climate warms.


Influence of aberrations of Fizeau interferometer elements on measurement errors.
The propagation of interfering waves through the whole optical system of the Fizeau interferometer is analyzed. A general formula is found that describes the measurement errors introduced by optical elements of the system. In particular, we studied the influence of the position of the beam splitter and the objective of the imaging system of the interferometer.


Thermal regulatory dysfunction of growth hormone in classical heat stroke.
Growth hormone (GH) secretion associated with classical (non-exertional) heat stroke (HS) was evaluated in 26 HS victims and 10 control (non heat-exhausted) subjects during the annual Hajj in Makkah, Saudi Arabia. On admission to the HS treatment unit, the GH level was 1.54 +/- 0.14 ng/ml (approximately 3.5-fold higher in the HS victims compared to controls; p = 0.005). The GH levels subsequently declined by 78% by 24 h. The categorized GH response was significantly associated with survival for those subjects with a GH level of < 5.53 ng/ml by 6 h (chi-squared test; p = 0.06). In those patients who died (N = 6), there was a continued increase in GH levels from the time of admission, which peaked at 6 h. In those patients who survived, the GH levels peaked at the time of admission and declined rapidly thereafter. There was a direct correlation of age and GH level upon admission (p = 0.02), as well as to peak GH (p = 0.041). However, there was no relationship of GH level to either body core temperature or the cooling time. In summary, HS induced significant GH secretion. The degree of GH response was not related to the body core temperature and was more pronounced in older individuals and in those that died. Although patients with GH deficiency and HS are characterized by anhidrosis/hypohidrosis, there does not appear to be dysfunction of GH response to heat stress-associated HS. In contrast, a vigorous GH response at 6 h suggested a worse outcome.


A systematic review and meta-analysis of magnetic resonance imaging studies in late-life depression.
Gray matter abnormalities within frontal-subcortical and limbic networks are hypothesized to play a key role in the pathophysiology of late-life depression. In this work, gray matter abnormalities in late-life depression are examined in a systematic review and meta-analysis of magnetic resonance imaging studies. In the systematic review, 27 articles were identified that compared participants with late-life depression with comparison group participants, and 17 studies were suitable for inclusion in meta-analyses of volumes of the whole brain, orbitofrontal cortex, caudate, hippocampus, putamen, and thalamus. Volume reductions were detected in 7 of 15 comparisons of the hippocampus and a meta-analysis revealed a significant, but small, effect size. Although examined by fewer studies, meta-analyses also revealed significant volume reductions in the orbitofrontal cortex, putamen, and thalamus. A more systematic and comprehensive analysis of the global distribution of gray matter abnormalities, and an examination of subcortical abnormalities were identified as key areas for future research.


[The spatial distribution of population exposure to outdoor air pollution in Valencia (Spain) and its association with a privation index].
To evaluate spatial variation in exposure to nitrogen dioxide (NO2) air pollution in the city of Valencia, Spain, and its association with socioeconomic deprivation and age. Census tract population data were obtained from the National Statistics Institute of Spain. Outdoor NO2 was monitored in 100 sites in the study area, through the use of passive samplers, in three campaigns between 2002 and April 2004. Land use regression (LUR) was used to obtain a map of NO2 levels. The LUR predictions were compared with the NO2 level obtained by: a) the nearest sampler of the monitoring network, b) the nearest passive sampler, c) the mean distance-weighted levels of the samplers in the neighborhood, and d) the NO2 level obtained by using Kriging. For each census tract, the NO2 levels were obtained. The association of NO2 air pollution exposure with population age (≥65 years) and the 5-category deprivation index was analyzed. The LUR models showed less error than the other prediction methods. The safety levels proposed by the World Health Organization were exceeded in more than 99% of the population. An inverse relationship was found between NO2 levels and the deprivation index (β = -2.01μg/m(3) in the most deprived quintile compared with lower deprivation, 95%CI: -3.07; -0.95) and a direct relationship was found with age (β = 0.12μg/m(3) per unit increase in percentage of the population ≥ 65 years, 95%CI: 0.08; 0.16). The method allowed pollution maps to be obtained and the association between NO2 levels and sociodemographic characteristics to be described.


Hypooxytocinaemia in obese Zucker rats relates to oxytocin degradation in liver and adipose tissue.
The metabolic action of oxytocin has recently been intensively studied to assess the ability of the peptide to regulate energy homeostasis. Despite the obvious weight-reducing effect of oxytocin observed in experimental studies, plasma oxytocin levels were found to be unchanged or even elevated in human obesity. The aim of our study was to evaluate the changes in the oxytocin system in Zucker rats, an animal model closely mirroring morbid obesity in humans. Plasma oxytocin levels were measured in obese Zucker rats and lean controls by enzyme immunoassay after plasma extraction. The expression of oxytocin and oxytocin receptor (OXTR) was assessed at the mRNA and protein levels by quantitative real-time PCR and immunoblotting respectively. Plasma and tissue activity of oxytocinase, the main enzyme involved in oxytocin degradation, were measured by fluorometric assay using an arylamide derivate as the substrate. Obese Zucker rats displayed a marked reduction in plasma oxytocin levels. Elevated liver and adipose tissue oxytocinase activity was noticed in obese Zucker rats. Hypothalamic oxytocin gene expression was not altered by the obese phenotype. OXTR mRNA and protein levels were upregulated in the adipose tissue of obese animals in contrast to the reduced OXTR protein levels in skeletal muscle. Our results show that obesity is associated with reduced plasma oxytocin due to increased peptide degradation by liver and adipose tissue rather than changes in hormone synthesis. This study highlights the importance of the oxytocin system in the pathogenesis of obesity and suggests oxytocinase inhibition as a candidate approach in the therapy of obesity.


Motor correlates of learning behaviour: feeding on novel prey by pumpkinseed sunfish (Lepomis gibbosus).
The functional basis of learning in prey capture was investigated in the pumpkinseed sunfish (Lepomis gibbosus). Feeding performance of sunfishes was assessed when the fish were first fed a novel, elusive prey (guppies) and compared with their performance after several weeks of experience with capturing guppies. During these feedings electromyographic recordings were made to document the pattern of activity in four jaw muscles at the strike. With experience, the L. gibbosus improved their ability to capture guppies, and several changes in the pattern of muscle activity were associated with this improved performance. Average duration and maximum amplitude of activity in all muscles increased between trials. Previous studies of muscle activity modulation in fishes indicate that these changes could improve feeding performance on an elusive prey. Thus, specific modifications of muscle activity appear to be one functional determinant of feeding success in fishes.


Biological costs and mechanisms of fosfomycin resistance in Escherichia coli.
Fosfomycin is a cell wall inhibitor used mainly for the treatment of uncomplicated lower urinary tract infections. As shown here, resistance to fosfomycin develops rapidly in Escherichia coli under experimental conditions, but in spite of the relatively high mutation rate in vitro, resistance in clinical isolates is rare. To examine this apparent contradiction, we mathematically modeled the probability of resistance development in the bladder during treatment. The modeling showed that during a typical episode of urinary tract infection, the probability of resistance development was high (>10(-2)). However, if resistance was associated with a reduction in growth rate, the probability of resistance development rapidly decreased. To examine if fosfomycin resistance causes a reduced growth rate, we isolated in vitro and in vivo a set of resistant strains. We determined their resistance mechanisms and examined the effect of the different resistance mutations on bacterial growth in the absence and presence of fosfomycin. The types of mutations found in vitro and in vivo were partly different. Resistance in the mutants isolated in vitro was caused by ptsI, cyaA, glpT, uhpA/T, and unknown mutations, whereas no cyaA or ptsI mutants could be found in vivo. All mutations caused a decreased growth rate both in laboratory medium and in urine, irrespective of the absence or presence of fosfomycin. According to the mathematical model, the reduced growth rate of the resistant strains will prevent them from establishing in the bladder, which could explain why fosfomycin resistance remains rare in clinical isolates.


Transcranial Direct Current Stimulation of motor cortex enhances running performance.
Transcranial direct current stimulation (tDCS) is a technique used to modulate neuronal excitability through non-invasive brain stimulation that can enhance exercise performance. We hypothesize that tDCS would improve submaximal running time to exhaustion (TTE) and delay the increase in the rating of perceived exertion (RPE) over time. We also hypothesize that tDCS would not lead to difference in cardiorespiratory responses. We employed a randomized, single-blinded, and counterbalanced design in which 10 trained men participated. After receiving either 20 min of 1.98 mA anodal tDCS applied over the primary motor cortex (M1) or sham-operated control on separate days, participants completed a constant-load test involving running at a speed equivalent to 80% of their own maximum oxygen consumption (VO2max). During this constant-load test, RPE, heart rate (HR), VO2, pulmonary ventilation (VE), respiratory exchange ratio (RER), and ventilatory threshold (VT) were continuously monitored. TTE was recorded at the end of the test. TTEs were significantly longer in the tDCS than in the sham conditions (21.18 ± 7.13 min; 18.44 ± 6.32 min; p = 0.011). For TTE, no significant differences were found in RPE between conditions at isotime. In addition, no significant differences in HR, VO2, VE, RER, and VT were found during TTE between the two stimulation conditions at any time point. These results indicate that the application of tDCS does not induce a change of the exercise performance-related index; however, it can affect the increase of the exercise duration due to the stimuli in the M1 area.


Cryoimmunoglobulinemia in rheumatoid arthritis. Significance in serum of patients with rheumatoid vasculitis.
Cryogloculins were examined in a standardized manner in an unselected group of 35 patients with rheumatoid arthritis (RA) and 8 patients with RA complicated by cutaneous vasuclitis and neuropathy. Optimum conditions for detection and characterization of cryoglobulins were established; the proportion of resolubilized to total precipitable protein remained constant in an individual patient under these conditions. All 8 vascultis patients and 9 of 35 other patients with RA exhibited cryoglobulins; total protein and immunoglobin content were significantly higher in the cryoglobulins of patients with vasculitis. Immunoglobulins G and M constituted two-thirds and three-quarters of the total protein in the cryoglobulins from uncomplicated rheumatoid and vasculitis patients, respectively. Serum antiglobulin titers were higher, and serum C3 levels were lower, in vasculitis patients compared to rheumatoid patients without vasclitis. Anti-gamma globulin activity was detected in all cryoglobulins from vasculitis patients. Cryoglobulin IgG and IgM were polyclonal. Density gradient analyses demonstrated the majority of the cryoglobulin activity to reside in the 19S IgM fraction. There was no evidence of a light weight (8S) IgM. A monoclonal rheumatoid factor did not detect 7S-ANTI-7S complexes in the cryoprecipitates, but acid eluates from some cryoglobulins absorbed with insoluble IgG revealed an antiglobulin of the IgG class. Serial studies performed on vasculitis patients treated with cyclophosphamide disclosed a relationship between clinical evidence of vasculitis and the presence of cryoglobulins. The antigen (IgG) and antibody (largely IgM rheumatoid factor) nature of these cryglobulins is presented as evidence that the widespread vascular complications of RA are mediated, at least in part, by circulating immune complexes.


Recreational Cannabis Legalization and Opioid-Related Deaths in Colorado, 2000-2015.
To examine the association between Colorado's legalization of recreational cannabis use and opioid-related deaths. We used an interrupted time-series design (2000-2015) to compare changes in level and slope of monthly opioid-related deaths before and after Colorado stores began selling recreational cannabis. We also describe the percent change in opioid-related deaths by comparing the unadjusted model-smoothed number of deaths at the end of follow-up with the number of deaths just prior to legalization. Colorado's legalization of recreational cannabis sales and use resulted in a 0.7 deaths per month (b = -0.68; 95% confidence interval = -1.34, -0.03) reduction in opioid-related deaths. This reduction represents a reversal of the upward trend in opioid-related deaths in Colorado. Legalization of cannabis in Colorado was associated with short-term reductions in opioid-related deaths. As additional data become available, research should replicate these analyses in other states with legal recreational cannabis.


Development of a treatment selection algorithm for SGLT2 and DPP-4 inhibitor therapies in people with type 2 diabetes: a retrospective cohort study.
Current treatment guidelines do not provide recommendations to support the selection of treatment for most people with type 2 diabetes. We aimed to develop and validate an algorithm to allow selection of optimal treatment based on glycaemic response, weight change, and tolerability outcomes when choosing between SGLT2 inhibitor or DPP-4 inhibitor therapies. In this retrospective cohort study, we identified patients initiating SGLT2 and DPP-4 inhibitor therapies after Jan 1, 2013, from the UK Clinical Practice Research Datalink (CPRD). We excluded those who received SGLT2 or DPP-4 inhibitors as first-line treatment or insulin at the same time, had estimated glomerular filtration rate (eGFR) of less than 45 mL/min per 1·73 m2, or did not have a valid baseline glycated haemoglobin (HbA1c) measure (<53 or ≥120 mmol/mol). The primary efficacy outcome was the HbA1c value reached 6 months after drug initiation, adjusted for baseline HbA1c. Clinical features associated with differential HbA1c outcome on the two therapies were identified in CPRD (n=26 877), and replicated in reanalysis of 14 clinical trials (n=10 414). An algorithm to predict individual-level differential HbA1c outcome on the two therapies was developed in CPRD (derivation; n=14 069) and validated in head-to-head trials (n=2499) and CPRD (independent validation; n=9376). In CPRD, we further explored heterogeneity in 6-month weight change and treatment discontinuation. Among 10 253 patients initiating SGLT2 inhibitors and 16 624 patients initiating DPP-4 inhibitors in CPRD, baseline HbA1c, age, BMI, eGFR, and alanine aminotransferase were associated with differential HbA1c outcome with SGLT2 inhibitor and DPP-4 inhibitor therapies. The median age of participants was 62·0 years (IQR 55·0-70·0). 10 016 (37·3%) were women and 16 861 (62·7%) were men. An algorithm based on these five features identified a subgroup, representing around four in ten CPRD patients, with a 5 mmol/mol or greater observed benefit with SGLT2 inhibitors in all validation cohorts (CPRD 8·8 mmol/mol [95% CI 7·8-9·8]; CANTATA-D and CANTATA-D2 trials 5·8 mmol/mol [3·9-7·7]; BI1245.20 trial 6·6 mmol/mol [2·2-11·0]). In CPRD, predicted differential HbA1c response with SGLT2 inhibitor and DPP-4 inhibitor therapies was not associated with weight change. Overall treatment discontinuation within 6 months was similar in patients predicted to have an HbA1c benefit with SGLT2 inhibitors over DPP-4 inhibitors (median 15·2% [13·2-20·3] vs 14·4% [12·9-16·7]). A smaller subgroup predicted to have greater HbA1c reduction with DPP-4 inhibitors were twice as likely to discontinue SGLT2 inhibitors than DPP-4 inhibitors (median 26·8% [23·4-31·0] vs 14·8% [12·9-16·8]). A validated treatment selection algorithm for SGLT2 inhibitor and DPP-4 inhibitor therapies can support decisions on optimal treatment for people with type 2 diabetes. BHF-Turing Cardiovascular Data Science Award and the UK Medical Research Council.


Metabolic basis for low urine pH in type 2 diabetes.
Type 2 diabetes is associated with excessively low urine pH, which increases the risk for uric acid nephrolithiasis. This study was conducted to assess the metabolic basis responsible for the excessive urinary acidity of individuals with type 2 diabetes. Nine non-stone-forming patients who had type 2 diabetes and low urine pH and 16 age- and body mass index-matched non-stone-forming volunteers without type 2 diabetes were maintained on a constant metabolic diet for 7 days, and 24-hour urine was collected on the last 2 days of the diet. Urine dietary markers (potassium, sulfate, phosphorus, and urea nitrogen) were not different between the two groups. Patients with type 2 diabetes exhibited a significantly lower 24-hour urine pH (5.45+/-0.27 versus 5.90+/-0.42; P<0.01) and higher net acid excretion (NAE; 57+/-12 versus 38+/-18 mEq/d; P<0.01) compared with control subjects. The proportion of NAE excreted as ammonium (NH4+/NAE) was significantly lower in patients with type 2 diabetes than in control subjects (0.70+/-0.12 versus 0.94+/-0.36; P<0.01); however, the greater NAE in patients with type 2 diabetes was not accounted for by the differences in unmeasured urinary anions. The overly acidic urine in patients with type 2 diabetes persists after controlling for dietary factors, body size, and age. The lower pH is due to a combination of greater NAE and lower use of ammonia buffers in patients with diabetes, which predisposes them to uric acid urolithiasis.


[Public health competencies and contents of Nursing degree programs in Spanish universities].
The Forum of Public Health University Teachers aims to update the Public Health training in the degree studies. The aim was to determine the competences and basic contents of Public Health of Nursing Degree in Spain according to the criterion of the university academic staff. Qualitative study, based on the nominal group technique. The snowball sampling was used to recruit Public Health professors of the Nursing degree, with full time dedication and preferably of the area of Preventive Medicine and Public Health. Finally, 17 professors from 11 public universities participated, who formed the Forum of University Professors of Public Health of the Nursing Degree, which was held at the University of Barcelona. Nursing professors selected 43 of the 80 competences which are recognized for Public Health professionals. The majority corresponded to the functions 'Assessing population health needs' and 'Developing health policies'. Professors also got to agree about 47 issues organized in 7 blocks, with contents on introduction of Public Health, demography, health determinants, epidemiology of communicable and non-communicable diseases, health systems and health management, and health promotion and education for health. The university teachers agreed on Public Health competencies and contents suitable for the Nursing Degree. This consensus constitutes a reference to elaborate educational guides of Public Health for Nursing Degree.


A Dynamic Neural Field Model of Multimodal Merging: Application to the Ventriloquist Effect.
Multimodal merging encompasses the ability to localize stimuli based on imprecise information sampled through individual senses such as sight and hearing. Merging decisions are standardly described using Bayesian models that fit behaviors over many trials, encapsulated in a probability distribution. We introduce a novel computational model based on dynamic neural fields able to simulate decision dynamics and generate localization decisions, trial by trial, adapting to varying degrees of discrepancy between audio and visual stimulations. Neural fields are commonly used to model neural processes at a mesoscopic scale-for instance, neurophysiological activity in the superior colliculus. Our model is fit to human psychophysical data of the ventriloquist effect, additionally testing the influence of retinotopic projection onto the superior colliculus and providing a quantitative performance comparison to the Bayesian reference model. While models perform equally on average, a qualitative analysis of free parameters in our model allows insights into the dynamics of the decision and the individual variations in perception caused by noise. We finally show that the increase in the number of free parameters does not result in overfitting and that the parameter space may be either reduced to fit specific criteria or exploited to perform well on more demanding tasks in the future. Indeed, beyond decision or localization tasks, our model opens the door to the simulation of behavioral dynamics, as well as saccade generation driven by multimodal stimulation.


Hydrodisplacement of sural nerve for safety and efficacy of endovenous thermal ablation for small saphenous vein incompetence.
Background Endovenous radio frequency ablation for small saphenous vein incompetence by and large appears to be superior and safer than conventional open surgery. Small saphenous vein ablation from approximately mid-calf to the point proximally where the small saphenous vein dives into the popliteal fossa is considered to be safe, as the sural nerve is in most cases separated from this segment of the small saphenous vein by the deep fascia. The outcome of the distal incompetent small saphenous vein remains unclear. Efficacy of the endovenous radio frequency ablation can be enhanced by increasing the length of the ablatable small saphenous vein segment. Methodology To optimise endovenous radio frequency ablation outcome, the distal small saphenous vein may be made amenable to ablation if safety of the sural nerve can be assured. The sural nerve was successfully located using duplex ultrasound in 100% of our cohort in this study. The standard entry point for venous access was just above the lateral malleolus. After introduction of the introducer sheath, the radio frequency catheter was advanced proximally; the sural nerve was displaced from the small saphenous vein by approximately 1 cm with the administration of tumescent anaesthesia ( hydrodisplacement). A total of 118 patients underwent extended endovenous radio frequency ablation of 124 incompetent small saphenous vein trunks using the method described. Results Successful extended ablation of the small saphenous vein was achieved in 100% of cases and it was confirmed by duplex scanning at one and six weeks. Two neurological events were recorded during the study: 1. One patient with temporary foot drop lasting for less than 6 h with complete recovery. 2. A second patient with a sural nerve sensory deficit reported by the patient at day 2-3, which remains current at six weeks. Conclusions Extended endovenous radio frequency ablation of the small saphenous vein to optimise length of the ablatable vein segment is feasible with careful identification and hydrodisplacement of the sural nerve. This method is shown to be associated with fewer neurological complications than other methods reported in the literature.


Evidence of a non-conventional role for the urokinase tripartite complex (uPAR/uPA/PAI-1) in myogenic cell fusion.
Urokinase can form a tripartite complex binding urokinase receptor (uPAR) and plasminogen activator inhibitor type-1 (PAI-1), a component of the extracellular matrix (ECM). The components of the tripartite complex are modulated throughout the in vitro myogenic differentiation process. A series of experiments aimed at elucidating the role of the urokinase tripartite complex in the fusion of human myogenic cells were performed in vitro. Myogenic cell fusion was associated with increased cell-associated urokinase-type plasminogen activator (uPA) activity, cell-associated uPAR, and uPAR occupancy. Incubation of cultures with either uPA anticatalytic antibodies, or the amino-terminal fragment of uPA (ATF), which inhibits competitively uPA binding to its receptor, or anti-PAI-1 antibodies, which inhibit uPA binding to PAI-1, resulted in a 30 to 47% decrease in fusion. Incubation of cultures with the plasmin inhibitor aprotinin did not affect fusion. Decreased fusion rates induced by interfering with uPAR/uPA/PAI-1 interactions were not associated with significant changes in mRNA levels of both the myogenic regulatory factor myogenin and its inhibitor of DNA binding, Id. Incubation of cultures with purified uPA resulted in a decrease in fusion, likely due to a competitive inhibition of PAI-1 binding of endogenous uPA. We conclude that muscle cell fusion largely depends on interactions between the members of the urokinase complex (uPAR/uPA/PAI-1), but does not require proteolytic activation of plasmin. Since the intrinsic muscle cell differentiation program appears poorly affected by the state of integrity of the urokinase complex, and since cell migration is a prerequisite for muscle cell fusion in vitro, it is likely that the urokinase system is instrumental in fusion through its connection with the cell migration process. Our results suggest that the urokinase tripartite complex may be involved in cell migration in a non conventional way, playing the role of an adhesion system bridging cell membrane to ECM.


Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system.
Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.


Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4.
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)(2)Vitamin D(3) levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)(2)Vitamin D(3) levels remained elusive. To determine the FGFRs regulating 1,25(OH)(2)Vitamin D(3) levels, we studied FGFR3(-/-)FGFR4(-/-) mice as these mice have shortened life span and are growth retarded similar to FGF23(-/-) and Klotho(-/-) mice. Baseline serum 1,25(OH)(2)Vitamin D(3) levels were elevated in the FGFR3(-/-)FGFR4(-/-) mice compared with wild-type mice (102.2 ± 14.8 vs. 266.0 ± 34.0 pmol/l; P = 0.001) as were the serum levels of FGF23. Administration of recombinant FGF23 had no effect on serum 1,25(OH)(2)Vitamin D(3) in the FGFR3(-/-)FGFR4(-/-) mice (173.4 ± 32.7 vs. 219.7 ± 56.5 pmol/l; vehicle vs. FGF23) while it reduced serum 1,25(OH)(2)Vitamin D(3) levels in wild-type mice. Administration of FGF23 to FGFR3(-/-)FGFR4(-/-) mice resulted in a decrease in serum parathyroid hormone (PTH) levels and an increase in serum phosphorus levels mediated by increased renal phosphate reabsorption. These data indicate that FGFR3 and 4 are the receptors that regulate serum 1,25(OH)(2)Vitamin D(3) levels in response to FGF23. In addition, when 1,25(OH)(2)Vitamin D(3) levels are not affected by FGF23, as in FGFR3(-/-)FGFR4(-/-) mice, a reduction in PTH can override the effects of FGF23 on renal phosphate transport.


The Canadian Assessment of Physical Literacy: methods for children in grades 4 to 6 (8 to 12 years).
Physical literacy is described as the motivation, confidence, physical competence, knowledge and understanding to value and engage in a physically active lifestyle. As such, it is expected that those who have greater physical literacy would be more likely to obtain the health benefits offered by habitual physical activity. A theoretical model and assessment battery, the Canadian Assessment of Physical Literacy (CAPL), for the assessment of childhood physical literacy had been proposed in theory but validity data were lacking. The purpose of this study was to explore validity evidence for the CAPL among children in grades 4 to 6. CAPL validity was evaluated through three analyses that utilized cross-sectional data obtained through local schools in Eastern Ontario, Canada. A confirmatory factor analysis compared the data to the theoretical model. Patterns of association between self-reported age and gender and the CAPL total and domain scores were examined using regression models. Teacher ratings of participants' knowledge, attitude and physical activity competence were compared to assessment results. The CAPL was completed by 963 children (55 % female) in grades 4, 5 and 6. Children were 8 to 12 years of age (mean 10.1 years), with 85 % of children approached agreeing to participate. A confirmatory factor analysis using data from 489 children with complete raw scores supported a model with four domains: engagement in physical activity (active and sedentary), physical competence (fitness and motor skill), motivation and confidence, and knowledge and understanding. Raw domain scores followed expected patterns for age and gender, providing evidence for their validity. Interpretive categories, developed from age and gender adjusted normative data, were not associated with age indicating that the CAPL is suitable for use across this age range. Children's gender was associated with the physical competence, motivation and engagement in physical activity domain scores, indicating that further research is required regarding the gender adjustment of the raw CAPL scores. CAPL domain and total scores were statistically significantly associated with teacher ratings of the child's motivation, attitudes, fitness, skill and overall physical activity. CAPL offers a comprehensive assessment of engagement in physical activity, physical competence, motivation and confidence, and knowledge and understanding as components of childhood (grades 4 to 6, 8 to 12 years) physical literacy. Monitoring of these measures enhances our understanding of children's physical literacy, and assists with the identification of areas where additional supports are required.


Reimbursing live organ donors for incurred non-medical expenses: a global perspective on policies and programs.
Methods to reimburse living organ donors for the non-medical expenses they incur have been implemented in some jurisdictions and are being considered in others. A global understanding of existing legislation and programs would help decision makers implement and optimize policies and programs. We searched for and collected data from countries that practice living organ donation. We examined legislation and programs that facilitate reimbursement, focusing on policy mechanisms, eligibility criteria, program duration and types of expenses reimbursed. Of 40 countries, reimbursement is expressly legal in 16, unclear in 18, unspecified in 6 and expressly prohibited in 1. Donor reimbursement programs exist in 21 countries; 6 have been enacted in the last 5 years. Lost income is reimbursed in 17 countries, while travel, accommodation, meal and childcare costs are reimbursed in 12 to 19 countries. Ten countries have comprehensive programs, where all major cost categories are reimbursed to some extent. Out-of-country donors are reimbursed in 10 jurisdictions. Reimbursement is conditional on donor income in 7 countries, and recipient income in 2 countries. Many nations have programs that help living donors with their financial costs. These programs differ in operation and scope. Donors in other regions of the world are without support.


The effect of intramedullary pin size and monocortical screw configuration on locking compression plate-rod constructs in an in vitro fracture gap model.
To investigate the effect of intramedullary pin size in combination with various monocortical screw configurations on locking compression plate-rod constructs. A synthetic bone model with a 40 mm fracture gap was used. Locking compression plates with monocortical locking screws were tested with no pin (LCP-Mono) and intramedullary pins of 20% (LCPR-20), 30% (LCPR-30) and 40% (LCPR-40) of intramedullary diameter. Locking compression plates with bicortical screws (LCP-Bi) were also tested. Screw configurations with two or three screws per fragment modelled long (8-hole), intermediate (6-hole), and short (4-hole) plate working lengths. Responses to axial compression, biplanar four-point bending and axial load-to-failure were recorded. LCP-Bi were not significantly different from LCP-Mono control for any of the outcome variables. In bending, LCPR-20 were not significantly different from LCP-Bi and LCP-Mono. The LCPR-30 were stiffer than LCPR-20 and the controls. The LCPR-40 constructs were stiffer than all other constructs. The addition of an intramedullary pin of any size provided a significant increase in axial stiffness and load to failure. This effect was incremental with increasing intramedullary pin diameter. As plate working length decreased there was a significant increase in stiffness across all constructs. A pin of any size increases resistance to axial loads whereas a pin of at least 30% intramedullary diameter is required to increase bending stiffness. Short plate working lengths provide maximum stiffness. However, the overwhelming effect of intramedullary pin size obviates the effect of changing working length on construct stiffness.


Targeted Delivery of Bleomycin: A Comprehensive Anticancer Review.
Despite being one of the most effective broad-spectrum chemotherapeutic agents in the treatment of cancers, the clinical applications of bleomycins (BLMs) have been limited due to their poor drug delivery abilities, and the side effect of causing lung fibrosis. With the increased therapeutics and the reduction of side effects, research and development of targeted drug delivery systems (TDDS) with BLMs have become essential for the expansive clinical usage of BLM-based therapeutics. This review summarizes the recent developments of various TDDS for BLMs, including techniques such as photochemical internalization, ultrasound, and micelle, liposome, and nanoparticle formation. The advantages and disadvantages for each delivery approach are outlined, along with the specific challenges associated with each delivery system.


Exposure to Workplace Bullying, Distress, and Insomnia: The Moderating Role of the miR-146a Genotype.
Several lines of evidence show that systematic exposure to negative social acts at the workplace i.e., workplace bullying, results in symptoms of depression and anxiety among those targeted. However, little is known about the association between bullying, inflammatory genes and sleep problems. In the present study, we examined the indirect association between exposure to negative social acts and sleep through distress, as moderated by the miR-146a genotype. The study was based on a nationally representative survey of 1179 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. Exposure to workplace bullying was measured with the 9-item version of Negative Acts Questionnaire - Revised (NAQ-R) inventory. Seventeen items from Hopkins Symptom Checklist (HSCL-25) was used to measure distress. Insomnia was assessed with three items reflecting problems with sleep onset, maintenance of sleep and early morning awakening. Genotyping with regard to miR-146a rs2910164, previously linked to inflammatory processes, was carried out using Taqman assay. The data revealed that individuals systematically exposed to negative social acts at the workplace reported higher levels of sleep problems than non-exposed individuals. Moreover, the relationship between distress induced by exposure to negative social acts and insomnia was significantly stronger for individuals with the miR-146a GG genotype. Thus, the miR-146a genotype moderated the association between distress and insomnia among individuals exposed to negative social acts. The present report support the hypothesis that inflammation could play a role in stress-induced insomnia among individuals exposed to workplace bullying.


Suppression of autophagy during mitosis via CUL4-RING ubiquitin ligases-mediated WIPI2 polyubiquitination and proteasomal degradation.
Macroautophagy/autophagy is a cellular process in which cytosolic contents are degraded by lysosome in response to various stress conditions. Apart from its role in the maintenance of cellular homeostasis, autophagy also involves in regulation of cell cycle progression under nutrient-deprivation conditions. However, whether and how autophagy is regulated by the cell cycle especially during mitosis remains largely undefined. Here we show that WIPI2/ATG18B (WD repeat domain, phosphoinositide interacting 2), an autophagy-related (ATG) protein that plays a critical role in autophagosome biogenesis, is a direct substrate of CUL4-RING ubiquitin ligases (CRL4s). Upon mitosis induction, CRL4s are activated via neddylation, and recruit WIPI2 via DDB1 (damage specific DNA binding protein 1), leading to polyubiquitination and proteasomal degradation of WIPI2 and suppression of autophagy. The WIPI2 protein level and autophagy during mitosis could be rescued by knockdown of CRL4s or treatment with MLN4924/Pevonedistat, a selective inhibitor of CRLs, via suppression of NAE1 (NEDD8 activating enzyme E1 subunit 1). Moreover, restoration of WIPI2 rescues autophagy during mitosis and leads to mitotic slippage and cell senescence. Our study thus discovers a novel function of CRL4s in autophagy by targeting WIPI2 for polyubiquitination and proteasomal degradation during mitosis. Abbreviations: ACTB, actin beta; ATG, autophagy-related; AMPK, AMP-activated protein kinase; AURKB/ARK2, aurora kinase B; BafA1, bafilomycin A1; CCNB1, cyclin B1; CDK1, cyclin dependent kinase 1; CHX, cycloheximide; CQ, chloroquine; CRL4s, CUL4-RING ubiquitin ligases; DDB1, damage specific DNA binding protein 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; GST, glutathione S-transferase; MAP1LC3B/LC3B, microtubule associated protein 1 light chain 3 beta; STK11/LKB1,serine/threonine kinase 11; MTORC1/MTOR complex 1, mechanistic target of rapamycin kinase complex 1; NAE1, NEDD8 activating enzyme E1 subunit 1; NOC, nocodazole; RING, really interesting new gene; RBX1, ring-box 1; SA-GLB1/β-gal, senescence-associated galactosidase beta 1; TSC2, TSC complex subunit 2; TUBA, tubulin alpha; WIPI2, WD repeat domain, phosphoinositide interacting 2.


Microarray analysis of the primate luteal transcriptome during chorionic gonadotrophin administration simulating early pregnancy.
To explore chorionic gonadotrophin (CG)-regulated gene expression in the primate corpus luteum (CL), adult female rhesus macaques were treated in a model of simulated early pregnancy (SEP). Total RNA was isolated from individual CL after specific intervals of exposure (1, 3, 6 and 9 days) to recombinant hCG in vivo and hybridized to Affymetrix™ GeneChip Rhesus Macaque Genome Arrays. The mRNA levels of 1192 transcripts changed ≥2-fold [one-way ANOVA, false discovery rate (FDR) correction; P< 0.05] during SEP when compared with Day 10 untreated controls. Real-time PCR validation indicated that 15 of 17 genes matched in expression pattern between PCR and microarray. Protein levels of three genes identified as CG-sensitive, CYP19A1 (aromatase), PGRMC1 (progestin-binding protein) and STAR (steroidogenic acute regulatory protein) were quantified by western blot analysis. To further analyze global changes in gene expression induced by CG exposure, luteal gene expression was compared between SEP (rescued) and regressing CL, utilizing previously banked GeneChip data from the luteal phase of the menstrual cycle. Expression patterns and mRNA levels were analyzed between time-matched intervals. Transcripts for 7677 mRNAs differed in expression patterns ≥2-fold (one-way ANOVA, FDR correction; P< 0.05) between the hCG-exposed (SEP) CL and regressing CL. Regressed CL (at menses) were most unlike all other CL. Pathway analysis of significantly affected transcripts was performed; the pathway most impacted by CG exposure was steroid biosynthesis. Further comparisons of the genome-wide changes in luteal gene expression during CG rescue and luteolysis in the natural menstrual cycle should identify additional key regulatory pathways promoting primate fertility.


Biomarkers in kidney and heart disease.
There is much symptomatic similarity between acute kidney disease and acute heart disease. Both may present with shortness of breath and chest discomfort, and thus it is not surprising that biomarkers of acute myocardial and renal disease often coexist in many physicians' diagnostic work-up schedules. In this review we explore the similarities and differences between current and future tests of myocardial and renal injury and function, with particular emphasis on the diagnostic utility of currently available biomarkers to assist with the diagnosis of cardiorenal syndromes. Imaging studies have not traditionally been viewed as clinical biomarkers, but as tests of structure and function; they contribute to the diagnostic process, and we believe that they should be considered alongside more traditional biomarkers such as blood and urine measurements of circulating proteins and metabolites. We discuss the place of natriuretic peptides, novel tests of kidney damage as well as kidney function and conclude with a discussion of their place in guiding future research studies whose goals must include better characterization of the degree of dysfunction imposed on one organ system by failure of the other.


The effect of altitude on parasite density case definitions for malaria in northeastern Tanzania.
Malaria clinical trials need precise endpoints to measure efficacy. In endemic areas where asymptomatic parasitaemia is common, 'fever plus parasitaemia' may not differentiate between malaria cases and non-cases. Case definitions based on parasite cut-off densities may be more appropriate but may vary with age and transmission intensity. This study examines appropriate case definitions from parasitological surveys conducted over a broad range of transmission intensities, using altitude as a proxy for transmission intensity. Cross-sectional data collected from 24 villages at different altitudes in an endemic area of northeastern Tanzania were used to calculate malaria-attributable fractions using a modified Poisson regression method. We modelled fever as a function of parasite density and determined the optimum cut-off densities of parasites to cause fever using sensitivity and specificity analyses. The optimum cut-off density varied by altitude in children aged under 5 years: a case definition of 4,000 parasites per mul at altitudes <600 m (high transmission intensity) was most appropriate, compared with 1,000 parasites per mul at altitudes >600 m (low transmission intensity). In children aged over 5 years and adults, there was little variation by altitude and a case definition of any parasites plus fever was the most appropriate. Locally appropriate case definitions of malaria should be used for research purposes. In our setting, these varied independently with age and transmission intensity.


Atrial Fibrillation, Brain Volumes, and Subclinical Cerebrovascular Disease (from the Atherosclerosis Risk in Communities Neurocognitive Study [ARIC-NCS]).
The aim of the present study was to investigate the association between atrial fibrillation (AF) and total and regional brain volumes among participants in the community-based Atherosclerosis Risk in Communities Neurocognitive study (ARIC-NCS). A total of 1,930 participants (130 with AF) with a mean age of 76.3 ± 5.2, who underwent 3T brain MRI scans in 2011 to 2013 were included. Prevalent AF was ascertained from study ECGs and hospital discharge codes. Brain volumes were measured using FreeSurfer image analysis software. Markers of subclinical cerebrovascular disease included lobar microhemorrhages, subcortical microhemorrhages, cortical infarcts, subcortical infarcts, lacunar infarcts, and volume of white matter hyperintensities. Linear regression models were used to assess the associations between AF status and brain volumes. In adjusted analyses, AF was not associated with markers of subclinical cerebrovascular disease. However, AF was associated with smaller regional brain volumes (including temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus [all p <0.05]) after controlling for demographics, cardiovascular risk factors, prevalent cardiovascular disease, and markers of subclinical cerebrovascular disease. Subgroup analysis revealed a significant interaction between AF and total brain volume with respect to age (p = 0.02), with associations between AF and smaller brain volumes being stronger for older individuals. In conclusion, AF was associated with smaller brain volumes, and the association was stronger among older individuals. This finding may be related to the longer exposure period of the older population to AF or the possibility that older people are more susceptible to the effects of AF on brain volume.


Long-Term Management for Ventilator-Assisted Children in Hong Kong: 2 Decades' Experience.
The population of children receiving long-term mechanical ventilation is growing worldwide, but only limited data exist in Asian regions. The objective of the study was to review the management of these children in Hong Kong over the past 2 decades. This was a retrospective cohort study. Hospital records from subjects receiving mechanical ventilation for >3 months were retrieved. Demographic characteristics and medical information of subjects (≤21 y old) under the care of the ventilator program at the Duchess of Kent Children's Hospital between 1997 and 2015 were reviewed. There were a total of 96 subjects, with male predominance (75%). Twenty-five subjects (26%) required invasive mechanical ventilation via tracheostomy, and the median age of starting ventilation was much lower than for subjects receiving noninvasive ventilation (1.6 vs 11.2 y, P .003). Underlying causes included neuromuscular diseases (50%); abnormal ventilatory control related to neurological, metabolic, or genetic conditions (25%); airway problems (18%); and chronic lung diseases (6%). Comorbidities were frequent, with significantly more subjects receiving invasive mechanical ventilation who required gastrostomy or nasogastric tube feeding and had intellectual impairment. Despite their medical complexities, most of our subjects (87.5%) could be discharged and resided in the community. Social reasons were the obstacles for discharge in 12 subjects receiving invasive mechanical ventilation. Seventeen subjects who died were receiving noninvasive ventilation, and most had progressive neuromuscular diseases. Only 8% subjects could be weaned off of ventilator support. At the time of the report, about one third of the subjects have reached adult age. Our study showed a steady growth in the number of children receiving long-term mechanical ventilation, similar to that in western countries, yet these children have distinct demographic characteristics, underlying diseases, comorbidities, and outcomes. Home care is feasible in the majority of these children despite a lack of in-home nursing care provision. Prolonged survival of these subjects necessitates the enhancement of transitional care to adult service.


Hyponatremia augments kainic-acid induced status epilepticus in the mouse: a model for dysmetabolic status epilepticus.
Status epilepticus (SE) is a dreaded neurological emergency. A reignited interest in SE has resulted in a more adaptive use of treatment protocols. More knowledge on SE of various aetiologies is therefore needed. We are interested in treatment of SE under hyponatremia, and have here evaluated whether SE induced by systemic kainic acid could be a suitable platform for such studies. Acute hyponatremia was induced in C57/BL6 mice by intraperitoneal injection of dDAVP and water loading. Hyponatremic mice displayed an increased frequency of epileptiform spikes on EEG and 5/9 hyponatremic mice displayed electrographic seizures. After kainic acid (20mg/kg) treatment, hyponatremic mice displayed significantly longer time with electrographic seizure activity, which was also seen after treatment with diazepam (20mg/kg). We conclude that hyponatremia augments kainic acid-induced SE, This model might be a valuable platform for studies on treatment of SE in hyponatremia.


Ovine induced pluripotent stem cells are resistant to reprogramming after nuclear transfer.
Induced pluripotent stem cells (iPSCs) share similar characteristics of indefinite in vitro growth with embryonic stem cells (ESCs) and may therefore serve as a useful tool for the targeted genetic modification of farm animals via nuclear transfer (NT). Derivation of stable ESC lines from farm animals has not been possible, therefore, it is important to determine whether iPSCs can be used as substitutes for ESCs in generating genetically modified cloned farm animals. We generated ovine iPSCs by conventional retroviral transduction using the four Yamanaka factors. These cells were basic fibroblast growth factor (bFGF)- and activin A-dependent, showed persistent expression of the transgenes, acquired chromosomal abnormalities, and failed to activate endogenous NANOG. Nonetheless, iPSCs could differentiate into the three somatic germ layers in vitro. Because cloning of farm animals is best achieved with diploid cells (G1/G0), we synchronized the iPSCs in G1 prior to NT. Despite the cell cycle synchronization, preimplantation development of iPSC-NT embryos was lower than with somatic cells (2% vs. 10% blastocysts, p<0.01). Furthermore, analysis of the blastocysts produced demonstrated persistent expression of the transgenes, aberrant expression of endogenous SOX2, and a failure to activate NANOG consistently. In contrast, gene expression in blastocysts produced with the parental fetal fibroblasts was similar to those generated by in vitro fertilization. Taken together, our data suggest that the persistent expression of the exogenous factors and the acquisition of chromosomal abnormalities are incompatible with normal development of NT embryos produced with iPSCs.