Tagging-via-substrate strategy for probing O-GlcNAc modified proteins.
Identification of proteins bearing a specific post-translational modification would imply functions of the modification. Proteomic analysis of post-translationally modified proteins is usually challenging due to high complexity and wide dynamic range, as well as unavailability of efficient methods to enrich the proteins of interest. Here, we report a strategy for the detection, isolation, and profiling of O-linked N-acetylglucosamine (O-GlcNAc) modified proteins, which involves three steps: metabolic labeling of cells with an unnatural GlcNAc analogue, peracetylated azido-GlcNAc; chemoselective conjugation of azido-GlcNAc modified proteins via the Staudinger ligation, which is specific between phosphine and azide, using a biotinylated phosphine capture reagent; and detection and affinity purification of the resulting conjugated O-GlcNAc modified proteins. Since the approach relies on a tag (azide) in the substrate, we designated it the tagging-via-substrate (TAS) strategy. A similar strategy was used previously for protein farnesylation, phosphorylation, and sumoylation. Using this approach, we were able to specifically label and subsequently detect azido-GlcNAc modified proteins from the cytosolic lysates of HeLa, 3T3, COS-1, and S2 cell lines, suggesting the azido-substrate could be tolerated by the enzymatic systems among these cells from diverse biological species. We isolated azido-GlcNAc modified proteins from the cytosolic extract of S2 cells and identified 10 previously reported and 41 putative O-GlcNAc modified proteins, by nano-HPLC-MS/MS. Our study demonstrates that the TAS approach is a useful tool for the detection and proteomic analysis of O-GlcNAc modified proteins.


Attentional focusing instructions and force production.
Research progress assessing the role of attentional focusing instructions on skill acquisition and performance has lead researchers to apply this approach to force production tasks. Initial converging evidence indicates that force production tasks are sensitive to verbal instruction; externally focused instructions (onto movement outcomes, or onto the object force is being exerted against) are shown to be more beneficial than internally focused instructions (focusing attention onto the movements being executed). These benefits are observed for maximal and accurate force production, as well as the maintenance of force production in prolonged tasks. A range of mechanisms are identified supporting the proposal that an external focus promotes movement efficiency in line with energy and effort conservation. Future research is required to assess how this developing body of work interacts with the broader understanding of psychological and physiological factors implicated in the effective production, maintenance, and limitation of maximal or sub-maximal forces.


Single nucleotide polymorphisms in human Paneth cell defensin A5 may confer susceptibility to inflammatory bowel disease in a New Zealand Caucasian population.
Human Paneth cell alpha-defensins, especially DEFA5, are involved in maintaining homeostasis of the human microbial microflora. Since breakdown of normal mucosal antibacterial defence occurs in inflammatory bowel disease (IBD), variants in the DEFA5 gene could be associated with IBD risk. A cohort of 25 patients with indeterminate colitis (IC), 405 with ulcerative colitis (UC), and 385 with Crohn's disease (CD), were compared with 201 control individuals from the Canterbury region in New Zealand. A 15 kb haplotype block surrounding DEFA5 contained 35 HapMap markers which were polymorphic in Caucasians. Four markers (A-D) were selected to tag 27 of the 35 markers at r(2)>0.68, and were genotyped in DNA samples. Minor allele frequencies for all single nucleotide polymorphisms (SNPs) were somewhat elevated in patients. Subgroup analysis showed SNP A had odds ratio 1.44 in UC patients with pancolitis (95% C.I. 1.07-1.94), SNP B odds ratio 2.37 in CD patients with onset prior to 17 years age (95% C.I. 1.12-5.03), SNP C odds ratio 1.68 in UC patients with left colonic localisation (95% C.I. 1.12-2.52), and SNP D had odds ratio 1.56 in CD patients with one or more relatives with IBD (95% C.I. 1.03-2.35). Two two-marker haplotypes and one three-marker haplotype were associated with UC (p-values 0.025-0.05). The SNPs genotyped in our study were surrogates for common variants, and observed associations between these and IBD status are likely due to linkage disequilibrium with a functional common DEFA5 variant. Identifying such functional variants will be prioritized in subsequent work.


Germ-line transmitted, chromosomally integrated HHV-6 and classical Hodgkin lymphoma.
A unique feature of both human herpesvirus 6A and B (HHV-6A and B) among human herpesviruses is their ability to integrate into chromosomal telomeres. In some individuals integrated viral genomes are present in the germ-line and result in the vertical transmission of HHV-6; however, little is known about the disease associations of germ-line transmitted, chromosomally integrated HHV-6 (ciHHV-6). Recent publications suggest that HHV-6 is associated with classical Hodgkin lymphoma (cHL). Here we examine the prevalence of ciHHV-6 in 936 cases of cHL and 563 controls by screening with a duplex TaqMan assay and confirming with droplet digital PCR. ciHHV-6 was detected in 10/563 (1.8%) controls and in all but one individual the virus was HHV-6B. Amongst cases 16/936 (1.7%) harboured ciHHV-6, thus demonstrating no association between ciHHV-6 and risk of cHL.


Ethnodiagnostic skills of the digo community for malaria: a lead to traditional bioprospecting.
Malaria is a major public health problem that is presently complicated by the development of resistance by Plasmodium falciparum to the mainstay drugs. Thus, new drugs with unique structures and mechanism of action are required to treat drug-resistant strains of malaria. Historically, compounds containing a novel structure from natural origin represent a major source for the discovery and development of new drugs for several diseases. This paper presents ethnophytotherapeutic remedies, ethnodiagnostic skills, and related traditional knowledge utilized by the Digo community of the Kenyan Coast to diagnose malaria as a lead to traditional bioprospecting. The current study was carried out in three Digo villages of Diani sub-location between May 2009 and December 2009. Data was collected using semi-structured interviews, and open and close-ended questionnaires. A total of 60 respondents (34 men and 26 women) provided the targeted information. The results show that the indigenous knowledge of Digo community on malaria encompasses not only the symptoms of malaria but also the factors that are responsible for causing malaria, attributes favoring the breeding of mosquitoes and practices employed to guard against mosquito bites or to protect households against malaria. This knowledge is closely in harmony with scientific approaches to the treatment and control of the disease. The Digo community uses 60 medicinal plants distributed in 52 genera and 27 families to treat malaria. The most frequently mentioned symptoms were fever, joint pains, and vomiting while the most frequently mentioned practices employed to guard against mosquito bites and/or to protect households against malaria was burning of herbal plants such as Ocimum suave and ingestion of herbal decoctions and concoctions. The Digo community has abundant ethnodiagnostic skills for malaria which forms the basis of their traditional bioprospecting techniques.


Vegetable and fruit intake after diagnosis and risk of prostate cancer progression.
Cruciferous vegetables, tomato sauce and legumes have been associated with reduced risk of incident advanced prostate cancer. In vitro and animal studies suggest these foods may inhibit progression of prostate cancer, but there are limited data in men. Therefore, we prospectively examined whether intake of total vegetables, and specifically cruciferous vegetables, tomato sauce and legumes, after diagnosis reduce risk of prostate cancer progression among 1,560 men diagnosed with non-metastatic prostate cancer and participating in the Cancer of the Prostate Strategic Urologic Research Endeavor, a United States prostate cancer registry. As a secondary analysis, we also examined other vegetable subgroups, total fruit and subgroups of fruits. The participants were diagnosed primarily at community-based clinics and followed from 2004 to 2009. We assessed vegetable and fruit intake via a semi-quantitative food frequency questionnaire, and ascertained prostate cancer outcomes via urologist report and medical records. We observed 134 events of progression (53 biochemical recurrences, 71 secondary treatments likely due to recurrence, 6 bone metastases and 4 prostate cancer deaths) during 3,171 person-years. Men in the fourth quartile of post-diagnostic cruciferous vegetable intake had a statistically significant 59% decreased risk of prostate cancer progression compared to men in the lowest quartile (hazard ratio (HR): 0.41; 95% confidence interval (CI): 0.22, 0.76; p-trend: 0.003). No other vegetable or fruit group was statistically significantly associated with risk of prostate cancer progression. In conclusion, cruciferous vegetable intake after diagnosis may reduce risk of prostate cancer progression.


Effect of prenatal bisphenol A exposure on early childhood body mass index through epigenetic influence on the insulin-like growth factor 2 receptor (IGF2R) gene.
Epigenetic mechanisms have been suggested to play a role in the link between in utero exposure to bisphenol A (BPA) and pediatric obesity; however, there is little evidence regarding this mechanism in humans. We obtained data on obesity-associated CpG sites from a previous epigenome-wide association study, and then examined whether methylation at those CpG sites was influenced by prenatal BPA exposure. We then evaluated the relationship between CpG methylation status and body mass index (BMI) in a prospective children's cohort at ages 2, 4, 6, and 8 years. Methylation profiles of 59 children were longitudinally analyzed at ages 2 and 6 years using the Infinium Human Methylation BeadChip. A total of 594 CpG sites known to be BMI or obesity-associated sites were tested for an association with prenatal BPA levels, categorized into low and high exposure groups based on the 80th percentile of maternal BPA levels (2.68 μg/g creatinine), followed by an analysis of the association between DNA methylation and BMI from ages 2-8. There was a significant increase in the methylation levels of cg19196862 (IGF2R) in the high BPA group at age 2 years (p = 0.00030, false discovery rate corrected p < 0.10) but not at age 6. With one standard deviation increase of methylation at cg19196862 (IGF2R) at age 2 years, the linear mixed model analysis revealed that BMI during ages 2-8 years significantly increased by 0.49 (95% confidence interval; 0.08, 0.90) in girls, but not in boys. The indirect effect of prenatal BPA exposure on early childhood BMI through methylation at cg19196862 (IGF2R) at age 2 years was marginally significant. Prenatal exposure to BPA may influence differential methylation of IGF2R at age 2. This result indicates that a possible sensitive period of DNA methylation occurs earlier during development, which may affect BMI until later childhood in a sex-specific manner.


Long-term outcomes after transoral incisionless fundoplication in patients with GERD and LPR symptoms.
A retrospective study evaluated safety, symptom resolution, patient satisfaction, and medication use 1-2 years after transoral incisionless fundoplication (TIF) in patients with gastroesophageal reflux disease (GERD) and/or laryngopharyngeal reflux (LPR) symptoms. Thirty-four patients with a confirmed diagnosis of GERD symptoms that were inadequately controlled by antisecretory medications, and who where either dissatisfied with their current therapy or not willing to continue taking medication, underwent TIF using EsophyX at our community-based hospital. Follow-up assessments were completed in 28 patients. Median age of the study group was 57 (range = 23-77) years, BMI was 25.7 (18.3-36.4) kg/m(2), and 50% were female. All patients had documented chronic GERD for a median 5 (1-20) years and refractory symptoms to proton pump inhibitors (PPIs). Hiatal hernia was present in 75% (21/28) of patients, and 21% (6/28) had erosive esophagitis (LA grade A or B). TIF was performed following a standardized TIF-2 protocol and resulted in reducing hiatal hernia and restoring the natural anatomy of the gastroesophageal (GE) junction (Hill grade I). There were no postoperative complications. At a median 14-months follow-up, 82% (23/28) of patients were off daily PPIs (64% completely off PPIs), and 68% (19/28) were satisfied with their current health condition compared to 4% before TIF. Median GERD Health-Related Quality of Life scores were significantly reduced to 4 (0-25) from 26 (0-45) before TIF (P < 0.001). Heartburn was eliminated in 65% (17/26) and improved by >50% in 86% (24/28) of patients. Regurgitation was eliminated in 80% (16/20) of patients. Atypical LPR symptoms such as hoarseness, coughing, and throat clearing were eliminated in 63% (17/27) of patients as measured by Reflux Symptom Index scores. Our results in 28 patients confirm the safety and effectiveness of TIF, documenting symptomatic improvement of GERD and LPR symptoms and clinically significant discontinuation of daily PPIs in 82% of patients.


Synchronization within synchronization: transients and intermittency in ecological networks.
Transients are fundamental to ecological systems with significant implications to management, conservation and biological control. We uncover a type of transient synchronization behavior in spatial ecological networks whose local dynamics are of the chaotic, predator-prey type. In the parameter regime where there is phase synchronization among all the patches, complete synchronization (i.e. synchronization in both phase and amplitude) can arise in certain pairs of patches as determined by the network symmetry-henceforth the phenomenon of 'synchronization within synchronization.' Distinct patterns of complete synchronization coexist but, due to intrinsic instability or noise, each pattern is a transient and there is random, intermittent switching among the patterns in the course of time evolution. The probability distribution of the transient time is found to follow an algebraic scaling law with a divergent average transient lifetime. Based on symmetry considerations, we develop a stability analysis to understand these phenomena. The general principle of symmetry can also be exploited to explain previously discovered, counterintuitive synchronization behaviors in ecological networks.


Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques.
IL-15 uses the heterotrimeric receptor IL-2/IL-15Rβ and the γ chain shared with IL-2 and the cytokine-specific IL-15Rα. Although IL-15 shares actions with IL-2 that include activation of natural killer (NK) and CD8 T cells, IL-15 is not associated with capillary leak syndrome, activation-induced cell death, or with a major effect on the number of functional regulatory T cells. To prepare for human trials to determine whether IL-15 is superior to IL-2 in cancer therapy, recombinant human IL-15 (rhIL-15) was produced under current good manufacturing practices. A safety study in rhesus macaques was performed in 4 groups of 6 animals each that received vehicle diluent control or rhIL-15 at 10, 20, or 50 μg/kg/d IV for 12 days. The major toxicity was grade 3/4 transient neutropenia. Bone marrow examinations demonstrated increased marrow cellularity, including cells of the neutrophil series. Furthermore, neutrophils were observed in sinusoids of enlarged livers and spleens, suggesting that IL-15 mediated neutrophil redistribution from the circulation to tissues. The observation that IL-15 administration was associated with increased numbers of circulating NK and CD8 central and effector-memory T cells, in conjunction with efficacy studies in murine tumor models, supports the use of multiple daily infusions of rhIL-15 in patients with metastatic malignancies.


Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study.
Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented. Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint. Arm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months. The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose. Clinicaltrials.gov identifier: NCT01472081 . Registered 16 November 2011.


INCREASING SAVING BEHAVIOR THROUGH AGE-PROGRESSED RENDERINGS OF THE FUTURE SELF.
Many people fail to save what they need to for retirement (Munnell, Webb, and Golub-Sass 2009). Research on excessive discounting of the future suggests that removing the lure of immediate rewards by pre-committing to decisions, or elaborating the value of future rewards can both make decisions more future-oriented. In this article, we explore a third and complementary route, one that deals not with present and future rewards, but with present and future selves. In line with thinkers who have suggested that people may fail, through a lack of belief or imagination, to identify with their future selves (Parfit 1971; Schelling 1984), we propose that allowing people to interact with age-progressed renderings of themselves will cause them to allocate more resources toward the future. In four studies, participants interacted with realistic computer renderings of their future selves using immersive virtual reality hardware and interactive decision aids. In all cases, those who interacted with virtual future selves exhibited an increased tendency to accept later monetary rewards over immediate ones.


The intestinal parasite infection status of inhabitants in the Roxas city, The Philippines.
We carried out a small-scale survey to investigate the status of intestinal protozoa and helminthes infection of inhabitants in Roxas city, Mindoro, the Philippines. Total 301 stool samples were subjected to the formalin-ether concentration method for the detection of helminth ova and protozoan cysts. The overall positive rate was 64.5%, and that of male and female were 56.6% and 72.5%, respectively. The highest infected helminth was Ascaris lumbricoudes (51.2%), followed by Trichuris trichiura (27.6%), hookworm (8.0%) and Enterobius vermicularis (0.3%). The protozoa infection status revealed that Entamoeba coli was the most frequent (15.0%). Iodoamoeba buetschlii and E. histolytica were found but few. The multiple infection more than two parasites was 29.6%, and double infection with A. lumbricoides and T. trichiura was most common. The intestinal helminth infections were highly prevalent in this area, according to this result, and we concluded that anthelminthic drugs should be given to inhabitants, especially to children of 1 to 15 years-old.


Aortic stenosis in children: 19-year experience.
In the Taiwanese literature, few articles describe the pertinent features of aortic stenosis (AS). This study explores the features of AS in Chinese children. 3808 children with congenital heart diseases have undergone cardiac catheterization at our institution over the past 19 years. Among them, 51 (1.3%) cases were AS. The clinical, electrocardiographic, echocardiographic and catheterization findings, the methods of treatment and outcomes were reviewed. Valvular AS occurred in 39 children (76.5%), subvalvular AS in 5 (9.8%), and supravalvular AS in 7(13.7%). Male was predominant (M/F ratio, 2.6) except in supravalvular type. Forty-three patients had associated cardiovascular defects. Aortic regurgitation (AR) was the most common one. Most patients (56.9%) were asymptomatic. Classic symptoms included exertional dyspnea (17.6%), syncope (9.8%), and chest pain (7.8%), etc. Left ventricular hypertrophy was noted in 31.2% of cases. The mean duration of follow-up was 3.9 +/- 3.4 years. Ten patients received open-heart surgery and 2 received balloon dilation. The pressure gradients across the stenotic area dropped from 95.3 +/- 29.3 to 51.4 +/- 35.8 and 53.1 +/- 12.3 mm Hg in early and late Doppler follow-up studies, respectively (p < 0.05). The average gradient increased from 36.9 +/- 25.3 to 40.8 +/- 32.6 mm Hg in nonsurgical patients. The result was insignificant. No mortality occurred following open-heart surgery. One child expired due to heart failure after the ligation of the patent ductus arteriosus and dilation of the stenotic aortic valve on the surgical table under general anesthesia. Autopsy revealed valvular rupture. In the nonsurgical group, no mortality occurred, but one patient was brought home by parents in critical condition and later died. We found that some clinical features of AS in Chinese children were different from those in occidental populations. (1) The incidence of AS was relatively low. (2) Subvalvular AS was the least common type in contrast to supravalvular AS in western studies. (3) Male predominance was not present in the supravalvular type, which lacked sexual proclivity. (4) Williams syndrome was a more frequently associated anomaly. Turner syndrome was not present in our study. (5) Isolated AS was less frequent. (6) The unusual finding such as right ventricular hypertrophy on EKG was present due to associated cardiac anomalies. Open-heart surgery is effective and safe, but the efficacy of balloon dilation requires further investigation.


Molecular markers in upper urothelial carcinoma associated to Balkan endemic nephropathy. Aristolochic acid as the major risk factor of the worldwide disease.
The role of aristolochic acid in the etiology of Balkan endemic nephropathy (BEN) and associated upper urothelial carcinoma (UUC) was recently confirmed. The aim of this study was to determine the marker(s) specific for BEN-associated UUC. A total of 82 patients with UUC (38 from the BEN region and 44 control tumors) were included in the study. The Ki-67 index in BEN tumors correlated with the grade and multifocality (p < 0.05), but in regression analysis, only the grade of BEN tumor. The p53 index was significantly higher in BEN than in control tumors (p < 0.05), as well as the alteration of p53 (p < 0.05). BEN low-stage tumors, tumors without limphovascular invasion (LVI), and tumors of the renal pelvis had a higher p53 index than the control tumors (p < 0.05, 0.01, 0.05, respectively). The Ki-67 index was higher in control tumors with high-stage and solid growth than in BEN UUC (p < 0.050, 0.005). The Ki-67 correlated with the grade, growth, stage, LVI, and multifocality of UUC on the best way, but not with the group. In regression analysis, only multifocality of UUC had predictive influence on Ki-67 activity (p < 0.001). P53 correlated with the grade, growth, and group (p < 0.05). This investigation identifies the p53 pathway as the specific cell cycle marker involved in BEN-associated UUC.


Postoperative pain management with tramadol after craniotomy: evaluation and cost analysis.
Patients undergoing craniotomies have traditionally received opiates with acetaminophen for the management of their postoperative pain. The use of narcotic pain medications can be costly, decrease rates of early postoperative ambulation, lengthen hospital stays, and alter a patient's neurological examination. The use of alternative pain medications such as tramadol may benefit patients by resolving many of these issues. The authors conducted a randomized, blinded prospective study to evaluate the efficacy of alternative pain management strategies for patients following craniotomies. Fifty patients were randomly assigned either to a control group who received narcotics and acetaminophen alone or an experimental group who received tramadol in addition to narcotic pain medications (25 patients assigned to each group). The control group was noted to have statistically significant higher visual analog scale pain scores, an increased length of hospital stay, and increased narcotic use compared with the tramadol group. The narcotics and acetaminophen group also had increased hospitalization costs when compared with the tramadol group. The use of scheduled atypical analgesics such as tramadol in addition to narcotics with acetaminophen for the management of postoperative pain after craniotomy may provide better pain control, decrease the side effects associated with narcotic pain medications, encourage earlier postoperative ambulation, and reduce total hospitalization costs.


LincRNA-Cox2 Promotes Late Inflammatory Gene Transcription in Macrophages through Modulating SWI/SNF-Mediated Chromatin Remodeling.
Long intergenic noncoding RNAs (lincRNAs) are long noncoding transcripts (>200 nt) from the intergenic regions of annotated protein-coding genes. One of the most highly induced lincRNAs in macrophages upon TLR ligation is lincRNA-Cox2, which was recently shown to mediate the activation and repression of distinct classes of immune genes in innate immune cells. We report that lincRNA-Cox2, located at chromosome 1 proximal to the PG-endoperoxide synthase 2 (Ptgs2/Cox2) gene, is an early-primary inflammatory gene controlled by NF-κB signaling in murine macrophages. Functionally, lincRNA-Cox2 is required for the transcription of NF-κB-regulated late-primary inflammatory response genes stimulated by bacterial LPS. Specifically, lincRNA-Cox2 is assembled into the switch/sucrose nonfermentable (SWI/SNF) complex in cells after LPS stimulation. This resulting lincRNA-Cox2/SWI/SNF complex can modulate the assembly of NF-κB subunits to the SWI/SNF complex, and ultimately, SWI/SNF-associated chromatin remodeling and transactivation of the late-primary inflammatory-response genes in macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role for NF-κB-induced lincRNA-Cox2 as a coactivator of NF-κB for the transcription of late-primary response genes in innate immune cells through modulation of epigenetic chromatin remodeling.


Peripherally administered CRH suppresses the vocalizations of isolated guinea pig pups.
In Experiment 1, an SC injection of 14 micrograms CRH greatly suppressed the vocalizing of isolated guinea pig pups 1 h later and produced highly elevated plasma cortisol levels. In Experiment 2, SC injection of 18 international units of ACTH produced similar cortisol elevations, but had a negligible effect on vocalizations. In Experiment 3, the minimum effective dose of CRH for suppressing vocalizations was found to be about 7 micrograms. This dose also suppressed locomotor activity and produced cortisol elevations that were as great as those produced by the 14 micrograms dose. In Experiment 4, suppression of vocalizations by CRH was not reversed by 1 or 5 mg/kg body weight of naloxone. Rectal temperature was unaffected by CRH or naloxone. Thus, peripheral administration of CRH has a suppressive effect on the vocalizations of isolated guinea pig pups. The effect is accompanied by a reduction in locomotor activity and does not appear to be mediated by ACTH, cortisol, beta-endorphin, or an altered body temperature response to the isolation procedure. These results are consistent with the hypothesis that increased secretion of CRH contributes to the waning of the vocalizations of guinea pig pups during prolonged isolation.


Description and Results of a Comprehensive Care Protocol for Overnight-Stay Spine Surgery in Adults.
This is a prospective cohort study. The aim of this study was to define the probability of successful morning-after discharge after adult spine surgery achieved with a standard care protocol as applied to patients with a large variety of common degenerative spine disorders. Qualifying criteria for ambulatory or overnight-stay adult spine surgery are not well defined in either the spine or anesthesia literature. Most reports simply go to American Society of Anesthesiology risk classification or surgical technique alternatives and do not present a clearly defined patient care and case management protocol. A standardized protocol of patient preparation, preoperative comorbidities optimization, and perioperative care was applied in a prospective cohort of 126 patients including 83 lumbar and 41 cervical procedures. Office and hospital chart records were reviewed for relevant outcomes. Fully 122 of 124 appropriately selected cases were able to successfully achieve uneventful same-day discharge without any need for readmission, unscheduled early emergency room or clinic visits, or other major complications. Both failures were for urinary retention in senior males and resolved after a single-day admission to the main hospital. A wide variety of common degenerative spinal pathology in adults can be routinely and safely managed on an overnight-stay basis without requirement for formal hospital inpatient admission in patients appropriately selected and pre-educated to the experience and whose major comorbidities are preoperatively optimized. N/A.


The Effects of Data Padding Techniques on Continuous Relative-Phase Analysis Using the Hilbert Transform.
Continuous relative phase (CRP) analysis using the Hilbert transform is prone to end effects. The purpose was to investigate the impact of padding techniques (reflection, spline extrapolation, extraneous data, and unpadded) on end effects following Hilbert-transformed CRP calculations, using sinusoidal, nonsinusoidal, and kinematic data from a repeated sit-to-stand-to-sit task in adults with low back pain (n = 16, mean age = 30 y). CRP angles were determined using a Hilbert transform of sinusoidal and nonsinusoidal signals with set phase shifts, and for the left thigh/sacrum segments. Root mean square difference and true error compared test signals with a gold standard, for the start, end, and full periods, for all data. Mean difference and 95% bootstrapped confidence intervals were calculated to compare padding techniques using kinematic data. The unpadded approach showed near-negligible error using sinusoidal data across all periods. No approach was clearly superior for nonsinusoidal data. Spline extrapolation showed significantly less root mean square difference (all periods) when compared with double reflection (full period: mean difference = 2.11; 95% confidence interval, 1.41 to 2.79) and unpadded approaches (full period: mean difference = -15.8; 95% confidence interval, -18.9 to -12.8). Padding sinusoidal data when performing CRP analyses are unnecessary. When extraneous data have not been collected, our findings recommend padding using a spline to minimize data distortion following Hilbert-transformed CRP analyses.


Effects of tertatolol on post- and prejunctional beta adrenoceptors.
The effects of tertatolol, a new and powerful beta adrenoceptor blocking drug, on post- and prejunctional beta receptors were investigated; canine vascular tissues (saphenous veins, coronary arteries and splenic arteries) and guinea-pig trachea and atria were used. At concentrations below 10(-5) M, tertatolol did not alter basal tension or contractile responses to electrical stimulation, norepinephrine, K+ or prostaglandin F2 alpha; at doses at or above 10(-5) M the drug-evoked contractions which were reduced by phentolamine and were absent in denervated veins. Tertatolol at 10(-5) M and 3 X 10(-5) M augmented the basal efflux of [3H] norepinephrine in saphenous veins labeled with the 3H-transmitter. In veins, 10(-5) M of tertatolol depressed the contractions caused by electrical stimulation without affecting those to exogenous norepinephrine; this concentration of the drug also inhibited the stimulation-induced overflow of [3H]norepinephrine. The major part of the present study was designed to test the beta receptor blocking properties of tertatolol and to compare its effects with those of propranolol. Tertatolol inhibited, in a concentration-dependent manner, the relaxations caused by isoproterenol in saphenous veins, splenic arteries and coronary arteries and the relaxations evoked by norepinephrine and epinephrine in coronary arteries; the potency of tertatolol was higher than that of propranolol. In trachea and right atria of the guinea-pig, tertatolol inhibited, in a concentration-dependent manner, the dose-response curves to isoproterenol; the relative potency of tertatolol was higher than that of propranolol. In dog saphenous veins, previously incubated with [3H]norepinephrine, tertatolol (10(-7)M) blocked the increased stimulation-evoked overflow of the 3H-transmitter induced by isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)


Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection.
The Toll-like receptors (TLRs) are recently discovered germline-encoded receptors on APCs that are critically important in innate immune recognition of microbial pathogens. However, their role in solid-organ transplantation is unknown. To explore this role, we employed a skin allograft model using mice with targeted deletion of the universal TLR signal adaptor protein, MyD88. We report that minor antigen-mismatched (HY-mismatched) allograft rejection cannot occur in the absence of MyD88 signaling. Furthermore, we show that the inability to reject these allografts results from a reduced number of mature DCs in draining lymph nodes, leading to impaired generation of anti-graft-reactive T cells and impaired Th1 immunity. Hence, this work demonstrates that TLRs can be activated in a transplant setting and not solely by infections. These results link innate immunity to the initiation of the adaptive alloimmune response.


A decentralised, multidisciplinary model of care facilitates treatment of hepatitis C in regional Australia.
Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) has excellent cure rates and minimal side effects. Despite the high burden of disease, strategies to ultimately eradicate HCV are being developed. However, the delivery of care in regional settings is challenging and the efficacy of decentralised models of care is incompletely defined. A prospective cohort study of patients whose treatment was initiated or supervised by Cairns Hospital, a tertiary hospital which provides services to a culturally diverse population across a 380,748 km2 area in regional Australia. Patients' demographics, clinical features, DAA regimens and outcomes were recorded and correlated with their ensuing clinical course. Over 22 months, 734 patients were prescribed DAA therapy for HCV. No patients were prescribed interferon. Sofosbuvir/ledipasvir (n=371, 50.5%) and sofosbuvir/daclatasvir (n=287, 39.1%) were the most commonly prescribed regimens. No patients ceased treatment due to adverse effects. There were 612/734 (83.4%) patients with complete results, with 575 (94%) cured. At the end of the study period, there were 50 (6.8%) patients lost to follow-up and 72 (9.8%) awaiting SVR12 testing. The presence of cirrhosis (n=147/612, 24.1%) did not impact significantly on SVR12 rates, this being achieved in 136/147 (92.5%) cirrhotic patients versus 440/465 (94.6%) in non-cirrhotic patients (p=0.34). Treatment-experienced patients (95/612, 18.3%) were more likely to be non-responders than treatment-naïve patients (10/95 (10.5%) versus 26/517 (5%), p=0.04). Strategies to facilitate treatment included a dedicated clinical nurse consultant, education to primary health care providers, specialist outreach clinics to regional communities and shared care with general practitioners. SVR12 rates were similar amongst gastroenterologists (283/306, 92.5%), general practitioners (152/161, 94.4%), sexual health physicians (104/106, 98.1%) and other prescribers (37/39, 94.9%). This study confirms that decentralised, multidisciplinary models of care can provide HCV treatment in regional and remote settings with excellent outcomes.


Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair.
DNA methylation is a major epigenetic mechanism for gene silencing. Whereas methyltransferases mediate cytosine methylation, it is less clear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether an active demethylating activity is involved. Here, we show that either knockout or catalytic inactivation of the DNA repair enzyme thymine DNA glycosylase (TDG) leads to embryonic lethality in mice. TDG is necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, protection of CpG islands from hypermethylation, and active demethylation of tissue-specific developmentally and hormonally regulated promoters and enhancers. TDG interacts with the deaminase AID and the damage response protein GADD45a. These findings highlight a dual role for TDG in promoting proper epigenetic states during development and suggest a two-step mechanism for DNA demethylation in mammals, whereby 5-methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, followed by TDG-mediated thymine and 5-hydroxymethyluracil excision repair.


Abdominopelvic 1.5-T and 3.0-T MR Imaging in Healthy Volunteers: Relationship to Formation of DNA Double-Strand Breaks.
Purpose To investigate the relationship between abdominopelvic magnetic resonance (MR) imaging and formation of DNA double-strand breaks (DSBs) in peripheral blood lymphocytes among a cohort of healthy volunteers. Materials and Methods Blood samples were obtained from 40 healthy volunteers (23 women and 17 men; mean age, 27.2 years [range, 21-37 years]) directly before and 5 and 30 minutes after abdominopelvic MR imaging performed at 1.5 T (n = 20) or 3.0 T (n = 20). The number of DNA DSBs in isolated blood lymphocytes was quantified after indirect immunofluorescent staining of a generally accepted DSB marker, γ-H2AX, by means of high-throughput automated microscopy. As a positive control of DSB induction, blood lymphocytes from six volunteers were irradiated in vitro with x-rays at a dose of 1 Gy (70-90 keV). Statistical analysis was performed by using a Friedman test. Results No significant alteration in the frequency of DNA DSB induction was observed after MR imaging (before imaging: 0.22 foci per cell, interquartile range [IQR] = 0.54 foci per cell; 5 minutes after MR imaging: 0.08 foci per cell, IQR = 0.39 foci per cell; 30 minutes after MR imaging: 0.09 foci per cell, IQR = 0.63 foci per cell; P = .057). In vitro radiation of lymphocytes with 1 Gy led to a significant increase in DSBs (0.22 vs 3.43 foci per cell; P = .0312). The frequency of DSBs did not differ between imaging at 1.5 T and at 3.0 T (5 minutes after MR imaging: 0.23 vs 0.06 foci per cell, respectively [P = .57]; 30 minutes after MR imaging: 0.12 vs 0.08 foci per cell [P = .76]). Conclusion Abdominopelvic MR imaging performed at 1.5 T or 3.0 T does not affect the formation of DNA DSBs in peripheral blood lymphocytes.


Moderate weight loss in obese and overweight men preserves bone quality.
Weight loss (WL) negatively affects bone mineral density (BMD) in older populations and has specifically been shown in women. In this prospective controlled trial, we examined variables of bone quality and endocrine changes after intentional WL in men. Thirty-eight overweight and obese [mean ± SD body mass index (in kg/m²): 31.9 ± 4.4; age: 58 ± 6 y] men were recruited to either WL through caloric restriction or weight maintenance (WM) for 6 mo. There was a -7.9 ± 4.4% and +0.2 ± 1.6% change in body weight in the WL and WM groups, respectively. There was a greater increase in femoral neck and total body BMD and bone mineral content (BMC) in the WM group than in the WL group (P-interaction effect < 0.05). In contrast, there was a trend for the tibia cortical thickness and area to decrease more in the WM group than in the WL group (P ≤ 0.08). There was a decrease in the periosteal circumference in both groups over time (P < 0.01) and no statistically significant changes in trabecular bone. Circulating total, free, and bioavailable estradiol decreased in the WL group compared with the WM group, and changes were different between groups (P < 0.05). Serum total and bioavailable testosterone increased in both groups (P < 0.01). Serum 25-hydroxyvitamin D increased to a similar extent in both groups (P < 0.05). Moderate WL in overweight and obese men did not decrease BMD at any anatomical site or alter cortical and trabecular bone and geometry. Also, despite increased BMD at some sites when maintaining excess body weight, cortical bone showed a trend in the opposite direction.


Cognition-based interventions for healthy older people and people with mild cognitive impairment.
Evidence from some, but not all non-randomised studies suggest the possibility that cognitive training may influence cognitive functioning in older people. Due to the differences among cognitive training interventions reported in the literature, giving a general overview of the current literature remains difficult. To systematically review the literature and summarize the effect of cognitive training interventions on various domains of cognitive function (ie memory, executive function, attention and speed) in healthy older people and in people with mild cognitive impairment. The CDCIG Specialized Register was searched on 30 September 2007 for all years up to December 2005. The Cochrane Library, MEDLINE, EMBASE, PsycINFO and CINAHL were searched separately on 30 September 2007 to find trials with healthy people. These results were supplemented by searches from January 1970 to September 2007 in PsychInfo/Psyndex, ISI Web of Knowledge and PubMed. RCTs of interventions evaluating the effectiveness of cognitive training for healthy older people and people with mild cognitive impairment from 1970 to 2007 that met inclusion criteria were selected. Authors independently extracted data and assessed trial quality. Meta-analysis was performed when appropriate. Only data on memory training could be pooled for analysis. Within this domain, training interventions were grouped according to several outcome variables. Results showed that for healthy older adults, immediate and delayed verbal recall improved significantly through training compared to a no-treatment control condition. We did not find any specific memory training effects though as the improvements observed did not exceed the improvement in the active control condition. For individuals with mild cognitive impairment, our analyses demonstrate the same pattern. Thus, there is currently little evidence on the effectiveness and specificity of memory interventions for healthy older adults and individuals with mild cognitive impairment. There is evidence that cognitive interventions do lead to performance gains but none of the effects observed could be attributable specifically to cognitive training, as the improvements observed did not exceed the improvement in active control conditions. This does not mean that longer, more intense or different interventions might not be effective, but that those which have been reported thus far have only limited effect. We therefore suggest more standardized study protocols in order to maximize comparability of studies and to maximize the possibility of data pooling - also in other cognitive domains than memory.


Considerations on Circuit Design and Data Acquisition of a Portable Surface Plasmon Resonance Biosensing System.
The aim of this study was to develop a circuit for an inexpensive portable biosensing system based on surface plasmon resonance spectroscopy. This portable biosensing system designed for field use is characterized by a special structure which consists of a microfluidic cell incorporating a right angle prism functionalized with a biomolecular identification membrane, a laser line generator and a data acquisition circuit board. The data structure, data memory capacity and a line charge-coupled device (CCD) array with a driving circuit for collecting the photoelectric signals are intensively focused on and the high performance analog-to-digital (A/D) converter is comprehensively evaluated. The interface circuit and the photoelectric signal amplifier circuit are first studied to obtain the weak signals from the line CCD array in this experiment. Quantitative measurements for validating the sensitivity of the biosensing system were implemented using ethanol solutions of various concentrations indicated by volume fractions of 5%, 8%, 15%, 20%, 25%, and 30%, respectively, without a biomembrane immobilized on the surface of the SPR sensor. The experiments demonstrated that it is possible to detect a change in the refractive index of an ethanol solution with a sensitivity of 4.99838 × 10(5) ΔRU/RI in terms of the changes in delta response unit with refractive index using this SPR biosensing system, whereby the theoretical limit of detection of 3.3537 × 10(-5) refractive index unit (RIU) and a high linearity at the correlation coefficient of 0.98065. The results obtained from a series of tests confirmed the practicality of this cost-effective portable SPR biosensing system.


Identification and expression of GH-8 family chitosanases from several Bacillus thuringiensis subspecies.
The Gram-positive spore-forming bacterium, Bacillus thuringiensis, a member of the Bacillus cereus group, produces chitosanases that catalyze the hydrolysis of chitosan to chitosan-oligosaccharides (COS). Although fungal and bacterial chitosanases belonging to other glycoside hydrolase (GH) families have been characterized in a variety of microorganisms, knowledge on the genetics and phylogeny of the GH-8 chitosanases remains limited. Nine genes encoding chitosanases were cloned from 29 different serovar strains of B. thuringiensis and they were expressed in Escherichia coli. The ORFs of the chitosanases contained 1,359 nucleotides and the protein products had high levels of sequence identity (>96%) to other Bacillus species GH-8 chitosanases. Thin-layer chromatography and HPLC analyses demonstrated that these enzymes hydrolyzed chitosan to a chitosan-trimer and a chitosan-tetramer as major products, and this could be useful in the production of COS. In addition, a simple plate assay was developed, involving a soluble chitosan, for high-throughput screening of chitosanases. This system allowed screening for mutant enzymes with higher enzyme activity generated by error-prone PCR, indicating that it can be used for directed chitosanase evolution.


[Long term follow-up on emergent intracoronary autologous bone marrow mononuclear cell transplantation for acute inferior-wall myocardial infarction].
To investigate the effects of emergent intracoronary autologous bone marrow mononuclear cell (BM-MNC) transplantation on left ventricular function and myocardium lesion area in patients with first acute inferior-wall myocardial infarction. Forty patients with first onset of acute inferior-wall myocardial infarction, 28 males and 12 females, aged < or = 75, treated with emergent percutaneous coronary intervention (PCI) were randomly divided into 2 equal groups: group undergoing intracoronary transplantation of autologous BM-MNC via a micro-catheter right after PCI (BM-MNC group), and control group receiving normal saline and heparin. Blood routine examination, myocardium zymogram, and serum high sensitive C reactive protein (hsCRP) were detected, and 24-hour dynamic electrocardiography, delayed-enhancement myocardial magnetic resonance imaging (CMR), and angiography of the coronary artery and left ventricle were conducted before the transplantation and immediately, 1 week, and 6 months after transplantation. CMR showed that 6 months later the left ventricular ejection fraction (LVEF) of the control group was 47.9% +/- 6.7%, significantly higher than that 1 week later (43.4% +/- 6.7%, P = 0.001), and the LVEF of the BM-MNC group 6 months later was 51.5% +/- 5.2%, significantly higher than that 1 week later (44.5% +/- 7.1%, P = 0.001; however, the absolute change of LVEF (DeltaLVEF) of the BM-MNC group was 6.95% +/- 3.33%, significantly higher than that of the control group (4.05% +/- 1.68%, P = 0.047). Six months later the myocardial lesion area of the BM-MNC group decreased more significantly in comparison with the control group. Nevertheless, there was no difference in change of left ventricular end diastolic volume (LVEDV) between these two groups. The serum hsCRP 48 h after transplantation of the BM-MNC group was 2.8 g/L +/- 0.8 g/L, significantly lower than that before transplantation (13.4 g/L +/- 3.6 g/L, P < 0.001). No severe clinical events, such death, recurrent cardiac infarction, malignant arrhythmia, occur in these 2 groups. Emergent intracoronary transplantation of autologous BM-MNC in patients with acute inferior-wall myocardial infarction improves the left ventricular function and myocardial infusion, minimizes the myocardial lesion area significantly.


Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-beta 1.
A number of important neurological diseases, including HIV-1 encephalitis, Alzheimer's disease, and brain trauma, are associated with increased cerebral expression of the multifunctional cytokine transforming growth factor-beta 1 (TGF-beta 1). To determine whether overexpression of TGF-beta 1 within the central nervous system (CNS) can contribute to the development of neuropathological alterations, a bioactive form of TGF-beta 1 was expressed in astrocytes of transgenic mice. Transgenic mice with high levels of cerebral TGF-beta 1 expression developed a severe communicating hydrocephalus, seizures, motor incoordination, and early runting. While unmanipulated heterozygous transgenic mice from a low expressor line showed no such alterations, increasing TGF-beta 1 expression in this line by injury-induced astroglial activation or generation of homozygous offspring did result in the abnormal phenotype. Notably, astroglial overexpression of TGF-beta 1 consistently induced a strong upmodulation of the extracellular matrix proteins laminin and fibronectin in the CNS, particularly in the vicinity of TGF-beta 1-expressing perivascular astrocytes, but was not associated with obvious CNS infiltration by hematogenous cells. While low levels of extracellular matrix protein expression may assist in CNS wound repair and regeneration, excessive extracellular matrix deposition could result in the development of hydrocephalus. As an effective inducer of extracellular matrix components, TGF-beta 1 may also contribute to the development of other neuropathological alterations, eg, the formation of amyloid plaques in Alzheimer's disease.


Citrus peel flavonoids improve lipid metabolism by inhibiting miR-33 and miR-122 expression in HepG2 cells.
Citrus plants are rich in flavonoids and beneficial for lipid metabolism. However, the mechanism has not been fully elucidated. Both citrus peel flavonoid extracts (CPFE) and a mixture of their primary flavonoid compounds, namely, nobiletin, tangeretin and hesperidin, citrus flavonoid purity mixture (CFPM), were found to have lipid-lowering effects on oleic acid-induced lipid accumulation in HepG2 cells. The carnitine palmitoyltransferase 1α (CPT1α) gene was markedly increased, while the fatty acid synthase (FAS) gene was significantly decreased by both CPFE and CFPM in oleic acid-treated HepG2 cells. Flavonoid compounds from citrus peel suppressed miR-122 and miR-33 expression, which were induced by oleic acid. Changes in miR-122 and miR-33 expression, which subsequently affect the expression of their target mRNAs FAS and CPT1α, are most likely the principal mechanisms leading to decreased lipid accumulation in HepG2 cells. Citrus flavonoids likely regulate lipid metabolism by modulating the expression levels of miR-122 and miR-33.


Exercise-induced muscle damage is not attenuated by beta-hydroxy-beta-methylbutyrate and alpha-ketoisocaproic acid supplementation.
The purpose of this study was to examine the effects of combined oral beta-hydroxy-beta-methylbutyrate (HMB) and alpha-ketoisocaproic acid (KIC) supplementation on indices of exercise-induced muscle damage (EIMD) after an acute bout of eccentric-biased exercise. Fourteen male subjects were allocated to 2 groups: a placebo group (3 g.d corn flour, N = 7) or an HMB + KIC group (3 g.d HMB and 0.3 g.d KIC, N = 7). Supplementation commenced 11 days before a 40-minute bout of downhill running and continued for 3 days post-exercise. Delayed-onset muscle soreness, mid-thigh girth, knee extensor range of motion, serum creatine kinase (CK) activity, and isometric and concentric torque were assessed pre-exercise and at 24, 48, and 72 hours post-exercise. Delayed-onset muscle soreness, CK activity, and isometric and concentric torque all changed over the 72-hour period (p < 0.05); however, HMB + KIC had no significant effect on any of the indices of muscle damage. Although 14 days HMB and KIC supplementation did not attenuate indices of EIMD after an acute bout of unaccustomed eccentric-biased exercise, there was a trend for a more rapid rate of recovery in isometric and isokinetic muscle function. beta-hydroxy-beta-methylbutyrate and KIC may therefore provide limited benefit in the recovery of muscle function after EIMD in untrained subjects or after unaccustomed exercise.


Testing of extracorporeal membrane oxygenation circuit related hemolysis using long-term stored packed red cells and fresh frozen plasma.
The resistance of blood used in these studies to hemolysis differs markedly from that used in neonatal extracorporeal circulation under clinical circumstances. In this study, the possibility of using expired packed red cells to determine hemolysis caused by mechanical and/or environmental factors was investigated. Packed red blood cells stored for 42 days were mixed with fresh frozen plasma and the resultant mixture was divided into three groups, two study groups and a control. For the study groups, two different centrifugal pump heads (Medtronic BP 50 and Jostra RF 32) were used in an extracorporeal membrane oxygenation (ECMO) circuit. Free hemoglobin, lactate dehydrogenase, lactic acid, pH, potassium, and glucose were investigated at various time intervals. Hemolysis did not differ between the groups. Free hemoglobin increased in all groups after 12 h. Lactic acid increased linearly in all groups up to 12 h. Glucose and pH decreased steadily in all groups. Hemolysis created during mock ECMO did not differ between the circuits using the two different pump heads noted. Human donor blood stored up to its expiration date is a feasible medium for mock circulation tests of up to 12 h duration under the circumstances described.


Calculation of Canine Dose Rate Conversion Factors for Photons and Electrons.
Urban search and rescue (USAR) dogs are valuable members of their teams and play key roles in performing successful missions. A pair of dogs can do the work of dozens of people, the dogs are able to quickly sniff around collapsed structures and zip through constricted hallways with far greater accuracy than their plodding human counterparts. While in contaminated areas, their human counterparts are afforded the benefit of personal protective equipment (PPE) to keep exposures to chemical, biological and radiological substances to a minimum; USAR dogs, on the other hand, are not. In an effort to allow USAR dogs to be used to their full potential, PPE is often not worn as it inhibits their ability to move in and around obstacles to use their strong senses of smell and hearing. In addition, these animals may snag or be snagged on debris or structures, which may require rescue of the animal. In a collaborative effort between Texas A&M University's Department of Nuclear Engineering and the College of Veterinary Medicine, researchers are attempting to estimate the extent of the radiation doses received by these valuable team members during missions where radioactive contamination is present. Currently there are no dose rate conversion factors for USAR dogs, and those that are available are calculated at a height of 1 m. To address this issue, a more suitable height of 40 cm was chosen, and dose conversion factors were calculated for monoenergetic photon sources ranging from 15 keV to 15 MeV and for monoenergetic electron sources ranging from 10 keV to 10 MeV. The radioactivity is assumed to be uniformly distributed on the surface of the ground. Forty centimeters was chosen as the height of interest for the three breeds FEMA prefers as USAR dogs. These dose conversion factors will permit dose estimates to be made, allowing these animals to do their jobs successfully while keeping their radiation doses as low as possible.


Environmental and hormonal control of cambial stem cell dynamics.
Perennial trees have the amazing ability to adjust their growth rate to both adverse and favorable seasonally reoccurring environmental conditions over hundreds of years. In trunks and stems, the basis for the tuning of seasonal growth rate is the regulation of cambial stem cell activity. Cambial stem cell quiescence and dormancy protect the tree from potential physiological and genomic damage caused by adverse growing conditions and may permit a long lifespan. Cambial dormancy and longevity are both aspects of a tree's life for which the study of cambial stem cell behavior in the annual model plant Arabidopsis is inadequate. Recent functional analyses of hormone perception and catabolism mutants in Populus indicate that shoot-derived long-range signals, as well as local cues, steer cambial activity. Auxin is central to the regulation of cambial activity and probably also maintenance. Emerging genome editing and phenotyping technologies will enable the identification of down-stream targets of hormonal action and facilitate the genetic dissection of complex traits of cambial biology.


Atrial myxoma: a rare cause of cardioembolic stroke.
The authors present the case of a 45-year-old lady who presented to the emergency department with sudden onset of right hemiparesis, numbness, dysarthria, dysmetria, left upper motor neuron facial palsy and left extensor plantar. Initial laboratory investigations, ECG and MR angiography were normal. MRI brain revealed multiple ischaemic strokes in middle cerebral artery and posterior cerebral artery territory. Transthoracic echocardiography revealed large mobile mass in left atrium which was resected and the patient remained well postoperatively. Anticoagulants do not play any protective role making resection as the only effective treatment.


Monitoring Older Adult Blood Pressure Trends at Home as a Proxy for Brain Health.
Even when older adults monitor hypertension at home, it is difficult to understand trends and share them with their providers. MyHealthNetwork is a dashboard designed for patients and providers to monitor blood pressure readings to detect hypertension and ultimately warning signs of changes in brain health. A multidisciplinary group in a Digital Health course at Tufts University School of Medicine used Design Thinking to formulate a digital solution to promote brain health among older adults in the United States (US). Older adults (aged 65 and over) are a growing population in the US, with many having one or more chronic health conditions including hypertension. Nearly half of all American adults ages 50-64 worry about memory loss as they age and almost all (90%) wish to maintain independence and age in their homes. Given the well-studied association between hypertension and dementia, we designed a solution that would ultimately promote brain health among older adults by allowing them to measure and record their blood pressure readings at home on a regular basis. Going through each step in the Design Thinking process, we devised MyHealthNetwork, an application which connects to a smart blood pressure cuff and stores users' blood pressure readings in a digital dashboard which will alert users if readings are outside of the normal range. The dashboard also has a physician view where users' data can be reviewed by the physician and allow for shared treatment decisions. The authors developed a novel algorithm to visually display the blood pressure categories in the dashboard in a way straightforward enough that users with low health literacy could track and understand their blood pressure over time. Additional features of the dashboard include educational content about brain health and hypertension, a digital navigator to support users with application use and technical questions. Phase 1 in the development of our application includes a pilot study involving recruitment of Primary Care Providers with patients who are at risk of dementia to collect and monitor BP data with our prototype. Subsequent phases of development involve partnerships to provide primary users with a rewards program to promote continued use, additional connections to secondary users such as family members and expansion to capture other health metrics.


Arabidopsis PIS1 encodes the ABCG37 transporter of auxinic compounds including the auxin precursor indole-3-butyric acid.
Differential distribution of the plant hormone auxin within tissues mediates a variety of developmental processes. Cellular auxin levels are determined by metabolic processes including synthesis, degradation, and (de)conjugation, as well as by auxin transport across the plasma membrane. Whereas transport of free auxins such as naturally occurring indole-3-acetic acid (IAA) is well characterized, little is known about the transport of auxin precursors and metabolites. Here, we identify a mutation in the ABCG37 gene of Arabidopsis that causes the polar auxin transport inhibitor sensitive1 (pis1) phenotype manifested by hypersensitivity to auxinic compounds. ABCG37 encodes the pleiotropic drug resistance transporter that transports a range of synthetic auxinic compounds as well as the endogenous auxin precursor indole-3-butyric acid (IBA), but not free IAA. ABCG37 and its homolog ABCG36 act redundantly at outermost root plasma membranes and, unlike established IAA transporters from the PIN and ABCB families, transport IBA out of the cells. Our findings explore possible novel modes of regulating auxin homeostasis and plant development by means of directional transport of the auxin precursor IBA and presumably also other auxin metabolites.


Catch and release cell sorting: electrochemical desorption of T-cells from antibody-modified microelectrodes.
The development of integrated microsystems capable of interrogation, characterization and sorting of mammalian cells is highly significant for further advancement of point-of-care diagnostics and drug discovery fields. The present study sought to design a novel strategy for releasing antibody-bound cells through electrochemical disruption of the underlying antibody (Ab) layer. A microsystem for selective capture and release of cells consisted of an array of individually addressable gold microelectrodes fabricated on a glass substrate. Poly(ethylene glycol) (PEG) hydrogel photolithography was employed to make the glass regions non-fouling, thus, ensuring selective localization of proteins and cells on the microelectrodes. The gold surfaces were decorated with anti-CD4 Ab molecules using standard alkanethiol self-assembly and carbodiimide coupling approaches. The Ab-functionalized electrodes selectively captured model T-lymphocytes (Molt-3 cells) expressing CD4 antigen while minimal cell adhesion was observed on PEG hydrogel-modified glass substrates. Importantly, application of a reductive potential (-1.2V vs. Ag/AgCl reference electrode) resulted in release of surface-bound T-cells from the electrode surface. Cyclic voltammetry and fluorescence microscopy were employed to verify that the detachment of captured T-cells was indeed due to the electrochemical disruption of the underlying alkanethiol-Ab layer. In the future, the cell sorting approach described here may be combined with microfluidic delivery to enable Ab-mediated capture of T-lymphocytes or other cell types followed by release of select cells for downstream gene expression studies or re-cultivation.


Chemiluminescence selectivity enhancement in the on-chip Ru(bpy)32+ system: The potential role of buffer type and pH in the determination of hydrochlorothiazide in combined formulations and human plasma.
A simple and highly selective on-chip Ru(bpy)32+ -oxidant chemiluminescence (CL) approach for estimation of a diuretic drug, hydrochlorothiazide (HCZ), in biological fluids was realized in the presence of other fixed-dose combination drugs by manipulating simultaneously the method of active species (Ru(bpy)33+ ) production and type of carrier buffer with pH used for the CL reaction. Chemical oxidation processes involved in the Ru(bpy)32+ -Ce(IV) CL system have been successfully miniaturised in this study using a microfabricated device to generate Ru(bpy)33+ instantaneously. The proposed system was then screened using HCZ and other drugs in the presence of various buffers and pH to explore the difference in CL emission. Ammonium formate buffer (0.15 M) at pH 4.5 exhibited excellent selectivity towards HCZ when Ru(bpy)33+ was produced by chemical oxidation using Ce(IV). The newly developed conditions do not involve any kind of prior separation or isolation procedure to remove other combination therapy drugs in formulation and biological samples. The method under fully optimised conditions exhibited wide linearity over the concentration range 0.5-1000 ng ml-1 and low detection and quantification limits of 0.13 and 0.47 ng ml-1 respectively for HCZ. Acceptable levels of recoveries were obtained for HCZ from human plasma using the proposed method (98.9-100.8%) in the presence of other antihypertensive combination therapy drugs. This study postulates that such miniaturised devices may find applications especially for on-site analysis, such as doping control examinations.


[INSERM-FNCLCC collective expert's report. Recommendations for management of women having a genetic risk of developing breast and/or ovarian cancer. National Federation of Centers of the Fight Against Cancer].
Almost 10% of breast and ovarian cancer are inherited, and the majority are linked to BRCA1 and BRCA2 germline mutations. Despite the uncertainty, consensus guidelines were defined to assist practitioners', and patients' decisions about the health care decisions to be made. The Ad Hoc Committee consisted of 14 experts designated by the French National Institute for Health and Medical Research. They all attended eleven workshops at which a systematic analytical review of more than 3500 articles was carried out. Five additional experts critically analyzed the first version of the report. Two thresholds were defined on a probability scale giving the risk of developing breast or ovarian cancer, to serve as a means of deciding as whether an intervention is worthwhile. The first threshold is that above which an intervention can be envisaged or recommended; the second is that under which an intervention can be ruled out; between the two, the decision has to be made on a each by case basis. SCREENING AND PREVENTIVE STRATEGIES ANALYZED: About breast cancer: 1) hormonal interventions; 2) primary prevention (diet, family planning and chemoprevention); 3) screening (breast self-examination, clinician breast examination, tumor markers, imaging); 4) prophylactic mastectomy. About ovarian cancer: 1) hormonal stimulation; 2) screening (clinical screening, ultrasound and tumor markers); 3) prophylactic oophorectomy. With each strategy the following points were dealt with: the information to be delivered to the consultant, the procedure and the indications. The Committee's opinion about BRCA mutation screening is that population-based or even large scale implementation are not justified. The Committee feels that specific management is indispensable and advocates the use of defined and evaluated procedures, and involvement in clinical trials.


Effects of ageing and fitness on skin-microvessel vasodilator function in humans.
The impact of cardiopulmonary fitness (VO(2max)) on the age-related decline in skin-microvessel vasodilator function has not been fully established and the inter-relationships among different measures of microvascular vasodilator function are unknown. We used laser Doppler flowmetry to assess relative changes in forearm skin blood flow to various stimuli in three groups of adults: young (n = 15; 27 +/- 2 years), older sedentary (n = 14; 65 +/- 6 years) and older fit (n = 15; 61 +/- 5 years). Local-heating induced and post-occlusive hyperaemia responses were higher in the young and older fit groups compared to the older sedentary group (P < 0.05) and were moderately correlated with VO(2max) in the pooled cohort of older adults (r = 0.49-0.58; P < 0.05). Peak hyperaemia responses to acetylcholine and sodium nitroprusside were higher in young compared to older sedentary adults (P < 0.05) and were not associated with VO(2max) in older adults (P > 0.05). Associations among different measures of microvascular vasodilator function were generally moderate at best. In summary, the local heating and reactive hyperaemia data indicate that the age-related decline in skin-microvessel vasodilator function can be ameliorated through regular aerobic exercise training. As this is not supported by the iontophoresis data, we recommend that, when assessing microvascular function, the use of a single physiological or pharmacological stimulation coupled to laser Doppler flowmetry should be avoided. Finally, the moderate correlations between outcomes probably reflect the distinct mediators that are responsible for the vasodilator response to each test.


Asymmetric Organocatalytic Synthesis of Substituted Chiral 1,4-Dihydropyridine Derivatives.
The first cinchona-alkaloid-organocatalyzed enantioselective synthesis of chiral 1,4-dihydropyridine derivatives is described. Bis-cinchona catalyst 3b activates the Michael addition reaction between malononitrile derivatives 2 and enamines 1, affording the appealing and highly substituted 1,4-dihydropyridines 4 with very good results in most cases. This is one of very few examples of the synthesis of chiral 1,4-dihydropyridines by an enantioselective catalytic procedure. The highly substituted final compounds are of interest for their potential biological activity. This efficient protocol opens the door to a new area of research for the asymmetric construction of these skeletons for which enantioselective syntheses are still very limited.


Relationship of Office and Ambulatory Blood Pressure With Left Ventricular Global Longitudinal Strain.
Left ventricular (LV) global longitudinal strain (GLS) is an early indicator of subclinical cardiac dysfunction, even when LV ejection fraction (LVEF) is normal, and is an independent predictor of cardiovascular events. Ambulatory blood pressure (BP) is a better predictor of cardiovascular events, including heart failure, than office BP. We investigated the association of office and ambulatory BP measurements with subclinical LV systolic dysfunction in a community-based cohort with normal LVEF. Two-dimensional speckle-tracking echocardiography and 24-hour ambulatory BP monitoring were performed in 577 participants (mean age 70±9 years; 60% women) with LVEF ≥50% from the Cardiovascular Abnormalities and Brain Lesions (CABL) study. Univariable and multivariable linear regression analyses were used to assess the associations of BP measures with GLS. Higher ambulatory and office BP values were consistently associated with impaired GLS. After adjustment for pertinent covariates (age, sex, race/ethnicity, body mass index, diabetes mellitus, coronary artery disease, LV mass index, and antihypertensive medication), office diastolic BP and ambulatory systolic and diastolic BPs (24-hour, daytime and nighttime) were independently associated with GLS (P = 0.003 for office DBP, P ≤ 0.001 for all ambulatory BPs). When ambulatory and office BP values were included in the same model, all ambulatory BP measures remained significantly associated with GLS (all P < 0.01), whereas office BP values were not. Ambulatory BP values are significantly associated with impaired GLS and the association is stronger than for office BP. Ambulatory BP monitoring might have a role in the risk stratification of hypertensive patients for early LV dysfunction.


Aquaporin-0 targets interlocking domains to control the integrity and transparency of the eye lens.
Lens fiber cell membranes contain aquaporin-0 (AQP0), which constitutes approximately 50% of the total fiber cell membrane proteins and has a dual function as a water channel protein and an adhesion molecule. Fiber cell membranes also develop an elaborate interlocking system that is required for maintaining structural order, stability, and lens transparency. Herein, we used an AQP0-deficient mouse model to investigate an unconventional adhesion role of AQP0 in maintaining a normal structure of lens interlocking protrusions. The loss of AQP0 in AQP0(-/-) lens fibers was verified by Western blot and immunofluorescence analyses. Changes in membrane surface structures of wild-type and AQP0(-/-) lenses at age 3 to 12 weeks were examined with scanning electron microscopy. Preferential distribution of AQP0 in wild-type fiber cell membranes was analyzed with immunofluorescence and immunogold labeling using freeze-fracturing transmission electron microscopy. Interlocking protrusions in young differentiating fiber cells developed normally but showed minor abnormalities at approximately 50 μm deep in the absence of AQP0 in all ages studied. Strikingly, protrusions in maturing fiber cells specifically underwent uncontrolled elongation, deformation, and fragmentation, while cells still retained their overall shape. Later in the process, these changes eventually resulted in fiber cell separation, breakdown, and cataract formation in the lens core. Immunolabeling at the light microscopy and transmission electron microscopy levels demonstrated that AQP0 was particularly enriched in interlocking protrusions in wild-type lenses. This study suggests that AQP0 exerts its primary adhesion or suppression role specifically to maintain the normal structure of interlocking protrusions that is critical to the integrity and transparency of the lens.


Nocturnal enuresis: an update on management.
Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.


COVID-19 in patients with neuroendocrine neoplasms: 2-year results of the INTENSIVE study.
We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.


Surface manifestations of antibiotic-induced alterations in protein synthesis in bacterial cells.
Scanning electron microscopy of changes in bacteria induced by antimicrobial agents which interfere with cell wall synthesis revealed morphological alterations which correlated well with their mechanism of action. The present studies were undertaken to investigate the presence and characteristics of alterations in surface morphology resulting from the action of antibiotics known to interfere with intracellular protein synthesis. Strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa were exposed to kanamycin, chloramphenicol, and tobramycin during various phases of bacterial growth. A spectrum of morphological changes related to concentration of drug and duration of exposure was observed which was similar to those induced by penicillin or cephalothin. Cells were also exposed to sulfamethoxazole with similar results. The morphological abnormalities observed may be surface reflections of specific abnormalities of intracellular protein synthesis or may represent a final common pathway of druAg-induced injury at many sites within or on bacterial cells.


Accommodation and refractive error in children with Down syndrome: cross-sectional and longitudinal studies.
To examine the relationship between defective accommodation and refractive errors in children with Down syndrome. Children with Down syndrome aged 4 to 85 months were seen at their homes as part of an ongoing study of visual development. Seventy-five children contributed cross-sectional data and 69 children longitudinal data. Accommodation was measured using a modification of Nott dynamic retinoscopy technique, and refractive error measurements were obtained using Mohindra retinoscopy. Accommodation was poor, regardless of the refractive error present. The total accommodation produced by the children was related to the refractive error at the time of the test, with the degree of accommodation deficit increasing with the amount of positive refractive error. The longitudinal results showed that although children with Down syndrome did not accommodate accurately, the amount of accommodation elicited did not reflect their maximum amplitude of accommodation. Each child showed a consistent degree of underaccommodation for a given stimulus. Spectacles to correct hypermetropia did not improve the accommodative response. In children with Down syndrome, underaccommodation is substantial, even when there is no, or a fully corrected, refractive error. The accommodation system of children with Down syndrome may have the physical capacity to respond to a given stimulus, but the neural control of the system has an anomalous set point. Spectacles do not remedy the situation. This has important implications, especially for children in a learning environment, because near vision is consistently out of focus.


ACR Appropriateness Criteria® Chronic Back Pain Suspected Sacroiliitis-Spondyloarthropathy.
Inflammatory sacroiliitis or the seronegative axial spondyloarthropathies often presents as back pain or sacroiliac joint pain of more than 3-month duration with inflammatory symptoms and typically in patients younger than 45 years of age. Imaging plays an important role in diagnosis and disease monitoring. This article addresses the appropriate sequence of initial imaging for evaluation of a suspected spondyloarthropathy, the imaging follow-up of treatment response and the special considerations for imaging of trauma in patients with ankylosis of the spine. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


Reconstructing (super)trees from data sets with missing distances: not all is lost.
The wealth of phylogenetic information accumulated over many decades of biological research, coupled with recent technological advances in molecular sequence generation, presents significant opportunities for researchers to investigate relationships across and within the kingdoms of life. However, to make best use of this data wealth, several problems must first be overcome. One key problem is finding effective strategies to deal with missing data. Here, we introduce Lasso, a novel heuristic approach for reconstructing rooted phylogenetic trees from distance matrices with missing values, for data sets where a molecular clock may be assumed. Contrary to other phylogenetic methods on partial data sets, Lasso possesses desirable properties such as its reconstructed trees being both unique and edge-weighted. These properties are achieved by Lasso restricting its leaf set to a large subset of all possible taxa, which in many practical situations is the entire taxa set. Furthermore, the Lasso approach is distance-based, rendering it very fast to run and suitable for data sets of all sizes, including large data sets such as those generated by modern Next Generation Sequencing technologies. To better understand the performance of Lasso, we assessed it by means of artificial and real biological data sets, showing its effectiveness in the presence of missing data. Furthermore, by formulating the supermatrix problem as a particular case of the missing data problem, we assessed Lasso's ability to reconstruct supertrees. We demonstrate that, although not specifically designed for such a purpose, Lasso performs better than or comparably with five leading supertree algorithms on a challenging biological data set. Finally, we make freely available a software implementation of Lasso so that researchers may, for the first time, perform both rooted tree and supertree reconstruction with branch lengths on their own partial data sets.


Planning for intracavitary anti-EGFR radionuclide therapy of gliomas. Literature review and data on EGFR expression.
Targeting with radionuclide labelled substances that bind specifically to the epidermal growth factor receptor, EGFR, is considered for intracavitary therapy of EGFR-positive glioblastoma multiforme, GBM. Relevant literature is reviewed and examples of EGFR expression in GBM are given. The therapeutical efforts made so far using intracavitary anti-tenascin radionuclide therapy of GBM have given limited effects, probably due to low radiation doses to the migrating glioma cells in the brain. Low radiation doses might be due to limited penetration of the targeting agents or heterogeneity in the expression of the target structure. In this article we focus on the possibilities to target EGFR on the tumour cells instead of an extracellular matrix component. There seems to be a lack of knowledge on the degree of intratumoral variation of EGFR expression in GBM, although the expression seemed rather homogeneous over large areas in most of the examples (n=16) presented from our laboratory. The observed homogeneity was surprising considering the genomic instability and heterogeneity that generally characterises highly malignant tumours. However, overexpression of EGFR is, at least in primary GBMs, one of the steps in the development of malignancy, and tumour cells that lose or downregulate EGFR will probably be outgrown in an expanding tumour cell population. Thus, loss of EGFR expression might not be the critical factor for successful intracavitary radionuclide therapy. Instead, it is likely that the penetration properties of the targeting agents are critical, and detailed studies on this are urgent.


Migration as a Determinant in the Development of Children Emotional and Behavior Problems: A Quantitative Study for Lisbon Region, Portugal.
The role of migration as a determinant in child mental health has been demonstrated in a number of studies. However, results are not always consistent, and the research continues to be scarce, especially in Portugal. We examined the association between sociodemographic profiles and the chance for the development of emotional and behavioral difficulties in a group of 420 children, immigrant (n = 217) and born in Portugal to Portuguese born parents (n = 203). We used a structured questionnaire to obtain sociodemographic information and the Strength and Difficulties Questionnaire (SDQ). Descriptive statistics were used to characterize children and their families; variables were compared between groups using the Chi-squared, Fisher's Exact Test, or the Mann-Whitney U test and logistic regression was used to analyze the association between socio-demographic factors and emotional and behavioral difficulties. Results showed a pattern of social and mental health inequalities with immigrant children at a disadvantage: they are more often part of families with low income and where parents had low skilled jobs. Internalizing behaviors are more frequent in immigrants than in children born in Portugal to Portuguese-born parents (p = 0.001) whereas a high total SDQ difficulties score (p = 0.039) and externalizing behaviors were more frequent in 1st generation immigrant children (p = 0.009). A low family income (aOR 4.5; 95% CI: 1.43-13.95), low parental education level (aOR 2.5; 95% CI: 1.11-5.16), and being a first-generation immigrant child (aOR 2.2; 95% CI: 1.06-4.76) increased significantly the chance of developing emotional and behavioral difficulties. This study contributes to the identification of children vulnerable to mental health problems who can benefit from monitoring, early detection and preventive interventions in order to mitigate possible negative outcomes in the future.


Lower limb compression garment improves recovery from exercise-induced muscle damage in young, active females.
This study aimed to investigate the efficacy of lower limb compression as a recovery strategy following exercise-induced muscle damage (EIMD). Seventeen female volunteers completed 10 x 10 plyometric drop jumps from a 0.6-m box to induce muscle damage. Participants were randomly allocated to a passive recovery (n = 9) or a compression treatment (n = 8) group. Treatment group volunteers wore full leg compression stockings for 12 h immediately following damaging exercise. Passive recovery group participants had no intervention. Indirect indices of muscle damage (muscle soreness, creatine kinase activity, knee extensor concentric strength, and vertical jump performance) were assessed prior to and 1, 24, 48, 72, and 96 h following plyometric exercise. Plyometric exercise had a significant effect (p < or = 0.05) on all indices of muscle damage. The compression treatment reduced decrements in countermovement jump performance (passive recovery 88.1 +/- 2.8% vs. treatment 95.2 +/- 2.9% of pre-exercise), squat jump performance (82.3 +/- 1.9% vs. 94.5 +/- 2%), and knee extensor strength loss (81.6 +/- 3% vs. 93 +/- 3.2%), and reduced muscle soreness (4.0 +/- 0.23 vs. 2.4 +/- 0.24), but had no significant effect on creatine kinase activity. The results indicate that compression clothing is an effective recovery strategy following exercise-induced muscle damage.


Ultrafast current imaging by Bayesian inversion.
Spectroscopic measurements of current-voltage curves in scanning probe microscopy is the earliest and one of the most common methods for characterizing local energy-dependent electronic properties, providing insight into superconductive, semiconductor, and memristive behaviors. However, the quasistatic nature of these measurements renders them extremely slow. Here, we demonstrate a fundamentally new approach for dynamic spectroscopic current imaging via full information capture and Bayesian inference. This general-mode I-V method allows three orders of magnitude faster measurement rates than presently possible. The technique is demonstrated by acquiring I-V curves in ferroelectric nanocapacitors, yielding >100,000 I-V curves in <20 min. This allows detection of switching currents in the nanoscale capacitors, as well as determination of the dielectric constant. These experiments show the potential for the use of full information capture and Bayesian inference toward extracting physics from rapid I-V measurements, and can be used for transport measurements in both atomic force and scanning tunneling microscopy.


Immunotherapy for Bone and Soft Tissue Sarcomas.
Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.


Severe acute respiratory distress syndrome secondary to acute pancreatitis successfully treated with extracorporeal membrane oxygenation in three patients.
To review three patients who underwent extracorporeal membrane oxygenation (ECMO) for acute respiratory failure secondary to pancreatitis. Severe acute pancreatitis often causes the acute respiratory distress syndrome (ARDS), and if ventilation is required, the mortality rate is more than 50%. If the ratio of PaO2/FiO2 falls below 100 mm Hg or the Murray lung injury score exceeds 3.5, the mortality rate rises to more than 80%. Three patients who have severe ARDS secondary to pancreatitis, who were hypoxic despite ventilation with 100% oxygen and high airway pressures, and who were all successfully treated with ECMO are reported here. The consensus here is that all three patients would have died without ECMO. Retrospective chart review and discussion of the literature. Pre-ECMO data: mean PaO2/FiO2 59.3 mm Hg, mean Murray lung injury score 3.7, one patient administered 20 ppm inhaled nitric oxide. ECMO data: mean extracorporeal flow at initiation of ECMO 56.3 mL/kg per minute, all patients administered veno-venous ECMO, mean duration of ECMO 104.7 hours. All patients were successfully weaned from ECMO and extubated. One patient had a protracted hospital stay because of a colo-cutaneous fistula. All patients are long-term survivors. Extracorporeal membrane oxygenation proved an effective therapy for severe ARDS complicating acute pancreatitis. Extracorporeal membrane oxygenation was conducted without bleeding complications in these three patients.


Association Between Serotonin Syndrome and Second-Generation Antipsychotics via Pharmacological Target-Adverse Event Analysis.
Case reports suggest an association between second-generation antipsychotics (SGAs) and serotonin syndrome (SS). The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) was analyzed to generate hypotheses about how SGAs may interact with pharmacological targets associated with SS. FAERS was integrated with additional sources to link information about adverse events with drugs and targets. Using Proportional Reporting Ratios, we identified signals that were further investigated with the literature to evaluate mechanistic hypotheses formed from the integrated FAERS data. Analysis revealed common pharmacological targets perturbed in both SGA and SS cases, indicating that SGAs may induce SS. The literature also supported 5-HT2A antagonism and 5-HT1A agonism as common mechanisms that may explain the SGA-SS association. Additionally, integrated FAERS data mining and case studies suggest that interactions between SGAs and other serotonergic agents may increase the risk for SS. Computational analysis can provide additional insights into the mechanisms underlying the relationship between SGAs and SS.


COVID-19 Vaccination-Associated Myocarditis in Adolescents.
In this study, we aimed to characterize the clinical presentation, short-term prognosis, and myocardial tissue changes as noted on cardiovascular magnetic resonance (CMR) or cardiac MRI in pediatric patients with coronavirus disease 2019 vaccination-associated myocarditis (C-VAM). In this retrospective multicenter study across 16 US hospitals, patients <21 years of age with a diagnosis of C-VAM were included and compared with a cohort with multisystem inflammatory syndrome in children. Younger children with C-VAM were compared with older adolescents. Sixty-three patients with a mean age of 15.6 years were included; 92% were male. All had received a messenger RNA vaccine and, except for one, presented after the second dose. Four patients had significant dysrhythmia; 14% had mild left ventricular dysfunction on echocardiography, which resolved on discharge; 88% met the diagnostic CMR Lake Louise criteria for myocarditis. Myocardial injury as evidenced by late gadolinium enhancement on CMR was more prevalent in comparison with multisystem inflammatory syndrome in children. None of the patients required inotropic, mechanical, or circulatory support. There were no deaths. Follow-up data obtained in 86% of patients at a mean of 35 days revealed resolution of symptoms, arrhythmias, and ventricular dysfunction. Clinical characteristics and early outcomes are similar between the different pediatric age groups in C-VAM. The hospital course is mild, with quick clinical recovery and excellent short-term outcomes. Myocardial injury and edema are noted on CMR. Close follow-up and further studies are needed to understand the long-term implications and mechanism of these myocardial tissue changes.