[Structure and function of kinetoplast DNA of Trypanosomatidae].
Kinetoplast DNA of trypanosomatids represents a complex associate composed of mini- and maxicircular molecules, the latter being analogous to mitochondrial DNA of other eukaryotic species. Some new data on the structural organization and transcription of trypanosomatid mitochondrial genome are given. Detailed genetic and transcriptional maps of maxicircular kinetoplast DNAs of trypanosome and leishmania are presented. The replication mechanisms of mini- and maxicircular molecules of kinetoplast DNA are analyzed. Some characteristic features of trypanosomatid mitochondrial genome organization similar and different with respect to mitochondrial genomes of other eukaryotic species are discussed.


Cranial ontogeny of Thamnophis radix (Serpentes: Colubroidea) with a re-evaluation of current paradigms of snake skull evolution.
Accurate knowledge of skeletal ontogeny in extant organisms is crucial in understanding important morpho-functional systems and in enabling inferences of the ontogenetic stage of fossil specimens. However, detailed knowledge of skeletal ontogeny is lacking for most squamates, including snakes. Very few studies have discussed postnatal development in snakes, with none incorporating data from all three major ontogenetic stages-embryonic, juvenile and adult. Here, we provide the first analysis encompassing these three ontogenetic stages for any squamate, using the first complete micro-computed tomography (micro-CT)-based segmentations of any non-adult snake, based on fresh specimens of Thamnophis radix. The most significant ontogenetic changes involve the feeding apparatus, with major elongation of the tooth-bearing elements and jaw suspensorium causing a posterior shift in the jaw articulation. This shift enables macrostomy (large-gaped feeding in snakes) and occurs in T. radix via a different developmental trajectory than in most other macrostomatans, indicating that the evolution of macrostomy is more complex than previously thought. The braincase of T. radix is also evolutionarily unique among derived snakes in lacking a crista circumfenestralis, a phenomenon considered herein to represent paedomorphic retention of the embryonic condition. We thus present numerous important challenges to current paradigms regarding snake cranial evolution.


Prevalence of adherence to fluid restriction in kidney patients in haemodialysis: objective indicator and perceived compliance.
Studies of adherence to fluid restriction show high variability in prevalence data, as different methods of measuring IWG (interdialysis weight gain) and cut-off criteria are used. To describe the prevalence of adherence to fluid restriction using daily IWG (criterion: ≤1 Kg) and daily IWG adjusted for dry weight (DW) (cut-off point adjusted criterion: DW<70 kg, IWG=1 kg/day; DW>70 kg and ≤80 kg, IWG=1.1 kg/day; DW>80 kg and ≤90 kg, IWG=1.2 kg/day; DW>90 kg, IWG=1.3 kg/day) and to study the association between this objective indicator and adherence behaviour as reported by patient. Our study included a total of 146 patients with a mean age of 66 years (SD: 13.6 years; range: 25-88 years), 66% of which were male. Ours was a longitudinal study with one month of follow-up. We collected both sociodemographic and clinical variables and mean daily IWG. Patient-reported adherence behaviour was assessed through an interview by a trained staff member from outside the department who asked the following question: "In order to avoid complications between haemodialysis sessions: during the last month, how many days did you ingest less than 1 litre of fluid per day?" (0= no days; 10= every day). A score ≤5 led to categorisation of patients as compliant with treatment. Statistical analysis included descriptive analysis, correlation test, chi-square and Crosstabs, ROC curve and logistic regression procedures. Prevalence of "objective" adherence to fluid restriction was 61% (mean daily IWG≤1kg) and 73% (mean daily IWG adjusted for dry weight). Reported adherence (prevalence: 56.2%) was associated with IWG adjusted for weight (chi-square =31.34; P=.000). In patients with objective adherence adjusted for weight, the prevalence of reported adherence was 1.65 times that of non-adherence (PR=1.65; 95% CI: 1.29-2.11). The final model for estimating the association between reported adherence behaviour and daily adjusted IWG included: age (higher), dry weight (lower), potassium (lower), time on haemodialysis treatment (less) and its interaction with reported behaviour (F=50.70; P=.000; R2=44%). The sensitivity of reported adherence behaviour for detecting objective adherence adjusted for dry weight was 89%; specificity was 58%, and the overall classification power was 85% (AUC=.85; 95% CI: 0.78-0.92). The probability of objective adherence adjusted for weight in patients who claimed proper adherence was 9 times higher than in non-compliant patients in patients who had been on HD for 2.3 years (PORp25=9.16; 95% CI: 2.58-32.51); 6 times higher in patients on HD for 4.7 years (PORP50=6.16; 95% CI: 2.1217.92); and 3 times higher in those on HD for 8.2 years (PORp75=3.44; 95% CI: 1.32-8.96). Prevalence of adherence to fluid restriction was 73% and 16% depending on daily IWG adjusted/not adjusted for dry weight, respectively. Absolute daily IWG adjusted for weight seems a good indicator of adherence, as it allows for a personalised fluid restriction regimen. Significant association between this objective indicator and reported adherence behaviour supports a combination of patient approach and objective data, which can help with the adjustment of the individual cut-off for daily IWG. This also provides useful information for designing intervention strategies to maintain and increase adherence.


Clinical and molecular characteristics associated with Vitamin C deficiency in myeloid malignancies; real world data from a prospective cohort.
Vitamin C is an essential vitamin that acts as a co-factor for many enzymes involved in epigenetic regulation in humans. Low vitamin C levels in hematopoietic stem cells (HSC) promote self-renewal and vitamin C supplementation retards leukaemogenesis in vitamin C-deficient mouse models. Studies on vitamin C levels in patients with myeloid malignancies are limited. We thus conducted a retrospective analysis on a prospective cohort of patients with myeloid malignancies on whom plasma vitamin C levels were measured serially at diagnosis and during treatment. Baseline characteristics including hematological indices, cytogenetics, and molecular mutations are described in this cohort. Among 64 patients included in our study, 11 patients (17%) had low vitamin C levels. We noted a younger age at diagnosis for patients with myeloid malignancies who had low plasma vitamin C levels. Patients with low plasma vitamin C levels were more likely to have acute myeloid leukemia compared to other myeloid malignancies. Low vitamin C levels were associated with ASXL1 mutations. Our study calls for further multi-institutional studies to understand the relevance of low plasma vitamin C level in myeloid neoplasms, the role of vitamin C deficiency in leukemogenesis, and the potential benefit of vitamin C supplementation.


Running-based pica in rats. Evidence for the gastrointestinal discomfort hypothesis of running-based taste aversion.
Voluntary running in an activity wheel establishes aversion to paired taste in rats. A proposed mechanism underlying this taste aversion learning is gastrointestinal discomfort caused by running. We tested this hypothesis by measuring the pica behavior (kaolin clay intake) of rats, because it is known that rats engage in pica behavior after various nausea-inducing treatments including irradiation, motion sickness, and injection of emetic drugs such as lithium chloride (LiCl). Following a demonstration of the already-known phenomenon of LiCl-based pica in Experiment 1, we successfully showed running-based pica behavior in Experiment 2 where the running treatment was compared with a non-running control treatment (i.e., confinement in a locked wheel). These results suggest that not only LiCl but also running induces nausea in rats, supporting the gastrointestinal discomfort hypothesis of running-based taste aversion learning.


Poland syndrome: evaluation and treatment of the chest wall in 63 patients.
Poland syndrome is a sporadic, congenital unilateral absence of the sternocostal head of the pectoralis major muscle that can occur with other ipsilateral chest wall and limb derangements. The chest wall deficiency is primarily cosmetic, its incidence is unknown, male patients may be affected more than female patients, the right side is affected more than the left, and associated comorbidities may exist. Chest wall repair depends on anatomical type and gender. Sixty-three patients with Poland syndrome were divided into two treatment groups by chest wall anatomy and gender. Surgical repair was based on this division. Seventy-six operations were performed by the senior author (A.E.S.) during a 30-year period, and long-term outcomes are presented. Corrective methods included use of custom-made chest wall prostheses, mammary prostheses, latissimus dorsi muscle transfers, transverse rectus abdominis musculocutaneous flaps, sternal/rib reconstruction, or a combination of methods. Follow-up ranged from 1 to 21 years. Two anatomical forms of the disorder are described, each with unique surgical requirements. The simple deformity was effectively repaired with a latissimus dorsi muscle transfer plus, in female patients, a sublatissimus mammary prosthesis. Repair of the complex deformity, in addition to the latissimus transfer, selectively included musculoskeletal chest wall realignment. Custom-made chest wall prostheses carried a higher risk of complications. Poland syndrome of the chest wall exists in two forms: the more common simple variety and a complex form (as originally described by Poland). Repair of the chest wall can be effectively tailored to these anatomical types, gender, and patient preference.


Extracellular matrix-derived hydrogels for dental stem cell delivery.
Decellularized mammalian extracellular matrices (ECM) have been widely accepted as an ideal substrate for repair and remodelling of numerous tissues in clinical and pre-clinical studies. Recent studies have demonstrated the ability of ECM scaffolds derived from site-specific homologous tissues to direct cell differentiation. The present study investigated the suitability of hydrogels derived from different source tissues: bone, spinal cord and dentine, as suitable carriers to deliver human apical papilla derived mesenchymal stem cells (SCAP) for spinal cord regeneration. Bone, spinal cord, and dentine ECM hydrogels exhibited distinct structural, mechanical, and biological characteristics. All three hydrogels supported SCAP viability and proliferation. However, only spinal cord and bone derived hydrogels promoted the expression of neural lineage markers. The specific environment of ECM scaffolds significantly affected the differentiation of SCAP to a neural lineage, with stronger responses observed with spinal cord ECM hydrogels, suggesting that site-specific tissues are more likely to facilitate optimal stem cell behavior for constructive spinal cord regeneration. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 319-328, 2017.


[Lymphatic vessels and blood vessels of the lung and of the bronchial anastomosis after autotransplantation--an experimental study].
Changes of the lymph and blood vessels of the lung and of the bronchus anastomosis were investigated in dogs in several times after 180 autotransplantations of a lobe of the lung. The regeneration of the lymph vessels in the lung autograft started 8-14 days after the operation and was concluded 30-60 days after the operation. Afterwards the lymph vessels had the normal structure and there was no difference to the intact lung. The anatomic regeneration of the lymph vessels in the bronchus anastomosis and the lymph drain from the lung autograft started 8-9 days after the operation and was concluded within the first 14 days. The regeneration of the bronchial arterial system began 6-7 days after the autotransplantation and was completed within the first 14 days.


NEIMiner: nanomaterial environmental impact data miner.
As more engineered nanomaterials (eNM) are developed for a wide range of applications, it is crucial to minimize any unintended environmental impacts resulting from the application of eNM. To realize this vision, industry and policymakers must base risk management decisions on sound scientific information about the environmental fate of eNM, their availability to receptor organisms (eg, uptake), and any resultant biological effects (eg, toxicity). To address this critical need, we developed a model-driven, data mining system called NEIMiner, to study nanomaterial environmental impact (NEI). NEIMiner consists of four components: NEI modeling framework, data integration, data management and access, and model building. The NEI modeling framework defines the scope of NEI modeling and the strategy of integrating NEI models to form a layered, comprehensive predictability. The data integration layer brings together heterogeneous data sources related to NEI via automatic web services and web scraping technologies. The data management and access layer reuses and extends a popular content management system (CMS), Drupal, and consists of modules that model the complex data structure for NEI-related bibliography and characterization data. The model building layer provides an advanced analysis capability for NEI data. Together, these components provide significant value to the process of aggregating and analyzing large-scale distributed NEI data. A prototype of the NEIMiner system is available at http://neiminer.i-a-i.com/.


Predicting the postoperative intraocular lens position using continuous intraoperative optical coherence tomography measurements.
The aim of this study was to assess, if measuring the position of the lens capsule intraoperatively with a continuous intraoperative optical coherence tomography (OCT) device could be useful to improve the prediction of the intraocular lens (IOL) position. This prospective study included patients who were scheduled for cataract surgery. A prototype operating microscope with an integrated continuous OCT device was used to measure the anterior and posterior lens capsule position at different time points during cataract surgery. In all cases, a capsular tension ring (CTR) was used to tauten the lens capsule. Partial coherence interferometry was used to measure anterior chamber depth (ACD) immediately before, and 1 hour and 3 months postoperatively. Partial least squares regression (PLSR) was used to assess the influence of different pre- and intraoperatively measured parameters. In total, 70 eyes of 70 patients were included. Mean axial eye length was 23.6 mm (range, 20.6 mm-30.8 mm), mean used IOL power was 22.2 diopters (D; range, 6.0 D-31.5 D). PLSR showed that the anterior lens capsule measured after removing the crystalline lens and after implanting a CTR was a significantly better predictor for the postoperative ACD compared with preoperative ACD measurements. The main problem of IOL power calculation, the prediction of the IOL position after surgery, could possibly be reduced by using intraoperative lens capsule measurements instead of preoperative ACD measurements. (ClinicalTrials.gov number, NCT01867541.).


The Michael addition-elimination of ylides to alpha,beta-unsaturated imines. Highly stereoselective synthesis of vinylcyclopropanecarbaldehydes and vinylcyclopropylaziridines.
The Michael addition-elimination of ylide to alpha,beta-unsaturated imines leads to a highly diastereoselective and enantioselective synthesis of vinylcyclopropanecarbaldehydes in good to high yields for the first time. A sequential cyclopropanation-aziridination protocol for the preparation of cyclopropylaziridines is also developed with good diastereoselectivity in good to high yields.


Understanding the regulation of iron nutrition: can it contribute to improving iron toxicity tolerance in rice?
Iron nutrition in plants is highly regulated in order to supply amounts sufficient for optimal growth while preventing deleterious effects. In response to iron deficiency, plants induce either reduction-based or chelation-based mechanisms to enhance iron uptake from the soil. Major physiological traits and genes involved in these mechanisms have been fairly well described in model plants like Arabidopsis thaliana (L. Heynh.) and rice (Oryza sativa L.). However, for rice, iron toxicity presents a major challenge worldwide and causes yield reductions because rice is widely cultivated in flooded soils. Nonetheless, rice employs different mechanisms of adaptation to iron-toxicity, which range from avoidance to tissue tolerance. The physiological and molecular bases of such mechanisms have not been fully investigated and their use in breeding for iron-toxicity tolerance remains limited. Efforts to precisely characterise iron-toxicity control mechanisms may help speed-up the development of tolerant rice varieties. Considering how far the understanding of iron dynamics in the soil and plants has progressed, we consider it valuable to exploit such knowledge to improve rice tolerance to iron toxicity. Here we present the mechanisms that regulate iron uptake from the rhizosphere to the plant tissues together with the possible regulators involved. In addition, a genetic model for iron-toxicity tolerance in rice, which hypothesises possible modulation of key genes involved in iron nutrition and regulation is presented. The possibility of incorporating such relevant regulators in breeding is also discussed.


IL-10 mediates resistance to adoptive transfer experimental autoimmune encephalomyelitis in MyD88(-/-) mice.
MyD88 is an adaptor molecule that functions in the innate signaling induced by proinflammatory adjuvants that interact with TLRs. Mice lacking MyD88, for example, resist active experimental autoimmune encephalomyelitis (EAE) induced by immunization with an encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide in CFA. We reasoned that MyD88(-/-) mice, nevertheless, should be susceptible to EAE mediated by adoptive transfer of activated encephalitogenic T cell lines, which do not require adjuvant signaling for their effector functions. We now report, however, that mice lacking MyD88 also resist adoptive EAE mediated by an anti-MOG T cell line that is strongly encephalitogenic in wild-type (WT) mice. The transferred anti-MOG T cells proliferated, secreted INF-gamma, and migrated to the CNS in the MyD88(-/-) mice, as they did in WT mice, but inflammatory infiltrates did not progress and clinical EAE did not develop. The resistance of the MyD88(-/-) mice to adoptive EAE mediated by the otherwise encephalitogenic T cells was found to result from the secretion of IL-10 by recipient T cells of two different specificities: those specific for MOG and those responding to the T cell clone itself-both anticlonotypic and antiergotypic T regulators were detected. IL-10-producing anti-MOG T cells isolated from immunized MyD88(-/-) mice suppressed the induction of active EAE in WT recipients. Moreover, the absence of IL-10 production in MyD88/IL-10 double-knockout mice rendered the mice susceptible to adoptive transfer of EAE. Thus, MyD88 signaling appears to be a key factor in determining the cytokine phenotype of T cells involved in autoimmune inflammation and regulation.


Effectiveness of a Mental Health Service Navigation Website (Link) for Young Adults: Randomized Controlled Trial.
Mental health and substance use disorders are the main causes of disability among adolescents and young adults yet fewer than half experiencing these problems seek professional help. Young people frequently search the Web for health information and services, suggesting that Web-based modalities might promote help-seeking among young people who need it. To support young people in their help-seeking, we developed a Web-based mental health service navigation website called Link. Link is based on the Theory of Planned Behavior and connects young people with treatment based on the type and severity of mental health symptoms that they report. The study aimed to investigate the effect of Link on young people's positive affect (PA) compared with usual help-seeking strategies immediately post intervention. Secondary objectives included testing the effect of Link on negative affect (NA), psychological distress, barriers to help-seeking, and help-seeking intentions. Young people, aged between 18 and 25 years, were recruited on the Web from an open access website to participate in a randomized controlled trial. Participants were stratified by gender and psychological distress into either the intervention arm (Link) or the control arm (usual help-seeking strategies). Baseline, immediate postintervention, 1-month, and 3-month surveys were self-reported and administered on the Web. Measures included the PA and NA scales, Kessler psychological distress scale (K10), barriers to adolescent help-seeking scale (BASH), and the general help-seeking questionnaire (GHSQ). In total 413 young people were recruited to the trial (intervention, n=205; control, n=208) and 78% (160/205) of those randomized to the intervention arm visited the Link website. There was no evidence to support a difference between the intervention and control arms on the primary outcome, with PA increasing equally by approximately 30% between baseline and 3 months in both arms. NA decreased for the intervention arm compared with the control arm with a difference of 1.4 (95% CI 0.2-2.5) points immediately after the intervention and 2.6 (95% CI 1.1-4.1) at 1 month. K10 scores were unchanged and remained high in both arms. No changes were found on the BASH or GHSQ; however, participants in the intervention arm appeared more satisfied with their help-seeking process and outcomes at 1 and 3 months postintervention. The process of prompting young people to seek mental health information and services appears to improve their affective state and increase help-seeking intentions, regardless of whether they use a Web-based dedicated youth-focused tool, such as Link, or their usual search strategies. However, young people report greater satisfaction using tools designed specifically for them, which may encourage future help-seeking. The ability of Web-based tools to match mental health needs with appropriate care should be explored further. Australian New Zealand Clinical Trials Registry ACTRN12614001223628; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366731.


Defining NELF-E RNA binding in HIV-1 and promoter-proximal pause regions.
The four-subunit Negative Elongation Factor (NELF) is a major regulator of RNA Polymerase II (Pol II) pausing. The subunit NELF-E contains a conserved RNA Recognition Motif (RRM) and is proposed to facilitate Poll II pausing through its association with nascent transcribed RNA. However, conflicting ideas have emerged for the function of its RNA binding activity. Here, we use in vitro selection strategies and quantitative biochemistry to identify and characterize the consensus NELF-E binding element (NBE) that is required for sequence specific RNA recognition (NBE: CUGAGGA(U) for Drosophila). An NBE-like element is present within the loop region of the transactivation-response element (TAR) of HIV-1 RNA, a known regulatory target of human NELF-E. The NBE is required for high affinity binding, as opposed to the lower stem of TAR, as previously claimed. We also identify a non-conserved region within the RRM that contributes to the RNA recognition of Drosophila NELF-E. To understand the broader functional relevance of NBEs, we analyzed promoter-proximal regions genome-wide in Drosophila and show that the NBE is enriched +20 to +30 nucleotides downstream of the transcription start site. Consistent with the role of NELF in pausing, we observe a significant increase in NBEs among paused genes compared to non-paused genes. In addition to these observations, SELEX with nuclear run-on RNA enrich for NBE-like sequences. Together, these results describe the RNA binding behavior of NELF-E and supports a biological role for NELF-E in promoter-proximal pausing of both HIV-1 and cellular genes.


Comparative study of percutaneous vertebral body perforation and vertebroplasty for the treatment of painful vertebral compression fractures.
Percutaneous vertebral body perforation is a new technique for treating painful VCFs. Herein, we compare the therapeutic effect of vertebral perforation and conventional vertebroplasty for treating VCFs. One hundred eight patients with single painful VCFs were assigned to undergo vertebral perforation (perforation group) or vertebroplasty (PVP group). Clinical outcomes were assessed by using the VAS. The associations of analgesic effect and clinical factors were also analyzed by multivariate regression. Plain radiographs were used to quantify the progression of vertebral body compression after surgery and to evaluate cement leakage and new vertebral fractures. The median follow-up time was 10 months. Baseline characteristics were similar in the 2 groups. No factors correlated with analgesic effects in the PVP group. The analgesic effect of vertebral perforation was, however, related to the preoperative severity of vertebral compression and was low in patients with severe deformity (P < .05). Among patients with preoperative vertebral percentage of compression below 30%, there were no significant differences between the 2 groups in analgesic effect at any postoperative intervals. Progression of vertebral compression after surgery occurred in 22.2% and 16.0% of treated vertebrae in the perforation and PVP groups, respectively (P = .38). Respectively, 3.7% and 20.0% of the perforation and PVP groups had new postoperative fractures during follow-up (P < .05). There were no other complications. Vertebral perforation was safe and effective for painful VCFs with slight compression. However, vertebroplasty should be considered for patients with marked vertebral body compression.


Setting positive end-expiratory pressure by using electrical impedance tomography.
This review presents the principles and possibilities of setting positive end-expiratory pressure (PEEP) using electrical impedance tomography (EIT). It summarizes the major findings of recent studies where EIT was applied to monitor the effects of PEEP on regional lung function and to guide the selection of individualized PEEP setting. The most frequent approach of utilizing EIT for the assessment of PEEP effects and the PEEP setting during the time period from January 2022 till June 2023 was based on the analysis of pixel tidal impedance variation, typically acquired during stepwise incremental and/or decremental PEEP variation. The most common EIT parameters were the fraction of ventilation in various regions of interest, global inhomogeneity index, center of ventilation, silent spaces, and regional compliance of the respiratory system. The studies focused mainly on the spatial and less on the temporal distribution of ventilation. Contrast-enhanced EIT was applied in a few studies for the estimation of ventilation/perfusion matching. The availability of commercial EIT devices resulted in an increase in clinical studies using this bedside imaging technology in neonatal, pediatric and adult critically ill patients. The clinical interest in EIT became evident but the potential of this method in clinical decision-making still needs to be fully exploited.


Limitations of magnetic resonance imaging in measurement of hepatic iron.
To evaluate the usefulness of magnetic resonance imaging for the quantitative determination of hepatic iron, we examined 43 patients with thalassemia major and assessed the influence of pathologic changes in the liver on the precision of estimates of the hepatic iron concentration. Tissue signal intensities were measured from magnetic resonance T1-weighted images derived from gradient-echo (GE) pulse sequences and the ratio of the signal intensity of liver to muscle calculated. By excluding patients (n = 9) having a signal intensity ratio (SIR) less than or equal to 0.2, a linear relationship with hepatic iron was found and subsequent analyses were limited to these 34 patients. In 27 patients with hepatic fibrosis, an overall correlation of -0.848 was found between hepatic iron and SIR. By contrast, in the seven patients with no fibrosis, the correlation coefficient (-0.993) was significantly greater (P < .0001). Despite the differences in correlation, the regression line between hepatic iron and SIR for the patients with no fibrosis did not differ significantly with respect to either slope or intercept from that of the patients with fibrosis. Thus, the presence of fibrosis did not seem to affect the pattern of the relationship between hepatic iron and the SIR, but rather to increase the variability of the relationship. Clinically, the presence of fibrosis makes estimates of hepatic iron derived from magnetic resonance imaging so variable as to be of little practical use in the management of transfusional iron overload.


Effect of Fentanyl and Nalbuphine for Prevention of Etomidate-Induced Myoclonus.
Etomidate is a potent intravenous inducing agent with known undesirable side effects such as myoclonus and pain on injection in nonpremedicated patients. The aim of this study is to compare the effect of fentanyl and nalbuphine in the prevention of etomidate-induced myoclonus. Randomized double-blind, placebo-controlled, and prospective comparative study. A total of 120 patients were randomly allocated to one of the three groups containing 40 patients each for intravenous administration of fentanyl 2 μg/kg diluted in 10 mL normal saline (NS) (Group 1), nalbuphine 0.3 mg/kg diluted in 10 mL NS (Group 2), and only 10 mL NS (Group 3) over 10 min. All groups subsequently received 0.3 mg/kg etomidate by intravenous bolus injection over 15-20 s and were assessed for the severity of pain using Grade IV pain scale and observed for myoclonus for 2 min and graded according to clinical severity. Serum creatinine phosphokinase (CPK) levels were obtained prior and postetomidate injection. Statistical analysis was performed by the SPSS program version 17.0 for Windows. Tests used are Shaipro-Wilk test, ANOVA, Tukey's multiple comparison test, Tamhane's T2, and the Chi-square test. For all statistical tests, P < 0.05 was considered statistically significant with 5% level of significance (α). The incidence of myoclonus in Group 1 and 2 was 52.5% and 17.5%, respectively, whereas it was 92.45% in Group 3. There was no pain observed in 70%, 92.5%, and 50% of patients in Group 1, 2, and 3, respectively. There was a statistically significant difference in mean CPK level after induction among three groups (P < 0.001). Nalbuphine is more effective than fentanyl in the prevention of etomidate-induced myoclonus and pain with the minimum rise in CPK levels.


Exploring Frailty in the Intersection of Cardiovascular Disease and Cancer in Older People.
Advances in cardiovascular therapies and cancer treatments have resulted in longer patient survival. The coexistence of cancer and cardiovascular disease has been recognized as a complex clinical scenario. In addition to cardiovascular disease, older people with cancer are at greater risk of experiencing multimorbidity and geriatric syndromes, such as frailty. In older people, the concurrent presence of cancer and cardiovascular disease increases the risk of mortality, and the presence of frailty can exacerbate their conditions and hinder treatment effectiveness. Given the significant intersection among frailty, cardiovascular disease, and cancer in older people, this paper aims to provide an overview of the current research in this field and identifies gaps in the research to understand the burden and impact of frailty in these populations. While many studies have examined the prevalence and impact of frailty on adverse outcomes in patients with cancer or cardiovascular disease, evidence of frailty in individuals with both conditions is lacking. There is no universally accepted definition of frailty, which leads to inconsistencies in identifying and measuring frailty in older adults with cardiovascular disease and cancer. The frailty index seems to be a preferred frailty definition in studies of patients with cancer, while the frailty phenotype seems to be more commonly used in cardiovascular research. However, differences in how the frailty index was categorized and in how patients were classified as 'frail' depending on the cut points may have a negative effect on understanding the impact of frailty in the studied populations. This makes it challenging to compare findings across different studies and limits our understanding of the prevalence and impact of frailty in these populations. Addressing these research gaps will contribute to our understanding of the burden of frailty in older people with cardiovascular disease and cancer, and improve clinical care protocols in this vulnerable population.


Where is straight ahead to a patient with unilateral vestibular loss?
The vestibular system is classically associated with postural control, oculomotor reflexes and self-motion perception. The patients with vestibular loss are primarily concerned with balance and gait problems including head and trunk tilt and walking trajectory deviation to the lesioned side. These long-lasting postural and locomotor biases are thought to originate from changes in spatial perception of self. Indeed, we show here that vestibular cues are necessary for an accurate representation of body orientation. Patients with right (RVN; n=11) or left vestibular neurotomy (LVN; 9) as a treatment for Menière's disease were compared with 10 healthy controls. The subjective straight ahead (SSA) was investigated using a method disentangling lateral shift and tilt components of error. In the horizontal plane, subjects were required to align a rod with their body midline. In the frontal plane, they were asked to align the rod with the midline of head or trunk. The analysis of SSA clearly showed distinct results according to the side of the lesion. The LVN patients had a contralesional lateral shift of SSA. In addition, they showed an ipsilesional tilt, more severe for the head than for the trunk. By contrast, in RVN patients, the representation of the body midline was fairly accurate in both the horizontal and frontal planes and did not differ from that of control subjects. The present study shows deviations in body orientation representation after unilateral vestibular loss. Deviations are observed in the horizontal as well as in the frontal planes. Interestingly, only patients with left vestibular loss were concerned with these changes in perception of self-orientation in space. These data support the hypothesis of an asymmetric vestibular function in healthy subjects and confirm the similarity of functional disorders in patients with vestibular deficits or spatial neglect. For the first time, this similarity is found at the level of body representation.


Total anomalous pulmonary venous drainage beyond childhood.
We studied the anatomic characteristics and results of surgery in 27 patients with total anomalous pulmonary venous drainage who were 15 years or older between January 1997 and July 2007. Mean age was 19.7+/-11.6 years (15-48 years). The anatomic subtypes were supracardiac (n=15), cardiac (n=7), and mixed (n=5). Fourteen patients were in NYHA class II and 13 were in NYHA class III. Eleven patients had severe and the rest had moderate pulmonary arterial hypertension; six patients had significant right ventricular dysfunction. All patients underwent complete repair. A small inter-atrial communication was left open in four patients and in two patients, a fenestrated unidirectional valved patch was used to close the atrial septal defect. There were no early or late deaths. Follow-up was 3-127 months (mean 61.2+/-36.1 months). Twenty patients were in NYHA class I and seven were in class II. Echocardiography showed normal right and left ventricular function in all patients with reduction of pulmonary arterial pressures in 26 patients. One patient underwent radiofrequency ablation for new onset atrial flutter. Surgery can be safely undertaken in a few naturally selected group of patients with total anomalous pulmonary venous drainage who survive beyond childhood.


ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones.
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of connective tissue, affecting the retina, the skin, and the cardiovascular system. PXE is caused by mutations in ABCC6. Up to now, the literature reports that there are 180 different ABCC6 mutations in PXE. The purpose of this paper is to report eight novel mutations in ABCC6 and to update the spectrum and frequency of ABCC6 mutations in PXE patients. Eye, skin, and DNA examinations were performed using standard methodologies. We newly investigated the gene in 90 probands by denaturing high-performance liquid chromatography (dHPLC) and direct sequencing. We examined a total of 166 probands. Eight novel ABCC6 mutations (c.1685T>C, p.Met562Thr; c.2477T>C, p.Leu826Pro; c.2891G>C, p.Arg964Pro; c.3207C>A, p.Tyr1069X; c.3364delT, p.Ser1122fs; c.3717T>G, p.Tyr1293X; c.3871G>A, p.Ala1291Thr; c.4306_4312del, p.Thr1436fs) were found in seven unrelated patients. Currently, our mutation detection score is at least one ABCC6 mutation in 87% of patients with a clinical diagnosis of PXE. Our results support that ABCC6 is the most important, and probably the only, causative gene of PXE. In total, 188 different ABCC6 mutations have now been reported in PXE in the literature.


Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.
A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4d and 4e demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders.


Cognitive Complaints in Motor Functional Neurological (Conversion) Disorders: A Focused Review and Clinical Perspective.
Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition characterized by sensorimotor symptoms exhibiting features incompatible with other neurologic diseases. Individuals with motor FND (mFND) typically present with limb weakness, nonepileptic seizures, and/or abnormal movements. However, this population also frequently reports clouded thinking, inattention, and memory difficulties. Cognitive complaints in individuals with mFND are important to evaluate as they may negatively impact quality of life and impede treatment engagement. We provide a narrative review of the neuropsychological testing literature detailing neurocognitive profiles of individuals with mFND. We also present three illustrative clinical cases at the intersection of mFND and cognitive concerns. Several studies and our case examples highlight that generally normal cognitive performance can be observed concurrently with subjective cognitive complaints in some individuals with mFND; this mismatch may be a possible "rule-in" sign of functional cognitive symptoms. Other studies have reported impairments in attention, memory, language, visuospatial, and executive functioning in individuals with mFND. These impairments could be related to medical-psychiatric comorbidities, psychotropic medication side effects, and intrinsic disease mechanisms. When evaluating individuals with mFND and their cognitive complaints, clinicians can use performance validity test and psychopathology findings to help them interpret the neuropsychological test results. Perceptual mismatches between intact objective cognitive performance and subjective cognitive complaints may reflect a negative attentional bias for cognitive abilities that can be targeted with cognitive retraining and cognitive behavioral therapy. Neuropsychological evaluations may provide a useful adjunctive tool clinicians can use to help assess individuals with mFND and cognitive concerns.


Development of Antimicrobial and Antifouling Universal Coating via Rapid Deposition of Polydopamine and Zwitterionization.
Biomaterials-associated infections (BAIs) are related to bacterial colonization on medical devices, which lead to a serious medical burden, such as increased healthcare cost, prolonged hospital stays, and high mortality and morbidity. To reduce the risk of infections, in this work, a new approach which makes use of a bioinspired coating with dual antimicrobial and antifouling functions was developed through rapid deposition of functional polydopamine (pDA) and antimicrobial copper ions, and subsequent conjugation of zwitterionic antifouling sulfobetaine (SB) moieties by the aza-Michael addition reaction. pDA permits surface-independent versatile functionalization on a variety of substrates, such as TiO2, SiO2, gold, plastics, and Nitinol alloy. The characterizations for chemical elemental compositions and hydrophilicity by X-ray photoelectron spectroscopy and contact angle goniometer, respectively, indicating the successful grafting of SB moieties and the presence of copper ions in the pDA adlayers. Ellipsometric thicknesses of the thin films were followed to monitor the formation of pDA films and the changes after the post conjugation. UV-vis spectroscopy and inductively coupled plasma-mass spectrometry revealed the coordination structure of catechol-Cu, and release profile of Cu2+ from the constructed functional coatings. The superhydrophilic and charge-balanced SB interface allowed effective resistance of bacterial adsorption. Intriguingly, we scrutinized that the release of bactericidal copper ions enables killing the residual amount of adsorbed bacteria. Moreover, viability tests for fibroblast cells indicate the excellent biocompatibility of the developed medical coatings. For real-world implementation, the antifouling and antimicrobial coatings were applied on commercially available silicone-based urinary catheters, and the existence of bacteria was evaluated by using the plate-counting assay. The results showed an undetectable level of living bacteria. Consequently, the dual functional medical coating offers a promising approach to eliminate BAIs for practical applications.


The Relationship between Traumatic Life Events and Hoarding Symptoms: A Multi-Method Approach.
Hoarding Disorder is characterized by difficulties with discarding and frequently excessively acquiring possessions, resulting in substantial clutter. Previous research has implicated trauma in the development of hoarding, but no study to date has examined the relationship between trauma and hoarding using hypothetical hoarding paradigms. This study investigated the association between traumatic events and both self-report and hypothetical indices of hoarding symptoms. We predicted that frequency of trauma would be associated with greater hoarding symptoms (across self-report and hypothetical indices). Undergraduate students (N = 80) completed self-report measures of hoarding symptoms and trauma, and hypothetical measures of acquiring and saving tendencies. As expected, more frequent trauma, and physical/sexual trauma in particular, was associated with greater acquiring tendencies. However, frequency of trauma was not significantly correlated with saving tendencies or self-reported hoarding symptoms. Future research should replicate these findings using longitudinal designs to confirm whether trauma actually serves as a risk factor for hoarding. Replication in a clinical sample is needed to better understand the implications of these results for intervention.


Tracking paternal genes with DALP markers in a pseudoarrhenotokous reproductive system: biparental transmission but haplodiploid-like inheritance in the mite Neoseiulus californicus.
The complexity of some sexual reproductive systems in arthropods still leaves both their genetic and epigenetic determinism and their evolutionary significance poorly understood. Pseudoarrhenotoky is characterized by obligate fertilization and differential inactivation and/or elimination of paternal chromosomes in embryos that develop into males. Here, we investigate how the paternal genome is transmitted in a pseudoarrhenotokous mite, Neoseiulus californicus, using codominant genetic markers detected by DALP (direct amplification of length polymorphism). Transmission patterns of parental alleles through one and two generations are reported at four or five loci corresponding to four linkage groups. Our data provide strong evidence for selective elimination of the paternal genome among male tissues. Sperm contained maternal genes exclusively, whereas some male somatic tissues retained most if not all paternal chromosomes. No recombination between parental genomes prior to paternal genome elimination from the embryonic germ line was observed. These data allow a reinterpretation of previous phenotypic and cytogenetic observations in these mites, from which we suggest some relevant mechanistic and evolutionary implications. In addition, this is the first published study using polymorphic codominant loci detected by the recently developed DALP method.


Sexually Dimorphic Response of Increasing Dietary Intake of High Amylose Wheat on Metabolic and Reproductive Outcomes in Male and Female Mice.
High amylose wheat (HAW) has a higher resistant starch content and lower glycaemic index than standard amylose wheat (SAW), which may be associated with health benefits. This study aimed to determine the effects of replacing SAW with HAW on metabolic and reproductive parameters in male and female mice. Male and female C57BL/6 mice were randomly divided into groups (n = 8/group/sex) and fed either a SAW65 (65% SAW w/w; control), HAW35 (35% HAW w/w), HAW50 (50% HAW w/w) or HAW65 (65% HAW w/w) diet for eight weeks. In male but not female, the HAW65 group had a lower abdominal circumference, relative total fat mass, relative gonadal fat mass and plasma leptin concentration compared to the HAW35 group. There were no differences in fasting blood glucose concentrations or plasma concentrations of cholesterol, triglycerides or non-esterified fatty acids between groups in either males or females. The HAW-fed males had a higher testicular weight and HAW-fed females spent less time in diestrus and a longer time in metestrus compared to the SAW-fed mice. Higher dietary intake of HAW appears to reduce abdominal fat deposition compared to the lower level of HAW in a sexually dimorphic manner. The impacts on reproductive parameters in the HAW-fed mice require further investigation.


[Heterogeneity of the functional properties of macrocolonies of rat small intestine epitheliocytes].
The relationship was studied between the enzymatic activity of epitheliocyte macrocolonies of the rat small intestine and their size and the DNA synthesis rate. High degree of enzymatic differentiation was manifested by small colonies (1-4 mg) with a delayed 3H-thymidine incorporation into crypt cells. In macrocolonies sized over 5 mg with the normal DNA synthesis rate, the enzymatic differentiation was slightly marked. The evidence obtained indicates that epitheliocyte macrocolonies arising from individual stem cells have different functional properties depending on the DNA synthesis rate and the size of macrocolonies.


High variability between regional histories of long-term atmospheric Pb pollution.
The advent of metal processing was one of the key technological evolutions presaging the development of modern society. However, the interplay between metal use and the long-term changes it induced in the development and functioning of past societies remains unclear. We present a compilation of global records of anthropogenic atmospheric lead (Pb) spanning the last 4000 years, an effective indirect proxy for reliably assessing Pb emissions directly linked to human activities. Separating this global Pb pollution signal into regionally representative clusters allows identification of regional differences in pollution output that reflect technological innovations, market demands, or demise of various human cultures for last 4000 years. Our European reconstruction traces well periods of intensive metal production such as the Roman and Medieval periods, in contrast to clusters from the Americas, which show low levels of atmospheric Pb until the Industrial Revolution. Further investigation of the European synthesis results displays clear regional variation in the timing and extent of past development of polluting activities. This indicates the challenges of using individual reconstructions to infer regional or global development in Pb output and related pollution.


[Insulin and cancer: myth or reality?].
Several insulin analogues have been developed in recent years and are increasingly being used in the treatment of diabetes. However, modifying the insulin molecule not only changes its metabolic effects, but can also alter its mitogenic potency. In vitro experiments had previously suggested a potential association between insulin analogues and cancer. In 2009 several articles were published in Diabetologia describing an association between administration of glargine (Lantus) and higher incidence of cancer rates. The present article aims at briefly presenting the state of the art based upon currently available data on insulin and cancer. We will summarize the mechanisms by which insulin can increase cell proliferation, the observations reported in recent publications and finally conclude with some practical recommendations.


Aetiology of invasive bacterial infection and antimicrobial resistance in neonates in sub-Saharan Africa: a systematic review and meta-analysis in line with the STROBE-NI reporting guidelines.
Aetiological data for neonatal infections are essential to inform policies and programme strategies, but such data are scarce from sub-Saharan Africa. We therefore completed a systematic review and meta-analysis of available data from the African continent since 1980, with a focus on regional differences in aetiology and antimicrobial resistance (AMR) in the past decade (2008-18). We included data for microbiologically confirmed invasive bacterial infection including meningitis and AMR among neonates in sub-Saharan Africa and assessed the quality of scientific reporting according to Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection (STROBE-NI) checklist. We calculated pooled proportions for reported bacterial isolates and AMR. We included 151 studies comprising data from 84 534 neonates from 26 countries, almost all of which were hospital-based. Of the 82 studies published between 2008 and 2018, insufficient details were reported regarding most STROBE-NI items. Regarding culture positive bacteraemia or sepsis, Staphylococcus aureus, Klebsiella spp, and Escherichia coli accounted for 25% (95% CI 21-29), 21% (16-27), and 10% (8-10) respectively. For meningitis, the predominant identified causes were group B streptococcus 25% (16-33), Streptococcus pneumoniae 17% (9-6), and S aureus 12% (3-25). Resistance to WHO recommended β-lactams was reported in 614 (68%) of 904 cases and resistance to aminoglycosides in 317 (27%) of 1176 cases. Hospital-acquired neonatal infections and AMR are a major burden in Africa. More population-based neonatal infection studies and improved routine surveillance are needed to improve clinical care, plan health systems approaches, and address AMR. Future studies should be reported according to standardised reporting guidelines, such as STROBE-NI, to aid comparability and reduce research waste. Uduak Okomo was supported by a Medical Research Council PhD Studentship.


Erythrocytosis in children and adolescents-classification, characterization, and consensus recommendations for the diagnostic approach.
During recent years, the increasing knowledge of genetic and physiological changes in polycythemia vera (PV) and of different types of congenital erythrocytosis has led to fundamental changes in recommendations for the diagnostic approach to patients with erythrocytosis. Although widely accepted for adult patients this approach may not be appropriate with regard to children and adolescents affected by erythrocytosis. The "congenital erythrocytosis" working group established within the framework of the MPN&MPNr-EuroNet (COST action BM0902) addressed this question in a consensus finding process and developed a specific algorithm for the diagnosis of erythrocytosis in childhood and adolescence which is presented here.


[Psychomotor re-education--movement as therapeutic method].
Psychomotor re-education represents a multidimensional therapeutic approach in dealing with children and adults with psychomotor disorders. Therapeutic programs should be based on individual differences, abilities and capabilities, relationships, feelings and individual developmental needs as well as emotional condition of a child. BODY AND MOVEMENT AS THE Bases OF THE TREATMENT: A movement, glance, touch, voice and word, all being an integral part of a process of psychomotor re-education, are used with a purpose of helping children to discover their own body, their feelings, needs, behaviour. When moving, children discover the space of their own bodily nature, and, subsequently, gestural space and objective space. The body represents a source of pleasure and the freedom of movement, as well as one's own existence, are soon to be discovered. An adequate assessment is a precondition to design a work plan, select the best exercises for each child individually and direct the course of therapy. This is the most suitable method for treating children with slow or disharmonious development, mentally challenged children, children with speech and behaviour disorders. It is also used in the treatment of children with dyspraxic difficulties, difficulties in practognostic and gnostic development, pervasive developmental disorder and children with lateral dominance problems. Therefore, a systematic observation seems to be necessary as well as an increased number of research projects aimed at assessing results obtained by exercises in order to get a more precise insight into the process of re-education, selection of exercises, duration period and possible outcomes.


Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial.
Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa. Because rotavirus vaccines have proven effective in developed countries but had not been tested in developing countries, we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana, Kenya, and Mali between April, 2007, and March, 2009. In our multicentre, double-blind, placebo-controlled trial, undertaken in rural areas of Ghana and Kenya and an urban area of Mali, we randomly assigned infants aged 4-12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants with HIV infection were not excluded. Randomisation was done by computer-generated randomisation sequence in blocks of six. We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospectively by clinicians. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11), detected by enzyme immunoassay, arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. 5468 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735). 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per-protocol analysis. 79 cases of severe rotavirus gastroenteritis were reported in 2610.6 person-years in the vaccine group, compared with 129 cases in 2585.9 person-years in the placebo group, resulting in a vaccine efficacy against severe rotavirus gastroenteritis of 39.3% (95% CI 19.1-54.7, p=0.0003 for efficacy >0%). Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given. 42 (1.5%) of 2723 infants assigned to receive vaccine and 45 (1.7%) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was gastroenteritis (vaccine 17 [0.6%]; placebo 17 [0.6%]). Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years. We support WHO's recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa. PATH (GAVI Alliance grant) and Merck.


Relationship of weight-based teasing and adolescents' psychological well-being and physical health.
To date, research has focused primarily on psychological correlates of weight-based teasing. In this study, we extended previous work by also examining physical health-related variables (eg, physical self-concept and physical fitness [PF]). Participants included 1419 middle school students (637 boys and 782 girls). Of these, 245 (17.3%) reported being teased about being overweight. Participants completed measures of self-esteem, depression, physical self-concept, physical activity (PA) self-efficacy, and self-report physical and sedentary activities. Participants also completed PF testing. After controlling for demographic characteristics, participants who were teased about being overweight had higher scores on depression and lower scores on self-esteem, physical self-concept, PA self-efficacy, and health-related measures of PF in comparison to participants who were not teased. The results of this study support previous research indicating relationships between teasing and low levels of psychological well-being, physical self-concept, and PA self-efficacy, and establishes one between weight-based teasing and different types of PF. Research is needed to determine the potential causal nature of the relationships between teasing and fitness and evidence-based interventions are needed to reduce weight-based teasing and its potential effects on health and well-being.


Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk.
Foxp3 acetylation is essential to regulatory T (Treg) cell stability and function, but pharmacologically increasing it remains an unmet challenge. Here, we report that small-molecule compounds that inhibit TIP60, an acetyltransferase known to acetylate Foxp3, unexpectedly increase Foxp3 acetylation and Treg induction. Utilizing a dual experimental/computational approach combined with a newly developed FRET-based methodology compatible with flow cytometry to measure Foxp3 acetylation, we unraveled the mechanism of action of these small-molecule compounds in murine and human Treg induction cell cultures. We demonstrate that at low-mid concentrations they activate TIP60 to acetylate P300, a different acetyltransferase, which in turn increases Foxp3 acetylation, thereby enhancing Treg cell induction. These results reveal a potential therapeutic target relevant to autoimmunity and transplant.


In vitro interactions between farnesol and fluconazole, amphotericin B or micafungin against Candida albicans biofilms.
Biofilm formation by Candida albicans poses an important therapeutic challenge in human diseases. Typically, conventional antifungal agents encounter difficulty in treating and fully eradicating biofilm-related infections. Novel therapeutic approaches are needed to treat recalcitrant Candida biofilms. Farnesol is a quorum-sensing molecule, which induces apoptosis, inhibits Ras protein pathways and profoundly affects the morphogenesis of C. albicans. We therefore investigated the interactions between farnesol and different classes of antifungal agents. The combined antifungal effects of triazoles (fluconazole), polyenes (amphotericin B) and echinocandins (micafungin) with farnesol against C. albicans biofilms were assessed in vitro. Antifungal activity was determined by the XTT metabolic assay and confocal microscopy. The nature and the intensity of the interactions were assessed using the Loewe additivity model [fractional inhibitory concentration (FIC) index] and the Bliss independence (BI) model. Significant synergy was found between each of the three antifungal agents and farnesol, while antagonism was not observed for any of the combinations tested. The greatest synergistic effect was found with the farnesol/micafungin combination, for which the BI-based model showed the observed effects as being 39%-52% higher than expected if the drugs had been acting independently. The FIC indices ranged from 0.49 to 0.79, indicating synergism for farnesol/micafungin and farnesol/fluconazole and no interaction for farnesol/amphotericin B. Structural changes in the biofilm correlated well with the efficacies of these combinations. The maximum combined effect was dependent on the farnesol concentration for micafungin and amphotericin B. Farnesol exerts a synergistic or additive interaction with micafungin, fluconazole and amphotericin B against C. albicans biofilms, thus warranting further in vivo study.


A study of the directional response of ultraviolet radiometers: II. Implications for ultraviolet phototherapy derived from computer simulations.
A theoretical model has been used to simulate irradiances for ultraviolet (UV) phototherapy cabinets and other sources. The accuracy of the simulation results has been checked by comparison with experimental measurements. The simulations have been used to study the influence of different factors on UV phototherapy exposure and to develop recommendations for the operation and calibration of phototherapy cabinets. Many radiometers used in the evaluation of skin doses have input optics with directional responses that are not proportional to the cosine of the angle of incidence for the UV radiation. Data on radiometer directional responses have been incorporated into the simulations, which show that the poor directional responses for some radiometers currently in use will give errors of 20-50% in the assessment of irradiance. The influence of lamp source geometries employed for radiometer calibration has been investigated. UV phototherapy dosimetry commonly uses a spectroradiometer and a radiometer in the transfer of irradiance calibrations from a small standard UV lamp to a large-area source with a different UV spectrum. Recommendations are given on the range of acceptability for radiometer directional responses and a method is described for determining whether these are fulfilled. Recommendations are made on the techniques that should be used for calibration.


Glycosylation and processing of prepro-alpha-factor through the yeast secretory pathway.
Events in the synthesis and processing of prepro-alpha-factor have been assessed with the aid of mutants blocked at various stages in the yeast secretory pathway. In normal cells treated with tunicamycin, a precursor accumulates which is identical in molecular weight to the primary translation product synthesized in vitro. At the restrictive temperature in a mutant blocked early in the pathway (sec53), a molecule of similar molecular weight accumulates. In mutants affecting translocation into (sec59) and passage from (sec 18) the endoplasmic reticulum, a glycosylated form of the precursor containing three N-linked core oligosaccharides accumulates; however, it appears that the signal peptide is not removed. The glycosylated precursor first experiences proteolytic processing when accumulated in a mutant (sec7) blocked at the stage of the Golgi apparatus. Substantially greater amounts of the mature pheromone are seen in mutants that accumulate secretory vesicles (sec1, sec2, sec3, sec5).


Lithology and paleontology of the reflective layer horizon a.
Cores recovered from horizon A are Late Cretaceous (Maestrichtian) in age and consist o alternating layers of calcareous turbidites and "red clay." The presence of red clay suggests that the water depth in this area during Cretaceous time was at least as great as at present-more than 5100 meters. A middle Cretaceous (Cenomanian) core consisting of interbedded sand and gravel and light-to-dark-gray lutite was taken in the same area from a layer stratigraphically below the horizon; the presence of hydrogen sulfide and iron sulfide may indicate anaerobic conditions that may be attributable to local ponding of sediment in Cenomanian time.


Bacillus subtilis strains carrying two non-tandem duplications of the trpE-ilvA and the purB-tre regions of the chromosome.
Bacillus subtilis strains possessing the trpE30 marker (splitting of the trpE locus and a non-tandem duplication of chromosome segment Ib: purB-tre) when transformed or transduced to tryptophan independence mainly give rise to haploid cells with the genetic structure of strain 168. However, among the Trp+ transformants or transductants about 10% are merodiploid carrying a non-tandem duplication of segment C (trpE-ilvA) while maintaining that of segment Ib. Linkage and segregation studies made it possible to determine their genetic structure, which can be represented by three different maps. In map a the copies of Ib are inverted repeats and one of them is flanked by two direct repeats of segment C; in map b two Ib-C segments are inverted repeats and in map c the copies of C are inverted repeats with one of them flanked by direct repeats of Ib. It is proposed that transition from map a to map b and then to map c, and vice versa, may occur by recombination between inverted repeats of either Ib or C. The merodiploids are unstable, recombination between direct repeats leading to haploid cells of 168-type structure. The models proposed for merodiploid formation call for fusion of two recipient chromosomes mediated by the donor segment and recombination between copies of a DNA sequence of the two chromosomes located in different regions. In the case of PBS-1 mediated transduction the greater length of the donor DNA segment makes it possible to obtain the merodiploids with a single recipient chromosome and this needs only a slight modification of the models. No trpE30+ merodiploids are found in transformation when the recipient carries a deletion of the SP beta prophage, or in transduction when both donor and recipient possess this deletion. These results indicate that the homologous sequences involved may be part of the SP beta prophage or that a sequence of bacterial DNA has a good homology with it.


Exercise-induced bronchospasm and atopy in Ghana: two surveys ten years apart.
Asthma and allergic diseases have increased in the developed countries. It is important to determine whether the same trends are occurring in the developing countries in Africa. We aimed to determine the time trend in the prevalence of exercise-induced bronchospasm (EIB) and atopic sensitisation over a ten-year period in Ghanaian schoolchildren. Two surveys conducted using the same methodology ten years apart (1993 and 2003) among schoolchildren aged 9-16 years attending urban rich (UR), urban poor (UP), and rural (R) schools. Exercise provocation consisted of free running for six minutes. Children were skin tested to mite, cat, and dog allergen. 1,095 children were exercised in 1993 and 1,848 in 2003; 916 were skin tested in 1993 and 1,861 in 2003. The prevalence of EIB increased from 3.1% (95% CI 2.2%-4.3%) to 5.2% (4.3%-6.3%); absolute percentage increase 2.1% (95% CI 0.6%-3.5%, p < 0.01); among UR, UP, and R children EIB had approximately doubled from 4.2%, 1.4%, and 2.2% to 8.3%, 3.0% and 3.9% respectively. The prevalence of sensitisation had also doubled from 10.6%, 4.7%, and 4.4% to 20.2%, 10.3%, and 9.9% (UR, UP, and R respectively). Mite sensitisation remained unchanged (5.6% versus 6.4%), but sensitisation to cat and dog increased considerably from 0.7% and 0.3% to 4.6% and 3.1%, respectively. In the multiple logistic regression analysis, sensitisation (odds ratio [OR] 1.77, 95% CI 1.12-2.81), age (OR 0.88, 95% CI 0.79-0.98), school (the risk being was significantly lower in UP and R schools: OR 0.40, 95% CI 0.23-0.68 and OR 0.54, 95% CI 0.34-0.86, respectively) and year of the study (OR 1.73, 95% CI 1.13-2.66) remained significant and independent associates of EIB. The prevalence of both EIB and sensitisation has approximately doubled over the ten-year period amongst 9- to 16-year-old Ghanaian children irrespective of location, with both EIB and atopy being more common among the UR than the UP and R children.


Using broadband infrastructure as a social sensor to detect inequities in unemployment during the COVID-19 pandemic.
This study explores the potential of using physical infrastructure as a "social sensor" for identifying marginalized communities. Prior work tends to explore biases in infrastructure as a retrospective "social autopsy". Instead, our study aims to create an introspective "social biopsy", using existing infrastructure gaps to inform how future policy and investment can address existing inequities more sharply and proactively. Specifically, this work explores the possibility of using U.S. county-level broadband penetration rates as a social sensor to predict rates of unemployment amidst the COVID-19 pandemic. The result is a 2 × 2 typology of where broadband as a social sensor is sharper (or coarser), as well as prone to error (either false positives or false negatives). We further explore combining broadband with other forms of physical infrastructure (i.e., bridges, buildings, and WiFi-enabled libraries) to create a sensor "array" to further enhance detection. Overall, this work proposes an "infrastructure-as-sensor" approach to better detect social vulnerability during times of crises in hopes of enhancing resilience through providing services more quickly and precisely to those who most need it.


Rare occurrence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients.
Doravirine is a novel HIV-1 NNRTI recently shown to be non-inferior to both darunavir/ritonavir and efavirenz in combination therapy with two NRTIs in treatment-naive patients. Doravirine has an in vitro resistance profile that is distinct from other NNRTIs and retains activity against viruses containing the most frequently transmitted NNRTI mutations. The aim of this study was to examine the prevalence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients in Europe. From 2010 to 2016, 9764 treatment-naive patients were tested for NNRTI antiretroviral drug resistance by bulk sequencing in Greece, Italy and France. We studied the prevalence of doravirine resistance-associated mutations previously identified in vitro: V106A/M, V108I, Y188L, V190S, H221Y, F227C/L/V, M230I/L, L234I, P236L, Y318F and K103N/Y181C. Among 9764 sequences, 53.0% and 47.0% of patients had B and non-B subtypes, respectively. Overall, the presence of at least one doravirine resistance-associated mutation (n = 137; 1.4%) or the K103N/Y181C mutations (n = 5; 0.05%) was very rare. The most prevalent mutations were V108I (n = 62; 0.6%), Y188L (n = 18; 0.2%), H221Y (n = 18; 0.2%) and Y318F (n = 23; 0.2%). The frequency of doravirine resistance-associated mutations was similar between B and non-B subtypes. In comparison, the prevalence of rilpivirine, etravirine, nevirapine and efavirenz resistance was higher whatever algorithm was used (ANRS: 8.5%, 8.1%, 8.3% and 3.9%, respectively; Stanford: 9.9%, 10.0%, 7.5% and 9.4%, respectively). The prevalence of doravirine resistance-associated mutations is very low in antiretroviral-naive patients. These results are very reassuring for doravirine use in naive patients.


A simple method to adapt the height of the sinotubular junction of the De Paulis Valsalva graft to the height of the patient's sinuses in David reimplantation procedure.
De Paulis and associated introduced a new aortic root conduit for valve-sparing operation. The use of this prosthesis for David I (reimplantation) procedure occasionally may be problematic when the top of the commissures, do not match the new sinotubular junction of the graft. We propose a simple method that allows to create a new sinotubular junction at the desired level in the skirt portion of the Valsalva prosthesis.


Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages.
Macrophages in advanced atherosclerotic lesions accumulate large amounts of unesterified, or "free," cholesterol (FC). FC accumulation induces macrophage apoptosis, which likely contributes to plaque destabilization. Apoptosis is triggered by the enrichment of the endoplasmic reticulum (ER) with FC, resulting in depletion of ER calcium stores, and induction of the unfolded protein response. To explain the mechanism of ER calcium depletion, we hypothesized that FC enrichment of the normally cholesterol-poor ER membrane inhibits the macrophage ER calcium pump, sarcoplasmic-endoplasmic reticulum calcium ATPase-2b (SERCA2b). FC enrichment of ER membranes to a level similar to that occurring in vivo inhibited both the ATPase activity and calcium sequestration function of SERCA2b. Enrichment of ER with ent-cholesterol or 14:0-18:0 phosphatidylcholine, which possess the membrane-ordering properties of cholesterol, also inhibited SERCA2b. Moreover, at various levels of FC enrichment of ER membranes, there was a very close correlation between increasing membrane lipid order, as monitored by 16-doxyl-phosphatidycholine electron spin resonance, and SERCA2b inhibition. In view of these data, we speculate that SERCA2b, a conformationally active protein with 11 membrane-spanning regions, loses function due to decreased conformational freedom in FC-ordered membranes. This biophysical model may underlie the critical connection between excess cholesterol, unfolded protein response induction, macrophage death, and plaque destabilization in advanced atherosclerosis.


Association between BDNF levels and suicidal behaviour: a systematic review protocol.
Suicide is a worldwide public health concern that claims close to 1 million lives each year. Suicidal behaviour is a significant risk factor for completed suicide and is much more prevalent than completed suicide. Many internal and external factors contribute to the risk of suicidal behaviour. Recent research has focused on biological markers in suicide risk, including brain-derived neurotrophic factor (BDNF). BDNF is a protein involved in the growth, function, and maintenance of the nervous system. It has been implicated in psychiatric disorders and suicide. While some evidence suggests that reduced levels of BDNF are associated with suicide, the precise relationship has yet to be determined. The aim of this study is to review the literature examining the relationship between levels of BDNF and suicidal behaviour. A predefined search strategy will be implemented to search the following electronic databases: PubMed/MEDLINE, Excerpta Medica Database (EMBASE), PsycINFO, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception. The articles will be screened by two independent authors (RE and SP) using predetermined inclusion and exclusion criteria. Discrepancies will be resolved by consensus, or by a third author (ZS) in cases of disagreement. The primary outcome will be the association between levels of BDNF and suicidal behaviour. A meta-analysis will be conducted if appropriate. Quality of evidence and risk of bias will be evaluated. The findings of this review will assist in identifying and treating individuals at increased risk of suicide. PROSPERO CRD42015015871 .


Development of a General Aza-Cope Reaction Trigger Applied to Fluorescence Imaging of Formaldehyde in Living Cells.
Formaldehyde (FA) is a reactive signaling molecule that is continuously produced through a number of central biological pathways spanning epigenetics to one-carbon metabolism. On the other hand, aberrant, elevated levels of FA are implicated in disease states ranging from asthma to neurodegenerative disorders. In this context, fluorescence-based probes for FA imaging are emerging as potentially powerful chemical tools to help disentangle the complexities of FA homeostasis and its physiological and pathological contributions. Currently available FA indicators require direct modification of the fluorophore backbone through complex synthetic considerations to enable FA detection, often limiting the generalization of designs to other fluorophore classes. To address this challenge, we now present the rational, iterative development of a general reaction-based trigger utilizing 2-aza-Cope reactivity for selective and sensitive detection of FA in living systems. Specifically, we developed a homoallylamine functionality that can undergo a subsequent self-immolative β-elimination, creating a FA-responsive trigger that is capable of masking a phenol on a fluorophore or any other potential chemical scaffold for related imaging and/or therapeutic applications. We demonstrate the utility of this trigger by creating a series of fluorescent probes for FA with excitation and emission wavelengths that span the UV to visible spectral regions through caging of a variety of dye units. In particular, Formaldehyde Probe 573 (FAP573), based on a resorufin scaffold, is the most red-shifted and FA sensitive in this series in terms of signal-to-noise responses and enables identification of alcohol dehydrogenase 5 (ADH5) as an enzyme that regulates FA metabolism in living cells. The results provide a starting point for the broader use of 2-aza-Cope reactivity for probing and manipulating FA biology.


Clinical-pathological correlations in three patients with fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder in which heterotopic bone forms in the soft tissues. This often occurs in response to injury or inflammation, leading to joint immobilization and significant disability. There are currently no definitive treatment options for this devastating disease. Although the most dramatic phenotype in FOP is the episodic and progressive heterotopic ossification, patients report a number of symptoms that affect other organ systems. Post-mortem examination of FOP patients may contribute to our understanding of the underlying pathophysiology and complications of this disease. Here, we present the autopsy findings from three patients with FOP. Autopsy findings in two of the three patients confirmed that the cause of death was cardiorespiratory failure in the setting of severe thoracic insufficiency from heterotopic ossification. Both of these patients also had evidence of right ventricular dilatation likely secondary to thoracic insufficiency. The third patient died from complications of a traumatic head injury after a fall but also had post-mortem evidence of thoracic insufficiency syndrome. All three patients had extensive, widespread heterotopic ossification and joint deformities consistent with FOP. There was extensive ossification of the spinal ligament in these patients, which may contribute to cervical spine rigidity. One patient was diagnosed post-mortem with a brainstem malformation. No additional significant abnormalities were noted in the other organ systems. Finally, we also demonstrate that cadaveric skin fibroblasts can be isolated for use as a potential source for future in vitro cell culture studies. This autopsy case series provides valuable information about the underlying complications of FOP and contributes significantly to our knowledge of this rare yet debilitating disorder. Thoracic insufficiency syndrome, right heart dysfunction, widespread heterotopic ossification, spinal ligament ossification, and CNS malformations were clearly evident; however, most other non-bone tissues appeared to be spared from gross malformations. Finally, the ability to isolate live cells from cadaveric skin is an important technique that will facilitate future studies, particularly as induced pluripotent stem cells and other cell-based technologies evolve. This case series highlights the importance of post-mortem examinations and their contribution to our current knowledge of disease pathophysiology and comorbidities.


Transcriptional regulation of breathless FGF receptor gene by binding of TRACHEALESS/dARNT heterodimers to three central midline elements in Drosophila developing trachea.
The development of Drosophila trachea is under the control of spatially and/or quantitatively regulated activity of BREATHLESS FGF receptor, which is also essential for midline glial migration. Here, we identified the minimum enhancer region of breathless, cloned the Drosophila ARNT gene (dARNT), and showed biochemical and genetic evidence that breathless expression in developing trachea is regulated by direct interactions between TRACHEALESS/dARNT heterodimers and three central midline elements (TACGTGs) situated in the minimum enhancer region. Our results also showed that SINGLE-MINDED/dARNT heterodimers, which are essential for breathless expression in midline precursor cells, share DNA targets in common with TRACHEALESS/dARNT, indicating that two different basic helix-loop-helix-PAS protein complexes act through the same target sites in vivo.


Genetic vulnerability and phenotypic expression of depression and risk for ischemic heart disease in the Vietnam era twin study of aging.
To determine if depression contributes to incident heart disease after accounting for genetic, behavioral, and medical factors associated with both conditions. We used a prospective twin study with a 12-year follow-up. In 1992, lifetime diagnosis of depression was assessed in 1159 male-male twins and merged with longitudinal health data from the Vietnam Era Twin Registry Study of Aging. Incident heart disease was defined as having myocardial infarction, heart surgery, or angina at 12-year follow-up when twins were 55.4 years (standard deviation, 2.5 years) of age. Risks for heart disease were computed in a logistic regression model that included comparing twins at different levels of phenotypic expression of depression and varying levels of genetic vulnerability at the same time adjusting for pertinent covariates. After adjusting for sociodemographics, co-occurring psychopathology, smoking, obesity, diabetes, hypertension, and social isolation, twins at high genetic risk and exposed to depression remained at greater risk of developing ischemic heart disease (IHD) (odds ratio, 2.55; 95% confidence interval, 1.44-4.49) compared with those at low genetic risk and without phenotypic expression of depression. Odds ratios suggest that twins at genetic liability but without phenotypic expression were at risk of IHD, but the effect was not statistically significant. A history of depression is a risk factor for incident heart disease after adjusting for numerous covariates. Twins with both high genetic vulnerability and phenotypic expression of depression were at greatest risk of IHD. Trends suggest the genetic contribution to IHD that overlaps with depression may partly explain this association, but studies in larger samples are warranted.


Intra- and inter-observer agreement on diagnosis of Dupuytren disease, measurements of severity of contracture, and disease extent.
Dupuytren disease (DD) is a fibrosing disease affecting the palmar aponeurosis, and is mostly treated by surgery based on measurement of severity of flexion contracture of the fingers. Literature concerning the measurement reliability is scarce. This study aimed to determine the intra- and inter-observer agreement of four variables for diagnosing DD, determining severity of contracture, and disease extent. One of them is a new measurement on the area of nodules and cords for measuring the disease extent in early disease stages. An agreement study (n = 54) was performed by two trained investigators. Agreement was calculated per finger, based on an intraclass correlation coefficient (ICC) using a latent variable model on subjects for diagnosis and Tubiana stage. For total passive extension deficit (TPED) and the area of nodules and cords, agreement was calculated with an ICC using a one-way random effects model with subject as random effect. Inter-observer agreement was very good for diagnosing DD (ICC: 95.5%-99.9%) and good to very good for classifying Tubiana stage (ICC: 73.5%-94.9%). Agreements for area and TPED were moderate (middle finger) to very good (ICC: 48.4%-98.6% and 45.0%-99.5%, respectively). Intra-observer agreement was slightly higher on average than inter-observer agreement. Overall, the intra- and inter-observer agreement in diagnosing DD, and determining the severity of flexion contracture is high. Also, the newly introduced variable area of nodules and cords has high intra- and inter-observer agreement, indicating that it is suitable to measure disease extent.


Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18.
Excitatory amino-acid carrier 1 (EAAC1) is a high-affinity Na+-dependent L-glutamate/D,L-aspartate cell-membrane transport protein. It is expressed in brain as well as several non-nervous tissues. In brain, EAAC1 is the primary neuronal glutamate transporter. It has a polarized distribution in cells and mainly functions perisynaptically to transport glutamate from the extracellular environment. In the kidney it is involved in renal acidic amino-acid re-absorption and amino-acid metabolism. Here we describe the identification and characterization of an EAAC1-associated protein, GTRAP3-18. Like EAAC1, GTRAP3-18 is expressed in numerous tissues. It localizes to the cell membrane and cytoplasm, and specifically interacts with carboxy-terminal intracellular domain of EAAC1. Increasing the expression of GTRAP3-18 in cells reduces EAAC1-mediated glutamate transport by lowering substrate affinity. The expression of GTRAP3-18 can be upregulated by retinoic acid, which results in a specific reduction of EAAC1-mediated glutamate transport. These studies show that glutamate transport proteins can be regulated potently and that GTRAP can modulate the transport functions ascribed to EAAC1. GTRAP3-18 may be important in regulating the metabolic function of EAAC1.


Applications of calixarenes in cancer chemotherapy: facts and perspectives.
Research on the therapeutic applications of calixarene derivatives is an emerging area of interest. The anticancer activity of various functionalized calixarenes has been reported by several research groups. Due to their superior geometric shape, calixarenes can accommodate drug molecules by forming inclusion complexes. Controlled release of anticancer drugs by calixarenes might help in targeted chemotherapy. This review summarizes the anticancer potential of the calixarenes and their drug loading properties. The potential use of calixarenes in chemoradiotherapy is also highlighted in brief.


Effects of a Smartphone-Based Self-management Intervention for Individuals With Bipolar Disorder on Relapse, Symptom Burden, and Quality of Life: A Randomized Clinical Trial.
Bipolar disorder-specific psychotherapy combined with pharmacotherapy improves relapse risk, symptom burden, and quality of life, but psychotherapy is not easily accessible. To determine if a smartphone-based self-management intervention (LiveWell) can assist individuals with bipolar disorder to maintain wellness. An assessor-blind randomized clinical trial enrolled participants from March 20, 2017, to April 25, 2019, with 48-week follow-up ending on April 10, 2020. Participants were randomly assigned to usual care or usual care plus the smartphone intervention stratified by relapse risk based on initial clinical status (low risk: asymptomatic recovery; high risk: continued symptomatic, prodromal, recovering, symptomatic recovery). Participants with bipolar disorder I were recruited from clinics in the Chicago and Minneapolis-Saint Paul areas. Data were analyzed from June 19, 2020, to May 25, 2022. The smartphone-based self-management intervention consisted of an application (app), coach, and website. Over 16 weeks, participants had a coach visit followed by 6 phone calls, and they completed daily and weekly app check-ins. The app provided adaptive feedback and information for developing a personalized wellness plan, the coach provided support, and the website provided summary data and alerts. The primary outcome was time to relapse. Secondary outcomes were percentage-time symptomatic, symptom severity, and quality of life. Of the 205 randomized participants (mean [SD] age, 42 [12] years; 125 female individuals [61%]; 5 Asian [2%], 21 Black [10%], 13 Hispanic or Latino [6%], 7 multiracial [3%], 170 White [83%], 2 unknown race [1%]), 81 (40%) were randomly assigned to usual care, and 124 (60%) were randomly assigned to usual care plus the smartphone intervention. This clinical trial did not detect a reduction in relapse risk for the smartphone intervention (hazard ratio [HR], 0.65; 95% CI, 0.39-1.09; log-rank P = .08). However, decreased relapse was observed for low-risk individuals (HR, 0.32; 95% CI, 0.12-0.88; log-rank P = .02) but not high-risk individuals (HR, 0.86; 95% CI, 0.47-1.57; log-rank P = .62). Reduced manic symptom severity was observed for low-risk individuals (mean [SE] difference, -1.4 [0.4]; P = .001) but not for high-risk individuals (mean [SE] difference, 0 [0.3]; P = .95). The smartphone-based self-management intervention decreased depressive symptom severity (mean [SE] difference, -0.80 [0.34]; P = .02) and improved relational quality of life (mean [SE] difference, 1.03 [0.45]; P = .02) but did not decrease percentage-time symptomatic (mean [SE] difference, -5.6 [4.3]; P = .20). This randomized clinical trial of a smartphone-based self-management intervention did not detect a significant improvement in the primary outcome of time to relapse. However, a significant decrease in relapse risk was observed for individuals in asymptomatic recovery. In addition, the intervention decreased depressive symptom severity and improved relational quality of life. These findings warrant further work to optimize the smartphone intervention and confirm that the intervention decreases relapse risk for individuals in asymptomatic recovery. ClinicalTrials.gov Identifier: NCT03088462.


Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy.
GATA factors interact with simple DNA motifs (WGATAR) to regulate critical processes, including hematopoiesis, but very few WGATAR motifs are occupied in genomes. Given the rudimentary knowledge of mechanisms underlying this restriction and how GATA factors establish genetic networks, we used ChIP-seq to define GATA-1 and GATA-2 occupancy genome-wide in erythroid cells. Coupled with genetic complementation analysis and transcriptional profiling, these studies revealed a rich collection of targets containing a characteristic binding motif of greater complexity than WGATAR. GATA factors occupied loci encoding multiple components of the Scl/TAL1 complex, a master regulator of hematopoiesis and leukemogenic target. Mechanistic analyses provided evidence for crossregulatory and autoregulatory interactions among components of this complex, including GATA-2 induction of the hematopoietic corepressor ETO-2 and an ETO-2-negative autoregulatory loop. These results establish fundamental principles underlying GATA factor mechanisms in chromatin and illustrate a complex network of considerable importance for the control of hematopoiesis.


Precursor-ion mass re-estimation improves peptide identification on hybrid instruments.
Mass spectrometry-based proteomics experiments have become an important tool for studying biological systems. Identifying the proteins in complex mixtures by assigning peptide fragmentation spectra to peptide sequences is an important step in the proteomics process. The 1-2 ppm mass-accuracy of hybrid instruments, like the LTQ-FT, has been cited as a key factor in their ability to identify a larger number of peptides with greater confidence than competing instruments. However, in replicate experiments of an 18-protein mixture, we note parent masses deviate 171 ppm, on average, for ion-trap data directed identifications and 8 ppm, on average, for preview Fourier transform (FT) data directed identifications. These deviations are neither caused by poor calibration nor by excessive ion-loading and are most likely due to errors in parent mass estimation. To improve these deviations, we introduce msPrefix, a program to re-estimate a peptide's parent mass from an associated high-accuracy full-scan survey spectrum. In 18-protein mixture experiments, msPrefix parent mass estimates deviate only 1 ppm, on average, from the identified peptides. In a cell lysate experiment searched with a tolerance of 50 ppm, 2295 peptides were confidently identified using native data and 4560 using msPrefixed data. Likewise, in a plasma experiment searched with a tolerance of 50 ppm, 326 peptides were identified using native data and 1216 using msPrefixed data. msPrefix is also able to determine which MS/MS spectra were possibly derived from multiple precursor ions. In complex mixture experiments, we demonstrate that more than 50% of triggered MS/MS may have had multiple precursor ions and note that spectra with multiple candidate ions are less likely to result in an identification using TANDEM. These results demonstrate integration of msPrefix into traditional shotgun proteomics workflows significantly improves identification results.


Exercise-associated hyponatremia, renal function, and nonsteroidal antiinflammatory drug use in an ultraendurance mountain run.
To study biochemical parameters and renal function in runners completing a 60 km mountain run and to investigate the incidence of exercise-associated hyponatremia (EAH). To assess the effects of nonselective nonsteroidal antiinflammatory medication (NSAIDs) and cyclooxygenase-2 (COX-2) selective nonsteroidal antiinflammatory medication (COXIBs) on these parameters. Observational cohort study. Kepler Challenge 60 km mountain run, Te Anau, New Zealand, December 2003. One hundred thirty-one of the 360 runners entered in the race were prospectively enrolled as volunteers on the day before the race. Subjects were weighed at race registration the day before the race and at the finish line. Blood was taken within 5 minutes of finishing and was analyzed for serum sodium, creatinine, urea, and potassium concentrations, and hematocrit. Participants were questioned about medication use in the 24 hours before and during the race (NSAIDs, COXIBs, other medications). Complete data sets were obtained on 123 runners. Five athletes were biochemically hyponatremic [(Na) 130-134 mM] and four were hypernatremic [(Na) 146-148 mM]. Hyponatremia was associated with a mean weight gain of 1.32 kg (range, -1.5 to 1.6 kg). Serum [Na] varied inversely with weight change. Estimated creatinine clearance did not vary with percent weight loss. Estimated creatinine clearance declined with increasing runner age. Sixty-five percent of runners did not use any medication, whereas 20% had used NSAIDs and 15% had taken COXIBs. There were no statistically significant differences between NSAID and COXIB users in any measured parameters or between all NSAID and COXIB users when compared with nonusers. Mild asymptomatic EAH was found to occur in 4% of the volunteer ultraendurance mountain runner study group and was associated with a mean weight gain of 1.32 kg (range, -1.5 to 1.6 kg) during the race. Seven percent gained weight but remained normonatremic, suggesting other compensatory mechanisms. Hypernatremia was found in 3% and was associated with a mean weight loss. Postrace serum sodium concentration varied inversely with percent weight change. Runners using any NSAID were more likely to become hyponatremic. Estimated creatinine clearance increased with increasing age. Elevated serum creatinine concentration at the end of the race returned to normal when remeasured the week after the race. Thirty-five percent of runners were found to use NSAIDs or COXIBs. The measures of weight change and of serum sodium, potassium, urea, and creatine concentration did not differ between NSAID and COXIB users or between all nonsteroidal antiinflammatory users and nonusers.


The next generation of LASIK patients.
With baby boomers aging, and despite a growing global population, there is a decreasing number of potential laser vision correction patients. Some believe that the worldwide economic downturn of these times will limit the number of potential patients as well. This article highlights looking to an alternative segment of the population to identify potential laser vision correction patients and the limitations of reaching this group. The group known as generation Y contains a large number of individuals who may be candidates for laser vision correction. Traditional marketing efforts present challenges in reaching this particular population segment. Many individuals in this group are already patients of eye doctors for contact lenses and glasses and can be reached by these eye doctors to address candidacy and education of laser vision correction. Generation Y represents a large population segment that contains technology-embracing individuals who, although hard to reach with traditional marketing efforts, may be reached by fellow eye doctors already managing these patients. There are many in this age group who would be good laser vision correction candidates.